Locomotor activity

Hyperlocomotion is induced by dopamine releasing agents (DRAs) and psychostimulants like amphetamine and methamphetamine.{{cite journal | vauthors = Ayyar P, Ravinder JR | title = Animal models for the evaluation of antipsychotic agents | journal = Fundam Clin Pharmacol | volume = 37 | issue = 3 | pages = 447–460 | date = June 2023 | pmid = 36410728 | doi = 10.1111/fcp.12855 | url = }}{{cite journal | vauthors = Yee BK, Singer P | title = A conceptual and practical guide to the behavioural evaluation of animal models of the symptomatology and therapy of schizophrenia | journal = Cell Tissue Res | volume = 354 | issue = 1 | pages = 221–246 | date = October 2013 | pmid = 23579553 | pmc = 3791321 | doi = 10.1007/s00441-013-1611-0 | url = }} These drugs likewise induce stereotypies.

The dopamine reuptake inhibitors (DRIs) amineptine, bupropion, and nomifensine increase spontaneous locomotor activity in animals.{{cite journal | vauthors = Tucker JC, File SE | title = The effects of tricyclic and 'atypical' antidepressants on spontaneous locomotor activity in rodents | journal = Neurosci Biobehav Rev | volume = 10 | issue = 2 | pages = 115–121 | date = 1986 | pmid = 3737024 | doi = 10.1016/0149-7634(86)90022-9 | url = }}{{cite journal | last1=Rampello | first1=Liborio | last2=Nicoletti | first2=Ferdinando | last3=Nicoletti | first3=Francesco | title=Dopamine and Depression | journal=CNS Drugs | publisher=Springer Science and Business Media LLC | volume=13 | issue=1 | year=2000 | issn=1172-7047 | doi=10.2165/00023210-200013010-00004 | pages=35–45}} The DRI cocaine increases locomotor activity similarly to the preceding DRIs and to amphetamines. The atypical DRI modafinil does not produce hyperlocomotion in animals.

Direct dopamine receptor agonists like apomorphine show biphasic effects, decreasing locomotor activity at low doses and increasing locomotor activity at high doses.{{cite journal | vauthors = D'Aquila PS, Collu M, Gessa GL, Serra G | title = The role of dopamine in the mechanism of action of antidepressant drugs | journal = Eur J Pharmacol | volume = 405 | issue = 1–3 | pages = 365–373 | date = September 2000 | pmid = 11033341 | doi = 10.1016/s0014-2999(00)00566-5 | url = }}

Drug-induced hyperlocomotion can be reversed by various drugs, such as antipsychotics acting as dopamine D₂ receptor antagonists. Reversal of drug-induced hyperlocomotion has been used as an animal test of drug antipsychotic-like activity. Reversal of amphetamine- and NMDA receptor antagonist-induced stereotypies is also employed as a test of drug antipsychotic-like activity.

Selective norepinephrine releasing agents (NRAs) include ephedrine, pseudoephedrine, phenylpropanolamine, levomethamphetamine, and D-phenylalaninol.{{cite journal | vauthors = Rothman RB, Baumann MH | title = Monoamine transporters and psychostimulant drugs | journal = European Journal of Pharmacology | volume = 479 | issue = 1–3 | pages = 23–40 | date = October 2003 | pmid = 14612135 | doi = 10.1016/j.ejphar.2003.08.054 }}{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Current Topics in Medicinal Chemistry | volume = 6 | issue = 17 | pages = 1845–1859 | year = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 }}{{cite journal | vauthors = Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, Birkes J, Young R, Glennon RA | title = In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates | journal = J Pharmacol Exp Ther | volume = 307 | issue = 1 | pages = 138–145 | date = October 2003 | pmid = 12954796 | doi = 10.1124/jpet.103.053975 | url = }} However, these drugs also release dopamine to a much lesser extent (e.g., ~10-fold less potently).

Ephedrine consistently stimulates locomotor activity in rodents.{{cite journal | vauthors = Marvola M, Kivirinta R | title = Pharmacokinetics and locomotor activity increasing effect of ephedrine in mice | journal = Acta Pharmacol Toxicol (Copenh) | volume = 43 | issue = 5 | pages = 381–386 | date = November 1978 | pmid = 726903 | doi = 10.1111/j.1600-0773.1978.tb02282.x | url = }}{{cite journal | vauthors = Zarrindast MR | title = Dopamine-like properties of ephedrine in rat brain | journal = Br J Pharmacol | volume = 74 | issue = 1 | pages = 119–122 | date = September 1981 | pmid = 7196787 | pmc = 2071871 | doi = 10.1111/j.1476-5381.1981.tb09962.x | url = }} However, the hyperlocomotion induced by ephedrine may be mediated by dopamine release rather than by norepinephrine release.{{cite journal | vauthors = Wellman PJ, Miller DK, Livermore CL, Green TA, McMahon LR, Nation JR | title = Effects of (-)-ephedrine on locomotion, feeding, and nucleus accumbens dopamine in rats | journal = Psychopharmacology (Berl) | volume = 135 | issue = 2 | pages = 133–140 | date = January 1998 | pmid = 9497018 | doi = 10.1007/s002130050494 | url = }} On the other hand, lesioning the brain noradrenergic system with the noradrenergic neurotoxin DSP-4 reduces dextroamphetamine-induced hyperlocomotion.{{cite journal | vauthors = Weinshenker D, Schroeder JP | title = There and back again: a tale of norepinephrine and drug addiction | journal = Neuropsychopharmacology | volume = 32 | issue = 7 | pages = 1433–1451 | date = July 2007 | pmid = 17164822 | doi = 10.1038/sj.npp.1301263 | url = }}{{cite journal | vauthors = Ogren SO, Archer T, Johansson C | title = Evidence for a selective brain noradrenergic involvement in the locomotor stimulant effects of amphetamine in the rat | journal = Neurosci Lett | volume = 43 | issue = 2–3 | pages = 327–31 | date = December 1983 | pmid = 6687006 | doi = 10.1016/0304-3940(83)90209-4 | url = }} In addition, the selective α₁-adrenergic receptor antagonist prazosin antagonizes amphetamine-induced hyperlocomotion{{cite journal | vauthors = Snoddy AM, Tessel RE | title = Prazosin: effect on psychomotor-stimulant cues and locomotor activity in mice | journal = Eur J Pharmacol | volume = 116 | issue = 3 | pages = 221–228 | date = October 1985 | pmid = 3878298 | doi = 10.1016/0014-2999(85)90156-6 | url = }} and knockout of the α_1B-adrenergic receptor dramatically reduces dextroamphetamine-induced hyperlocomotion.{{cite journal | vauthors = Drouin C, Darracq L, Trovero F, Blanc G, Glowinski J, Cotecchia S, Tassin JP | title = Alpha1b-adrenergic receptors control locomotor and rewarding effects of psychostimulants and opiates | journal = J Neurosci | volume = 22 | issue = 7 | pages = 2873–2884 | date = April 2002 | pmid = 11923452 | pmc = 6758308 | doi = 10.1523/JNEUROSCI.22-07-02873.2002 | url = }} In contrast to ephedrine and amphetamine, pseudoephedrine{{cite journal | vauthors = Akiba K, Satoh S, Matsumura H, Suzuki T, Kohno H, Tadano T, Kisara K | title = [Effect of d-pseudoephedrine on the central nervous system in mice] | language = Japanese | journal = Nihon Yakurigaku Zasshi | volume = 79 | issue = 5 | pages = 401–408 | date = May 1982 | pmid = 6813205 | doi = 10.1254/fpj.79.401| url = }}{{cite journal | vauthors = Sa-Ih N, Reakkamnuan C, Samerphob N, Cheaha D, Niyomdecha S, Kumarnsit E | title = Local field potential power spectra and locomotor activity following treatment with pseudoephedrine in mice | journal = Acta Neurobiol Exp (Wars) | volume = 80 | issue = 1 | pages = 19–31 | date = 2020 | pmid = 32214271 | doi = 10.21307/ane-2020-002| url = | doi-access = free }} and phenylpropanolamine do not stimulate locomotor activity in rodents.{{cite journal | vauthors = Eisenberg MS, Maher TJ, Silverman HI | title = A comparison of the effects of phenylpropanolamine, d-amphetamine and d-norpseudoephedrine on open-field locomotion and food intake in the rat | journal = Appetite | volume = 9 | issue = 1 | pages = 31–37 | date = August 1987 | pmid = 3662492 | doi = 10.1016/0195-6663(87)90051-1 | url = }}{{cite journal | vauthors = Wellman PJ, Shelton K, Schenk S | title = Self-administration of phenylpropanolamine (PPA) by rats previously trained to self-administer amphetamine | journal = Pharmacol Biochem Behav | volume = 34 | issue = 1 | pages = 187–191 | date = September 1989 | pmid = 2626448 | doi = 10.1016/0091-3057(89)90371-7 | url = }}{{cite journal | vauthors = Wellman PJ | title = The pharmacology of the anorexic effect of phenylpropanolamine | journal = Drugs Exp Clin Res | volume = 16 | issue = 9 | pages = 487–495 | date = 1990 | pmid = 2100250 | doi = | url = }} However, in another study, pseudoephedrine was able to increase locomotor activity.{{cite journal | vauthors = Walker RB, Fitz LD, Williams LM, Linton H, Smith CC | title = The effect of ephedrine isomers and their oxazolidines on locomotor activity in rats | journal = Gen Pharmacol | volume = 24 | issue = 3 | pages = 669–673 | date = May 1993 | pmid = 8365649 | doi = 10.1016/0306-3623(93)90229-q | url = }} A potential confounding factor with β-hydroxyamphetamines like phenylpropanolamine, ephedrine, and pseudoephedrine is that they have lower lipophilicity compared to their amphetamine counterparts, with consequent reduced capacity to cross the blood–brain barrier and produce central nervous system effects.{{cite journal | vauthors = Chua SS, Benrimoj SI, Triggs EJ | title = Pharmacokinetics of non-prescription sympathomimetic agents | journal = Biopharm Drug Dispos | volume = 10 | issue = 1 | pages = 1–14 | date = 1989 | pmid = 2647163 | doi = 10.1002/bdd.2510100102 | url = }}{{cite journal | vauthors = Bouchard R, Weber AR, Geiger JD | title = Informed decision-making on sympathomimetic use in sport and health | journal = Clin J Sport Med | volume = 12 | issue = 4 | pages = 209–224 | date = July 2002 | pmid = 12131054 | doi = 10.1097/00042752-200207000-00003 | url = }}{{cite journal | vauthors = Bharate SS, Mignani S, Vishwakarma RA | title = Why Are the Majority of Active Compounds in the CNS Domain Natural Products? A Critical Analysis | journal = J Med Chem | volume = 61 | issue = 23 | pages = 10345–10374 | date = December 2018 | pmid = 29989814 | doi = 10.1021/acs.jmedchem.7b01922 | url = }}{{cite journal | vauthors = Schep LJ, Slaughter RJ, Beasley DM | title = The clinical toxicology of metamfetamine | journal = Clin Toxicol (Phila) | volume = 48 | issue = 7 | pages = 675–694 | date = August 2010 | pmid = 20849327 | doi = 10.3109/15563650.2010.516752 | url = | quote = Metamfetamine acts in a manner similar to amfetamine, but with the addition of the methyl group to the chemical structure. It is more lipophilic (Log p value 2.07, compared with 1.76 for amfetamine),⁴ thereby enabling rapid and extensive transport across the blood–brain barrier.¹⁹}}

Conversely, the potencies of monoamine releasing agents (MRAs) in producing amphetamine-type subjective effects in humans have been found to correlate with their potency to induce norepinephrine release and not with their potencies to induce dopamine release.{{cite web | last=Bauer | first=Clayton T. | title=Determinants of Abuse-Related Effects of Monoamine Releasers in Rats | website=VCU Scholars Compass | date=5 July 2014 | url=https://scholarscompass.vcu.edu/etd/522/ | access-date=21 January 2025 | quote=Another potential determinant for increased abuse potential of MARs is selectivity for DA versus NE. Although DA is well-established to be a key neurotransmitter in mediating abuse-related effects of monoamine releasers and other drugs (for review, Leshner and Koob, 1999), amphetamine and other abused monoamine releasers have slightly (2 to 3x) higher potency to release NE than DA (Rothman et al., 2001). Moreover, methamphetamine self-administration in rats was relatively resistant to pretreatment with DA-antagonists (Brennan et al., 2009), and ephedrine (a 19-fold NE-selective releaser) has been shown to maintain self-administration in monkeys (Anderson et al., 2001) and substitute for amphetamine (Young et al., 1998) and methamphetamine (Bondareva et al., 2002) in drug discrimination studies in rats. Perhaps the most compelling data on the importance of NE comes from human subjects where amphetamine-like discriminative stimuli produced by monoamine releasers correlate with potency to release NE, not DA (Rothman et al., 2001). [...] There is also evidence of noradrenergic innervation of the dopaminergic system (Geisler and Zahm, 2005; Jones and Moore, 1977). Electrical stimulation of the locus coeruleus (LC) neurons increased levels of NE in the VTA and increased activity of DA neurons (Grenhoff et al., 1993). However, when exogenous NE was applied to the VTA, a decrease in firing rates of DA neurons was seen (Aghajanian and Bunney, 1977; White and Wang, 1984). Similar to the results of the latter study, lesions of the NE system by injection of 6-OHDA into the locus coeruleus increased firing of DA neurons in the VTA by 70% (Guiard et al., 2008). These data suggest that there may be both excitatory and inhibitory roles of NE on the activity of VTA dopaminergic neurons. [...] The receptors by which NE modulates DA at the level of the VTA are fairly well characterized. In particular, it appears that the α-1 receptor is responsible for increases in DA neuron firing following NE administration while the α-2 receptor mediates the inhibitory effects of NE (Grenhoff and Svensson, 1988; Grenhoff and Svensson 1989; Grenhoff and Svensson, 1993; Grenhoff et al., 1995). In addition to the α-2 receptor, it appears that NE can act directly on D2 dopaminergic autoreceptors to produce inhibitory effects (Grenhoff et al., 1995; Lacey et al., 1987; Arencibia-Albite et al., 2007; Guiard et al., 2008). ß-adrenoreceptors are not known to exist in the VTA (Grenhoff et al., 1995; Jones et al., 1990) and ß-adrenergic compounds do not mediate the effects of NE in the VTA (Grenhoff et al., 1995). }} In addition, self-administration of methamphetamine appeared to be relatively resistant to blockade by dopamine receptor antagonists. Findings on the modulation of the ventral tegmental area by the noradrenergic locus coeruleus are mixed and suggestive of both excitatory and inhibitory roles. The α₁-adrenergic receptor appears to be facilitatory, whereas the α₂-adrenergic receptor appears to be inhibitory, and the β-adrenergic receptors appear to not be involved. More research is needed to investigate the role of norepinephrine in dopamine modulation and stimulant-like effects.

In contrast to normal mice, psychostimulants like amphetamine, β-phenethylamine, and methylphenidate lose their ability to elevate brain dopamine but not norepinephrine in dopamine transporter (DAT) knockout mice and have been found to decrease locomotor activity in these mice.{{cite journal | vauthors = Lloyd JT, Yee AG, Kalligappa PK, Jabed A, Cheung PY, Todd KL, Karunasinghe RN, Vlajkovic SM, Freestone PS, Lipski J | title = Dopamine Dysregulation and Altered Responses to Drugs Affecting Dopaminergic Transmission in a New Dopamine Transporter Knockout (DAT-KO) Rat Model | journal = Neuroscience | volume = 491 | issue = | pages = 43–64 | date = May 2022 | pmid = 35331847 | doi = 10.1016/j.neuroscience.2022.03.019 | url = }}{{cite journal | vauthors = Leo D, Sukhanov I, Zoratto F, Illiano P, Caffino L, Sanna F, Messa G, Emanuele M, Esposito A, Dorofeikova M, Budygin EA, Mus L, Efimova EV, Niello M, Espinoza S, Sotnikova TD, Hoener MC, Laviola G, Fumagalli F, Adriani W, Gainetdinov RR | title = Pronounced Hyperactivity, Cognitive Dysfunctions, and BDNF Dysregulation in Dopamine Transporter Knock-out Rats | journal = J Neurosci | volume = 38 | issue = 8 | pages = 1959–1972 | date = February 2018 | pmid = 29348190 | pmc = 5824739 | doi = 10.1523/JNEUROSCI.1931-17.2018 | url = }}{{cite journal | vauthors = Sotnikova TD, Budygin EA, Jones SR, Dykstra LA, Caron MG, Gainetdinov RR | title = Dopamine transporter-dependent and -independent actions of trace amine beta-phenylethylamine | journal = J Neurochem | volume = 91 | issue = 2 | pages = 362–373 | date = October 2004 | pmid = 15447669 | doi = 10.1111/j.1471-4159.2004.02721.x | url = }}{{cite journal | vauthors = Giros B, Jaber M, Jones SR, Wightman RM, Caron MG | title = Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter | journal = Nature | volume = 379 | issue = 6566 | pages = 606–612 | date = February 1996 | pmid = 8628395 | doi = 10.1038/379606a0 | bibcode = 1996Natur.379..606G | url = }} Paradoxically however, cocaine retains reinforcing effects in DAT knockout mice and cocaine and amphetamine are still able to elevate dopamine in the medial nucleus accumbens in these mice.{{cite journal | vauthors = Carboni E, Spielewoy C, Vacca C, Nosten-Bertrand M, Giros B, Di Chiara G | title = Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene | journal = J Neurosci | volume = 21 | issue = 9 | pages = RC141: 1–4 | date = May 2001 | pmid = 11312315 | pmc = 6762548 | doi = 10.1523/JNEUROSCI.21-09-j0001.2001 | url = }} It was found that the norepinephrine reuptake inhibitor reboxetine increases dopamine levels in the nucleus accumbens in DAT knockout mice but not in normal mice, suggesting that the effects of norepinephrine elevation change in the brains of DAT knockout mice.

Whereas dextromethamphetamine is a well-balanced norepinephrine–dopamine releasing agent (NDRA), levomethamphetamine is a selective NRA.{{cite journal | vauthors = Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS | title = Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | journal = Synapse | volume = 39 | issue = 1 | pages = 32–41 | date = January 2001 | pmid = 11071707 | doi = 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3 | url = }}{{cite journal | vauthors = Kohut SJ, Jacobs DS, Rothman RB, Partilla JS, Bergman J, Blough BE | title = Cocaine-like discriminative stimulus effects of "norepinephrine-preferring" monoamine releasers: time course and interaction studies in rhesus monkeys | journal = Psychopharmacology (Berl) | volume = 234 | issue = 23–24 | pages = 3455–3465 | date = December 2017 | pmid = 28889212 | pmc = 5747253 | doi = 10.1007/s00213-017-4731-5 | url = | quote = In the present experiments, two monoamine releasers, l-MA and PAL-329, were shown to produce cocaine-like discriminative-stimulus effects in monkeys, suggesting that they meet the above criteria. One of these compounds, l-MA, also has been shown to serve as a positive reinforcer in rodents (Yokel and Pickens 1973) and monkeys (Winger et al 1994), further confirming the overlap with behavioral effects of cocaine. Both compounds also exhibit an approximately 15-fold greater potency in releasing NE than DA, which may be therapeutically advantageous. For example, the subjective effects of l-MA in human studies are similar in some respects to those of d-MA. However, the subjective effects of the two isomers also differ in potentially important ways. While both l-MA and d-MA produce subjective ratings of "drug liking" and "good effects" in experienced stimulant users, only l-MA produces concomitant ratings of bad or aversive drug effects (Mendelson et al 2006), a factor which may limit its abuse liability.}}{{cite journal | vauthors = Mendelson J, Uemura N, Harris D, Nath RP, Fernandez E, Jacob P, Everhart ET, Jones RT | title = Human pharmacology of the methamphetamine stereoisomers | journal = Clin Pharmacol Ther | volume = 80 | issue = 4 | pages = 403–420 | date = October 2006 | pmid = 17015058 | doi = 10.1016/j.clpt.2006.06.013 | url = | quote = The stereoisomers of methamphetamine produce markedly different dopamine, norepinephrine, and serotonin responses in various brain regions in rats.41,42 d-Methamphetamine (2 mg/kg) is more potent in releasing caudate dopamine than l-methamphetamine (12 and 18 mg/kg). By use of in vitro uptake and release assays, d-methamphetamine (50% effective concentration [EC50], 24.5 ± 2.1 nmol/L) was 17 times more potent in releasing dopamine than l-methamphetamine (EC50, 416 ± 20 nmol/L) and significantly more potent in blocking dopamine uptake (inhibition constant [Ki ], 114 ± 11 nm versus 4840 ± 178 nm).12,13}} Levomethamphetamine has similar potency as an NRA compared to dextromethamphetamine.{{cite journal | vauthors = Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present--a pharmacological and clinical perspective | journal = J Psychopharmacol | volume = 27 | issue = 6 | pages = 479–496 | date = June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532 | url = }}{{cite book | vauthors = Nishino S, Kotorii N | title=Narcolepsy: A Clinical Guide | edition=2nd | chapter=Modes of Action of Drugs Related to Narcolepsy: Pharmacology of Wake-Promoting Compounds and Anticataplectics | publisher=Springer International Publishing | publication-place=Cham | date=2016 | isbn=978-3-319-23738-1 | doi=10.1007/978-3-319-23739-8_22 | pages=307–329 | url = https://www.researchgate.net/publication/314626865 }}{{cite journal | vauthors = Xue Z, Siemian JN, Zhu Q, Blough BE, Li JX | title = Further pharmacological comparison of D-methamphetamine and L-methamphetamine in rats: abuse-related behavioral and physiological indices | journal = Behav Pharmacol | volume = 30 | issue = 5 | pages = 422–428 | date = August 2019 | pmid = 30480551 | pmc = 6529304 | doi = 10.1097/FBP.0000000000000453 | url = | quote = When considered with neurochemical data that l-MA is similarly potent in releasing norepinephrine (NE) but 15- to 20-fold less potent in releasing dopamine (DA), as compared to d-MA (Kuczenski et al., 1995; Melega et al., 1999), l-MA may appear to carry lower abuse liability than d-MA.}}{{cite journal | vauthors = Kuczenski R, Segal DS, Cho AK, Melega W | title = Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine | journal = The Journal of Neuroscience | volume = 15 | issue = 2 | pages = 1308–1317 | date = February 1995 | pmid = 7869099 | pmc = 6577819 | doi = 10.1523/jneurosci.15-02-01308.1995 | doi-access = free | quote = Consistent with our past results, in response to 2 mg/kg D-AMPH, mean caudate extracellular DA increased approximately 15-fold to a peak concentration of 688 ± 121 nM during the initial 20 min interval, then returned to baseline over the next 3 hr. Similarly, in response to 2 mg/kg D-METH, DA increased to a peak concentration of 648 ± 71 nM during the initial 20 min interval and then declined toward baseline. In contrast, in response to both 6 mg/kg L-AMPH and 12 mg/kg L-METH, peak DA concentrations (508 ± 51 and 287 ± 49 nM, respectively) were delayed to the second 20 min interval, before returning toward baseline. [...] Similar to our previous results, 2 mg/kg D-AMPH increased NE to a maximum of 29.3 ± 3.1 nM, about 20-fold over baseline, during the second 20 min interval. L-AMPH (6 mg/kg) produced a comparable effect, increasing NE concentrations to 32.0 ± 8.9 nM. In contrast, D-METH promoted an increase in NE to 12.0 ± 1.2 nM which was significantly lower than all other groups, whereas L-METH promoted an increase to 64.8 ± 4.9 nM, which was significantly higher than all other groups.}} Conversely, levomethamphetamine is about 15- to 20-fold less potent in inducing dopamine release than dextromethamphetamine. In accordance with the preceding, levomethamphetamine was found to selectively induce brain norepinephrine release with minimal effect on brain dopamine release across an assessed dosage range in rodents.{{cite journal | vauthors = Pauly RC, Bhimani RV, Li JX, Blough BE, Landavazo A, Park J | title = Distinct Effects of Methamphetamine Isomers on Limbic Norepinephrine and Dopamine Transmission in the Rat Brain | journal = ACS Chem Neurosci | volume = | issue = | pages = | date = March 2023 | pmid = 36976755 | doi = 10.1021/acschemneuro.2c00689 | url = }} The drug did not increase locomotor activity at the assessed doses, in which brain dopamine release was not affected. In contrast to levomethamphetamine, dextromethamphetamine at the same doses increased brain levels of both norepinephrine and dopamine and induced dose-dependent hyperlocomotion. Relatedly, levomethamphetamine shows similar sympathomimetic effects as dextromethamphetamine but is substantially less potent as a psychostimulant in animals.{{cite book | last1=Biel | first1=J. H. | last2=Bopp | first2=B. A. | title=Stimulants | chapter=Amphetamines: Structure-Activity Relationships | publisher=Springer US | publication-place=Boston, MA | date=1978 | isbn=978-1-4757-0512-6 | doi=10.1007/978-1-4757-0510-2_1 | pages=1–39 | quote=The configuration of the α-methyl group is also an important determinant of the stimulant activity. The dextro isomers of both amphetamine and methamphetamine are considerably more potent as stimulants than the levo isomers. Depending on the parameter measured, the potency difference may range from two- to tenfold (Taylor and Snyder, 1970; Snyder et at., 1970b; Svensson, 1971; Roth et at., 1954; Van Rossum, 1970; Moore, 1963). The anorexic activity of the dextro isomers also exceeds that of the levo isomers (Lawlor et at., 1969). However, the two isomers are approximately equipotent in eliciting certain peripheral effects, such as the vasoconstriction, vasopressor, and other cardiovascular effects (Roth et at., 1954; Swanson et at., 1943).}}{{cite journal | vauthors = Nishimura T, Takahata K, Kosugi Y, Tanabe T, Muraoka S | title = Psychomotor effect differences between l-methamphetamine and d-methamphetamine are independent of murine plasma and brain pharmacokinetics profiles | journal = J Neural Transm (Vienna) | volume = 124 | issue = 5 | pages = 519–523 | date = May 2017 | pmid = 28213761 | pmc = 5399046 | doi = 10.1007/s00702-017-1694-y | url = | quote = There have been no studies directly comparing the pharmacodynamics and pharmacokinetics of the methamphetamine enantiomers in mice. It is often suggested that dmethamphetamine exerts more potent physiological and pharmacological effects than l-methamphetamine does, and that the stimulating effects exerted by l-methamphetamine on the central nervous system are 2–10 times less potent than those of d-methamphetamine (Mendelson et al. 2006). The results of the present study indicated that psychostimulant effects induced by l-methamphetamine are lower than those elicited by one-tenth the dose of d-methamphetamine. In addition, plasma pharmacokinetic parameters and striatal concentrations of methamphetamine following administration of l-methamphetamine at 10 mg/ kg (which did not induce psychomotor activity) were approximately 11 and 16 times as high, respectively, as those following administration of 1 mg/kg d-methamphetamine. Despite the fact that there are differentiable psycho-stimulating effects between two enantiomers, no significant difference in plasma pharmacokinetic parameters was detected at 1 mg/kg. }}{{cite journal | vauthors = Siemian JN, Xue Z, Blough BE, Li JX | title = Comparison of some behavioral effects of d- and l-methamphetamine in adult male rats | journal = Psychopharmacology (Berl) | volume = 234 | issue = 14 | pages = 2167–2176 | date = July 2017 | pmid = 28386698 | pmc = 5482751 | doi = 10.1007/s00213-017-4623-8 | url = }} As in rodents, levomethamphetamine showed reduced reinforcing and stimulant-like effects compared to dextromethamphetamine in rhesus monkeys.{{cite journal | vauthors = Jacobs DS, Blough BE, Kohut SJ | title = Reinforcing and Stimulant-Like Effects of Methamphetamine Isomers in Rhesus Macaques | journal = J Pharmacol Exp Ther | volume = 378 | issue = 2 | pages = 124–132 | date = August 2021 | pmid = 33986037 | pmc = 8407528 | doi = 10.1124/jpet.121.000548 | url = }}{{cite journal | vauthors = Kohut SJ, Bergman J, Blough BE | title = Effects of L-methamphetamine treatment on cocaine- and food-maintained behavior in rhesus monkeys | journal = Psychopharmacology (Berl) | volume = 233 | issue = 6 | pages = 1067–1075 | date = March 2016 | pmid = 26713332 | pmc = 4761269 | doi = 10.1007/s00213-015-4186-5 | url = }}

Animal studies of the reinforcing and cocaine-like effects of dopamine releasing agents (DRAs) with varying capacities to release norepinephrine and serotonin in rodents and monkeys have suggested that in contrast to the case of serotonin release, which inhibits the reinforcing and stimulant-like effects of these agents, norepinephrine release has minimal influence on their misuse liability and associated effects.{{cite journal | vauthors = Banks ML, Bauer CT, Blough BE, Rothman RB, Partilla JS, Baumann MH, Negus SS | title = Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys | journal = Exp Clin Psychopharmacol | volume = 22 | issue = 3 | pages = 274–284 | date = June 2014 | pmid = 24796848 | pmc = 4067459 | doi = 10.1037/a0036595 | url = }}{{cite journal | last1=de Moura | first1=Fernando Barreto | last2=Sherwood | first2=Alexander | last3=Prisinzano | first3=Thomas Edward | last4=Kohut | first4=Stephen John | last5=Bergman | first5=Jack | title=Intravenous Self-Administration of Synthetic Cathinones in Rhesus Monkeys | journal=The FASEB Journal | volume=32 | issue=S1 | date=2018 | issn=0892-6638 | doi=10.1096/fasebj.2018.32.1_supplement.550.3 | page=| doi-access=free }}

Norepinephrine reuptake inhibitors (NRIs), like atomoxetine, reboxetine, and desipramine, do not increase locomotor activity in rodents and instead show no effect on locomotor activity or decrease it.{{cite journal | vauthors = Upadhyaya HP, Desaiah D, Schuh KJ, Bymaster FP, Kallman MJ, Clarke DO, Durell TM, Trzepacz PT, Calligaro DO, Nisenbaum ES, Emmerson PJ, Schuh LM, Bickel WK, Allen AJ | title = A review of the abuse potential assessment of atomoxetine: a nonstimulant medication for attention-deficit/hyperactivity disorder | journal = Psychopharmacology (Berl) | volume = 226 | issue = 2 | pages = 189–200 | date = March 2013 | pmid = 23397050 | pmc = 3579642 | doi = 10.1007/s00213-013-2986-z | url = }}{{cite journal | vauthors = Mitchell HA, Ahern TH, Liles LC, Javors MA, Weinshenker D | title = The effects of norepinephrine transporter inactivation on locomotor activity in mice | journal = Biol Psychiatry | volume = 60 | issue = 10 | pages = 1046–1052 | date = November 2006 | pmid = 16893531 | doi = 10.1016/j.biopsych.2006.03.057 | url = }}{{cite journal | vauthors = Rogóz Z, Wróbel A, Krasicka-Domka M, Maj J | title = Pharmacological profile of reboxetine, a representative of new class of antidepressant drugs, selective noradrenaline reuptake inhibitor (NARI), given acutely | journal = Pol J Pharmacol | volume = 51 | issue = 5 | pages = 399–404 | date = 1999 | pmid = 10817540 | doi = | url = }} In addition, NRIs decrease amphetamine-, cocaine-, methylphenidate-, and phencyclidine (PCP)-induced hyperlocomotion in rodents.{{cite journal | vauthors = Tyler TD, Tessel RE | title = Norepinephrine uptake inhibitors as biochemically and behaviorally selective antagonists of the locomotor stimulation induced by indirectly acting sympathomimetic aminetic amines in mice | journal = Psychopharmacology (Berl) | volume = 69 | issue = 1 | pages = 27–34 | date = 1980 | pmid = 6771822 | doi = 10.1007/BF00426517 | url = }}{{cite journal | vauthors = Harkin A, Morris K, Kelly JP, O'Donnell JM, Leonard BE | title = Modulation of MK-801-induced behaviour by noradrenergic agents in mice | journal = Psychopharmacology (Berl) | volume = 154 | issue = 2 | pages = 177–188 | date = March 2001 | pmid = 11314680 | doi = 10.1007/s002130000630 | url = }} Accordingly, atomoxetine has been reported to attenuate the stimulant and rewarding effects of dextroamphetamine in humans.{{cite journal | vauthors = Somaini L, Donnini C, Raggi MA, Amore M, Ciccocioppo R, Saracino MA, Kalluppi M, Malagoli M, Gerra ML, Gerra G | title = Promising medications for cocaine dependence treatment | journal = Recent Pat CNS Drug Discov | volume = 6 | issue = 2 | pages = 146–160 | date = May 2011 | pmid = 21599628 | doi = 10.2174/157488911795933893 | url = }}{{cite journal | vauthors = Sofuoglu M, Poling J, Hill K, Kosten T | title = Atomoxetine attenuates dextroamphetamine effects in humans | journal = Am J Drug Alcohol Abuse | volume = 35 | issue = 6 | pages = 412–6 | date = 2009 | pmid = 20014909 | pmc = 2796580 | doi = 10.3109/00952990903383961 | url = }}

A variety of different NRIs were shown to decrease spontaneous locomotor activity in a novel environment when given acutely and to decrease locomotor activity in both novel and familiar environments when given chronically in rodents. Similarly, norepinephrine transporter (NET) knockout mice had low basal locomotor activity. However, combination of an NRI with dopamine reuptake inhibition resulted in increased locomotor activity. It was concluded that norepinephrine reuptake inhibition by itself decreases locomotor activity unless it is combined with dopamine reuptake inhibition.

{{See also|Serotonin releasing agent#Stimulant-like and rewarding effects}}

Certain serotonin releasing agents (SRAs), like MDMA and MDAI, though notably not others, like chlorphentermine, fenfluramine, and MMAI,{{cite journal | vauthors = Rothman RB, Blough BE, Baumann MH | title = Dual dopamine-5-HT releasers: potential treatment agents for cocaine addiction | journal = Trends Pharmacol Sci | volume = 27 | issue = 12 | pages = 612–618 | date = December 2006 | pmid = 17056126 | doi = 10.1016/j.tips.2006.10.006 | url = }}{{cite journal | vauthors = Callaway CW, Wing LL, Nichols DE, Geyer MA | title = Suppression of behavioral activity by norfenfluramine and related drugs in rats is not mediated by serotonin release | journal = Psychopharmacology (Berl) | volume = 111 | issue = 2 | pages = 169–178 | date = 1993 | pmid = 7870948 | doi = 10.1007/BF02245519 | url = }} induce locomotor hyperactivity in animals.{{cite book | last1=Callaway | first1=C. W. | last2=Nichols | first2=D. E. | last3=Paulus | first3=M. P. | last4=Geyer | first4=M. A. | title=Serotonin: Molecular Biology, Receptors and Functional Effects | chapter=Serotonin Release is Responsible for the Locomotor Hyperactivity in Rats Induced by Derivatives of Amphetamine Related to MDMA | publisher=Birkhäuser Basel | publication-place=Basel | year=1991 | isbn=978-3-0348-7261-4 | doi=10.1007/978-3-0348-7259-1_49 | pages=491–505}}{{cite journal | vauthors = Stove CP, De Letter EA, Piette MH, Lambert WE | title = Mice in ecstasy: advanced animal models in the study of MDMA | journal = Curr Pharm Biotechnol | volume = 11 | issue = 5 | pages = 421–433 | date = August 2010 | pmid = 20420576 | doi = 10.2174/138920110791591508 | url = }}{{cite journal | vauthors = Aguilar MA, García-Pardo MP, Parrott AC | title = Of mice and men on MDMA: A translational comparison of the neuropsychobiological effects of 3,4-methylenedioxymethamphetamine ('Ecstasy') | journal = Brain Res | volume = 1727 | issue = | pages = 146556 | date = January 2020 | pmid = 31734398 | doi = 10.1016/j.brainres.2019.146556 | url = }}{{cite journal | vauthors = Fantegrossi WE, Godlewski T, Karabenick RL, Stephens JM, Ullrich T, Rice KC, Woods JH | title = Pharmacological characterization of the effects of 3,4-methylenedioxymethamphetamine ("ecstasy") and its enantiomers on lethality, core temperature, and locomotor activity in singly housed and crowded mice | journal = Psychopharmacology (Berl) | volume = 166 | issue = 3 | pages = 202–211 | date = March 2003 | pmid = 12563544 | doi = 10.1007/s00213-002-1261-5 | url = | hdl = 2027.42/41985 | hdl-access = free }} This is dependent on serotonin release allowed for by the serotonin transporter (SERT) and serotonin 5-HT_2B receptor.{{cite journal | last1=Martinez-Price | first1=Diana | last2=Krebs-Thomson | first2=Kirsten | last3=Geyer | first3=Mark | title=Behavioral Psychopharmacology of MDMA and MDMA-Like Drugs: A Review of Human and Animal Studies | journal=Addiction Research & Theory | publisher=Informa UK Limited | volume=10 | issue=1 | date=1 January 2002 | issn=1606-6359 | doi=10.1080/16066350290001704 | pages=43–67}}{{cite journal | vauthors = Fox MA, Andrews AM, Wendland JR, Lesch KP, Holmes A, Murphy DL | title = A pharmacological analysis of mice with a targeted disruption of the serotonin transporter | journal = Psychopharmacology (Berl) | volume = 195 | issue = 2 | pages = 147–166 | date = December 2007 | pmid = 17712549 | doi = 10.1007/s00213-007-0910-0 | url = }}{{cite journal | vauthors = Doly S, Valjent E, Setola V, Callebert J, Hervé D, Launay JM, Maroteaux L | title = Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro | journal = J Neurosci | volume = 28 | issue = 11 | pages = 2933–2940 | date = March 2008 | pmid = 18337424 | pmc = 6670669 | doi = 10.1523/JNEUROSCI.5723-07.2008 | url = }} SERT knockout, pretreatment with serotonin reuptake inhibitors (SRIs) (which block MDMA-induced SERT-mediated serotonin release), or serotonin 5-HT_2B receptor knockout (which likewise blocks MDMA-induced serotonin release), all completely block MDMA-induced locomotor hyperactivity. In addition, locomotor hyperactivity produced by MDMA is partially attenuated by serotonin 5-HT_1B receptor antagonism (or knockout){{cite journal | vauthors = Rempel NL, Callaway CW, Geyer MA | title = Serotonin1B receptor activation mimics behavioral effects of presynaptic serotonin release | journal = Neuropsychopharmacology | volume = 8 | issue = 3 | pages = 201–211 | date = May 1993 | pmid = 8099482 | doi = 10.1038/npp.1993.22 | url = }}{{cite journal | vauthors = Scearce-Levie K, Viswanathan SS, Hen R | title = Locomotor response to MDMA is attenuated in knockout mice lacking the 5-HT1B receptor | journal = Psychopharmacology (Berl) | volume = 141 | issue = 2 | pages = 154–161 | date = January 1999 | pmid = 9952039 | doi = 10.1007/s002130050819 | url = }} or by serotonin 5-HT_2A receptor antagonism.{{cite journal | vauthors = Liechti ME, Vollenweider FX | title = Which neuroreceptors mediate the subjective effects of MDMA in humans? A summary of mechanistic studies | journal = Hum Psychopharmacol | volume = 16 | issue = 8 | pages = 589–598 | date = December 2001 | pmid = 12404538 | doi = 10.1002/hup.348 | url = }}{{cite journal | vauthors = Bankson MG, Cunningham KA | title = Pharmacological studies of the acute effects of (+)-3,4-methylenedioxymethamphetamine on locomotor activity: role of 5-HT(1B/1D) and 5-HT(2) receptors | journal = Neuropsychopharmacology | volume = 26 | issue = 1 | pages = 40–52 | date = January 2002 | pmid = 11751031 | doi = 10.1016/S0893-133X(01)00345-1 | url = }}{{cite journal | vauthors = Baumann MH, Clark RD, Rothman RB | title = Locomotor stimulation produced by 3,4-methylenedioxymethamphetamine (MDMA) is correlated with dialysate levels of serotonin and dopamine in rat brain | journal = Pharmacol Biochem Behav | volume = 90 | issue = 2 | pages = 208–217 | date = August 2008 | pmid = 18403002 | pmc = 2491560 | doi = 10.1016/j.pbb.2008.02.018 | url = }} The locomotor hyperactivity produced by MDMA is fully attenuated by combined serotonin 5-HT_1B and 5-HT_2A receptor antagonism. Conversely, the serotonin 5-HT_1A receptor is not involved in MDMA-induced hyperlocomotion. Serotonin 5-HT_2C receptor activation appears to inhibit MDMA-induced hyperlocomotion, and antagonism of this receptor has been reported to markedly enhance the locomotor hyperactivity induced by MDMA.{{cite journal | vauthors = Conductier G, Crosson C, Hen R, Bockaert J, Compan V | title = 3,4-N-methlenedioxymethamphetamine-induced hypophagia is maintained in 5-HT1B receptor knockout mice, but suppressed by the 5-HT2C receptor antagonist RS102221 | journal = Neuropsychopharmacology | volume = 30 | issue = 6 | pages = 1056–1063 | date = June 2005 | pmid = 15668722 | doi = 10.1038/sj.npp.1300662 | url = }}{{cite journal | vauthors = Ball KT, Rebec GV | title = Role of 5-HT2A and 5-HT2C/B receptors in the acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on striatal single-unit activity and locomotion in freely moving rats | journal = Psychopharmacology (Berl) | volume = 181 | issue = 4 | pages = 676–687 | date = October 2005 | pmid = 16001122 | doi = 10.1007/s00213-005-0038-z | url = }} Activation of the serotonin 5-HT_2C receptor is known to inhibit dopamine release in the mesolimbic pathway as well as to inhibit dopamine release in the nigrostriatal and mesocortical pathways.{{cite book | vauthors = Rothman RB, Blough BE, Baumann MH | chapter = Dopamine/Serotonin releasers as medications for stimulant addictions | title = Serotonin–Dopamine Interaction: Experimental Evidence and Therapeutic Relevance | journal = Prog Brain Res | series = Progress in Brain Research | volume = 172 | issue = | pages = 385–406 | date = 2008 | pmid = 18772043 | doi = 10.1016/S0079-6123(08)00919-9 | isbn = 978-0-444-53235-0 | url = }}{{cite journal | vauthors = Rothman RB, Blough BE, Baumann MH | title = Dual dopamine/serotonin releasers: potential treatment agents for stimulant addiction | journal = Exp Clin Psychopharmacol | volume = 16 | issue = 6 | pages = 458–474 | date = December 2008 | pmid = 19086767 | pmc = 2683464 | doi = 10.1037/a0014103 | url = }}{{cite journal | vauthors = Canal CE, Murnane KS | title = The serotonin 5-HT2C receptor and the non-addictive nature of classic hallucinogens | journal = J Psychopharmacol | volume = 31 | issue = 1 | pages = 127–143 | date = January 2017 | pmid = 27903793 | pmc = 5445387 | doi = 10.1177/0269881116677104 | url = }}

Although the serotonin system has been implicated in the hyperlocomotion of SRAs, certain SRAs, such as MDMA, are actually serotonin–norepinephrine–dopamine releasing agents (SNDRAs), and catecholaminergic mechanisms are likely to additionally be involved.{{cite journal | vauthors = Baumann MH, Wang X, Rothman RB | title = 3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings | journal = Psychopharmacology (Berl) | volume = 189 | issue = 4 | pages = 407–424 | date = January 2007 | pmid = 16541247 | pmc = 1705495 | doi = 10.1007/s00213-006-0322-6 | url = }}{{cite book | vauthors = Pritchard LM, Hensleigh E | chapter=Psychopharmacology and Neurotoxicology of Methamphetamine and 3,4-Methylenedioxymethamphetamine | veditors = Rincón A | title = Amphetamines: Neurobiological Mechanisms, Pharmacology and Effects | pages = 1–43 | date = 2012 | publisher = Nova Biomedical Books | location = Hauppauge [NY] | isbn = 9781614703051 | oclc = 726822553 | ol = OL16643844W | url = https://psycnet.apa.org/record/2012-17476-001 }} Relatedly, the α₁-adrenergic receptor antagonist prazosin completely blocks MDMA-induced hyperlocomotion in animals.{{cite journal | vauthors = Sáez-Briones P, Hernández A | title = MDMA (3,4-Methylenedioxymethamphetamine) Analogues as Tools to Characterize MDMA-Like Effects: An Approach to Understand Entactogen Pharmacology | journal = Curr Neuropharmacol | volume = 11 | issue = 5 | pages = 521–534 | date = September 2013 | pmid = 24403876 | pmc = 3763760 | doi = 10.2174/1570159X11311050007 | url = }}{{cite journal | vauthors = Selken J, Nichols DE | title = Alpha1-adrenergic receptors mediate the locomotor response to systemic administration of (+/-)-3,4-methylenedioxymethamphetamine (MDMA) in rats | journal = Pharmacol Biochem Behav | volume = 86 | issue = 4 | pages = 622–630 | date = April 2007 | pmid = 17363047 | pmc = 1976288 | doi = 10.1016/j.pbb.2007.02.006 | url = }} In addition, the α₁-adrenergic receptor antagonists prazosin and doxazosin reduce the psychostimulant and/or euphoric effects of MDMA in humans.{{cite conference | vauthors = Baggott M, Galloway GP, Jang M, Didier R, Mendelson JE | title = Alpha-1 noradrenergic receptors contribute to psychostimulant-like effects of MDMA in humans (Poster 14) | date = June 2008 | conference = CPDD 70th Annual Scientific Meeting, The Caribe Hilton, San Juan, Puerto Rico, June 14–19, 2008 | url = https://cpdd.org/Pages/Meetings/Meetings_PDFs/2008Programbook.pdf#page=81 | archive-url = https://web.archive.org/web/20160730115358/https://cpdd.org/Pages/Meetings/Meetings_PDFs/2008Programbook.pdf#page=81 | archive-date = 30 July 2016 }}{{cite conference | vauthors = Baggott M, Galloway GP, Jang M, Didier R, Pournajafi-Nazarloo H, Carter CS | title = 3, 4-methylenedioxymethamphetamine (MDMA,'Ecstasy') and prazosin interactions in humans | date = June 2008 | conference = 70th Annual Meeting of the College on Problems of Drug Dependence, San Juan, Puerto Rico | url = https://scholar.google.com/scholar?cluster=14033061140609064122 }}{{cite journal | vauthors = Hysek CM, Fink AE, Simmler LD, Donzelli M, Grouzmann E, Liechti ME | title = α₁-Adrenergic receptors contribute to the acute effects of 3,4-methylenedioxymethamphetamine in humans | journal = J Clin Psychopharmacol | volume = 33 | issue = 5 | pages = 658–666 | date = October 2013 | pmid = 23857311 | doi = 10.1097/JCP.0b013e3182979d32 | url = }} Similarly, the norepinephrine reuptake inhibitor (NRI) reboxetine, which prevents MDMA from inducing norepinephrine release, likewise reduces the stimulant effects and emotional excitation of MDMA in humans.{{cite journal | vauthors = Hysek CM, Simmler LD, Ineichen M, Grouzmann E, Hoener MC, Brenneisen R, Huwyler J, Liechti ME | title = The norepinephrine transporter inhibitor reboxetine reduces stimulant effects of MDMA ("ecstasy") in humans | journal = Clin Pharmacol Ther | volume = 90 | issue = 2 | pages = 246–255 | date = August 2011 | pmid = 21677639 | doi = 10.1038/clpt.2011.78 | url = }} Dopamine receptors also appear to be involved in MDMA-induced hyperlocomotion, although findings in this area, both in animals and humans, seem to be conflicting.{{cite journal | last1=Kaur | first1=Harpreet | last2=Karabulut | first2=Sedat | last3=Gauld | first3=James W. | last4=Fagot | first4=Stephen A. | last5=Holloway | first5=Kalee N. | last6=Shaw | first6=Hannah E. | last7=Fantegrossi | first7=William E. | title=Balancing Therapeutic Efficacy and Safety of MDMA and Novel MDXX Analogues as Novel Treatments for Autism Spectrum Disorder | journal=Psychedelic Medicine | volume=1 | issue=3 | date=1 September 2023 | issn=2831-4425 | doi=10.1089/psymed.2023.0023 | pages=166–185 | quote=The role of DA in the abuse-related effects of psychostimulants is well established in animal models. Still, deletions of DA D1, D2, and D3 receptor genes in mice had minimal impact on MDMA-induced locomotor activity,97 and DAT inhibition did not affect neurocognitive effects of MDMA in cynomolgus monkeys.98 In humans, D2 receptor antagonists reduced amphetamine-induced and MDMA-induced euphoria only at doses that produced dysphoria on their own.99 Therefore, it seems likely that systems unrelated to DA may be principally responsible for the acute effects of MDMA.40 | pmc=11661495 }}{{cite journal | vauthors = Risbrough VB, Masten VL, Caldwell S, Paulus MP, Low MJ, Geyer MA | title = Differential contributions of dopamine D1, D2, and D3 receptors to MDMA-induced effects on locomotor behavior patterns in mice | journal = Neuropsychopharmacology | volume = 31 | issue = 11 | pages = 2349–2358 | date = November 2006 | pmid = 16855533 | doi = 10.1038/sj.npp.1301161 | url = }}

In contrast to non-selective SRAs like MDMA, the highly selective SRA MMAI induces hypolocomotion in animals.{{cite journal | vauthors = Marona-Lewicka D, Nichols DE | title = Behavioral effects of the highly selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan | journal = Eur J Pharmacol | volume = 258 | issue = 1–2 | pages = 1–13 | date = June 1994 | pmid = 7925587 | doi = 10.1016/0014-2999(94)90051-5 | url = }} Similarly, the highly selective SRA chlorphentermine is said to weakly stimulate locomotor activity at low doses and to progressively suppress locomotor activity at higher doses.{{cite journal | vauthors = Ogren SO, Ross SB | title = Substituted amphetamine derivatives. II. Behavioural effects in mice related to monoaminergic neurones | journal = Acta Pharmacol Toxicol (Copenh) | volume = 41 | issue = 4 | pages = 353–368 | date = October 1977 | pmid = 303437 | doi = 10.1111/j.1600-0773.1977.tb02674.x | url = }}

The reasons for the differences in locomotor activity with different SRAs are not fully clear. In any case, they may be related to factors such as whether the agents are selective SRAs, whether they additionally act as agonists of serotonin 5-HT₂ receptors, and whether they additionally induce the release of norepinephrine and/or dopamine.{{cite journal | vauthors = Bankson MG, Cunningham KA | title = 3,4-Methylenedioxymethamphetamine (MDMA) as a unique model of serotonin receptor function and serotonin-dopamine interactions | journal = J Pharmacol Exp Ther | volume = 297 | issue = 3 | pages = 846–852 | date = June 2001 | pmid = 11356903 | doi = 10.1016/S0022-3565(24)29607-5| url = https://bibliography.maps.org/resource/983 | url-access = subscription }}{{cite journal | vauthors = Higgins GA, Fletcher PJ | title = Therapeutic Potential of 5-HT2C Receptor Agonists for Addictive Disorders | journal = ACS Chem Neurosci | volume = 6 | issue = 7 | pages = 1071–1088 | date = July 2015 | pmid = 25870913 | doi = 10.1021/acschemneuro.5b00025 | url = }}

Selective serotonin reuptake inhibitors (SSRIs) have been reported to have no effect or to increase locomotor activity, at least under certain circumstances like novel environments.{{cite journal | vauthors = Prinssen EP, Ballard TM, Kolb Y, Nicolas LB | title = The effects of serotonin reuptake inhibitors on locomotor activity in gerbils | journal = Pharmacol Biochem Behav | volume = 85 | issue = 1 | pages = 44–49 | date = September 2006 | pmid = 16920181 | doi = 10.1016/j.pbb.2006.07.005 | url = }}{{cite journal | vauthors = Brocco M, Dekeyne A, Veiga S, Girardon S, Millan MJ | title = Induction of hyperlocomotion in mice exposed to a novel environment by inhibition of serotonin reuptake. A pharmacological characterization of diverse classes of antidepressant agents | journal = Pharmacol Biochem Behav | volume = 71 | issue = 4 | pages = 667–680 | date = April 2002 | pmid = 11888558 | doi = 10.1016/s0091-3057(01)00701-8 | url = }} However, in other studies, SSRIs have been reported to produce hypolocomotion, an effect that could be reversed by the serotonin 5-HT_2C receptor antagonist SB-242084.{{cite journal | vauthors = Bagdy G, Graf M, Anheuer ZE, Modos EA, Kantor S | title = Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635 | journal = Int J Neuropsychopharmacol | volume = 4 | issue = 04 | pages = 399–408 | date = December 2001 | pmid = 11806866 | doi = 10.1017/S1461145701002632 | url = }}{{cite journal | vauthors = Yamauchi M, Tatebayashi T, Nagase K, Kojima M, Imanishi T | title = Chronic treatment with fluvoxamine desensitizes 5-HT2C receptor-mediated hypolocomotion in rats | journal = Pharmacol Biochem Behav | volume = 78 | issue = 4 | pages = 683–689 | date = August 2004 | pmid = 15301922 | doi = 10.1016/j.pbb.2004.05.003 | url = }}{{cite journal | vauthors = Shishkina GT, Iudina AM, Dygalo NN | title = [Effects of fluoxetine on locomotor activity: possible involvement of dopamine] | language = Russian | journal = Zh Vyssh Nerv Deiat Im I P Pavlova | volume = 56 | issue = 4 | pages = 523–528 | date = 2006 | pmid = 17025197 | doi = | url = }} In another study, the SSRIs fluoxetine and citalopram had no effect on locomotor activity alone or in combination with SB-242084.

Fluoxetine has been found to not affect dextroamphetamine-induced hyperlocomotion. Similarly, sertraline did not affect cocaine-induced hyperlocomotion.{{cite journal | vauthors = Reith ME, Wiener HL, Fischette CT | title = Sertraline and cocaine-induced locomotion in mice. I. Acute studies | journal = Psychopharmacology (Berl) | volume = 103 | issue = 3 | pages = 297–305 | date = 1991 | pmid = 2057535 | doi = 10.1007/BF02244282 | url = }}

The serotonin precursor 5-hydroxytryptophan (5-HTP) combined with benserazide can suppress the hyperlocomotion induced by dextroamphetamine in rodents.{{cite journal | vauthors = Baumann MH, Williams Z, Zolkowska D, Rothman RB | title = Serotonin (5-HT) precursor loading with 5-hydroxy-l-tryptophan (5-HTP) reduces locomotor activation produced by (+)-amphetamine in the rat | journal = Drug Alcohol Depend | volume = 114 | issue = 2–3 | pages = 147–152 | date = April 2011 | pmid = 21071157 | pmc = 3044786 | doi = 10.1016/j.drugalcdep.2010.09.015 | url = }}

The non-selective serotonin receptor agonists and serotonergic psychedelics LSD and DOI decrease locomotor activity in animals.{{cite journal | vauthors = Hanks JB, González-Maeso J | title = Animal models of serotonergic psychedelics | journal = ACS Chem Neurosci | volume = 4 | issue = 1 | pages = 33–42 | date = January 2013 | pmid = 23336043 | pmc = 3547517 | doi = 10.1021/cn300138m | url = }} However, whereas LSD suppresses locomotion at all doses tested, DOI as well as DOM show an inverted U-shaped dose–response curve, with stimulation of locomotor activity at low doses and suppression of locomotion at higher doses.{{cite journal | vauthors = Halberstadt AL, van der Heijden I, Ruderman MA, Risbrough VB, Gingrich JA, Geyer MA, Powell SB | title = 5-HT(2A) and 5-HT(2C) receptors exert opposing effects on locomotor activity in mice | journal = Neuropsychopharmacology | volume = 34 | issue = 8 | pages = 1958–1967 | date = July 2009 | pmid = 19322172 | pmc = 2697271 | doi = 10.1038/npp.2009.29 | url = }}{{cite journal | vauthors = Zhu H, Wang L, Wang X, Yao Y, Zhou P, Su R | title = 5-hydroxytryptamine 2C/1A receptors modulate the biphasic dose response of the head twitch response and locomotor activity induced by DOM in mice | journal = Psychopharmacology (Berl) | volume = 241 | issue = 11 | pages = 2315–2330 | date = November 2024 | pmid = 38916640 | doi = 10.1007/s00213-024-06635-4 | url = }} The hyperlocomotion of DOI at low doses is abolished in serotonin 5-HT_2A receptor knockout mice, whereas the hypolocomotion with DOI at higher doses is blocked by the selective serotonin 5-HT_2C receptor antagonist SER-082. Similarly, the hyperlocomotion of low doses of DOM is reduced by the serotonin 5-HT_2A receptor antagonist volinanserin (MDL-100907) and enhanced by the serotonin 5-HT_2C receptor antagonist SB-242084 and its hypolocomotion at high doses is attenuated by SB-242084. As such, it has been concluded that serotonin 5-HT_2A receptor activation increases locomotor activity while serotonin 5-HT_2C receptor agonism decreases locomotor activity.{{cite book | vauthors = Halberstadt AL | title = Pharmacology and Toxicology of N-Benzylphenethylamine ("NBOMe") Hallucinogens | series = Current Topics in Behavioral Neurosciences | volume = 32 | issue = | pages = 283–311 | date = 2017 | pmid = 28097528 | doi = 10.1007/7854_2016_64 | isbn = 978-3-319-52442-9 | url = }}

The locomotor effects of many other serotonergic psychedelics have also been studied and have often been similar to the preceding agents.{{cite book | vauthors = Halberstadt AL, Geyer MA | title = Behavioral Neurobiology of Psychedelic Drugs | chapter = Effect of Hallucinogens on Unconditioned Behavior | series = Current Topics in Behavioral Neurosciences | volume = 36 | issue = | pages = 159–199 | date = 2018 | pmid = 28224459 | pmc = 5787039 | doi = 10.1007/7854_2016_466 | isbn = 978-3-662-55878-2 | chapter-url = }} However, in other cases, they have been different. The tryptamine psychedelics psilocin and 5-MeO-DMT produce profound hypolocomotion in mice and this is blocked by the serotonin 5-HT_1A receptor antagonist WAY-100635 or by serotonin 5-HT_1A receptor knockout but not by the serotonin 5-HT_2C receptor antagonist SB-242084. 5-MeO-DALT dose-dependently increased locomotor activity but produced a sharp decrease at the highest tested dose.{{cite journal | vauthors = Gatch MB, Dolan SB, Forster MJ | title = Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents | journal = Behav Pharmacol | volume = 28 | issue = 5 | pages = 375–385 | date = August 2017 | pmid = 28537942 | pmc = 5498282 | doi = 10.1097/FBP.0000000000000309 | url = }} The relatively selective serotonin 5-HT_2A receptor agonist 25I-NBOMe has been found to show similar locomotor effects to phenylalkylamine psychedelics, increasing locomotor activity at low doses at decreasing it at higher doses. The selective serotonin 5-HT_2A receptor agonist 25CN-NBOH modestly increased locomotor activity or did not affect it.{{cite journal | vauthors = Odland AU, Jessen L, Kristensen JL, Fitzpatrick CM, Andreasen JT | title = The 5-hydroxytryptamine 2A receptor agonists DOI and 25CN-NBOH decrease marble burying and reverse 8-OH-DPAT-induced deficit in spontaneous alternation | journal = Neuropharmacology | volume = 183 | issue = | pages = 107838 | date = February 2021 | pmid = 31693871 | doi = 10.1016/j.neuropharm.2019.107838 | url = }}{{cite journal | vauthors = Jensen AA, Halberstadt AL, Märcher-Rørsted E, Odland AU, Chatha M, Speth N, Liebscher G, Hansen M, Bräuner-Osborne H, Palner M, Andreasen JT, Kristensen JL | title = The selective 5-HT2A receptor agonist 25CN-NBOH: Structure-activity relationship, in vivo pharmacology, and in vitro and ex vivo binding characteristics of [3H]25CN-NBOH | journal = Biochem Pharmacol | volume = 177 | issue = | pages = 113979 | date = July 2020 | pmid = 32298690 | doi = 10.1016/j.bcp.2020.113979 | url = }}{{cite journal | vauthors = Buchborn T, Lyons T, Knöpfel T | title = Tolerance and Tachyphylaxis to Head Twitches Induced by the 5-HT2A Agonist 25CN-NBOH in Mice | journal = Front Pharmacol | volume = 9 | issue = | pages = 17 | date = 2018 | pmid = 29467649 | pmc = 5808243 | doi = 10.3389/fphar.2018.00017 | doi-access = free | url = }}

The non-selective serotonin 5-HT_2C receptor agonists meta-chlorophenylpiperazine (mCPP) and Ro60-0175 as well as the selective serotonin 5-HT_2C receptor agonists WAY-161503 and CP-809101 produce hypolocomotion in rodents. In serotonin 5-HT_2C receptor knockout mice, on the other hand, mCPP produced hyperlocomotion. In contrast to most serotonin 5-HT_2C receptor agonists, the selective serotonin 5-HT_2C receptor agonist WAY-163909 had no effect on spontaneous locomotor activity. The selective serotonin 5-HT_2C receptor agonists WAY-163909 and CP-809101 have been found to suppress dextroamphetamine-induced hyperlocomotion.{{cite journal | vauthors = Monck NJ, Kennett GA | title = 5-HT2C ligands: recent progress | journal = Prog Med Chem | series = Progress in Medicinal Chemistry | volume = 46 | issue = | pages = 281–390 | date = 2008 | pmid = 18381128 | doi = 10.1016/S0079-6468(07)00006-9 | isbn = 978-0-444-53018-9 | url = }} The non-selective serotonin 5-HT_2C receptor agonist Ro60-0175 has been found to suppress the hyperlocomotion induced by cocaine, and this effect could be blocked by the selective serotonin 5-HT_2C receptor antagonist SB-242084. CP-809101 has been found to decrease locomotor activity and antagonized phencyclidine (PCP)-induced hyperlocomotion.

Serotonin 5-HT_2A receptor antagonists like volinanserin (MDL-100907) and ketanserin counteract the hyperactivity induced by amphetamine, cocaine, and NMDA receptor antagonists like PCP in animals.{{cite journal | vauthors = Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, Hennessey JJ, Bock HA, Anderson EI, Sherwood AM, Morris H, de Klein R, Klein AK, Cuccurazzu B, Gamrat J, Fannana T, Zauhar R, Halberstadt AL, McCorvy JD | title = Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential | journal = Nat Commun | volume = 14 | issue = 1 | pages = 8221 | date = December 2023 | pmid = 38102107 | pmc = 10724237 | doi = 10.1038/s41467-023-44016-1 | url = }}{{cite journal | vauthors = Carlsson ML | title = The selective 5-HT2A receptor antagonist MDL 100,907 counteracts the psychomotor stimulation ensuing manipulations with monoaminergic, glutamatergic or muscarinic neurotransmission in the mouse--implications for psychosis | journal = J Neural Transm Gen Sect | volume = 100 | issue = 3 | pages = 225–237 | date = 1995 | pmid = 8748668 | doi = 10.1007/BF01276460 | url = }}{{cite journal | vauthors = O'Neill MF, Heron-Maxwell CL, Shaw G | title = 5-HT2 receptor antagonism reduces hyperactivity induced by amphetamine, cocaine, and MK-801 but not D1 agonist C-APB | journal = Pharmacol Biochem Behav | volume = 63 | issue = 2 | pages = 237–243 | date = June 1999 | pmid = 10371652 | doi = 10.1016/s0091-3057(98)00240-8 | url = }}{{cite journal | vauthors = Ninan I, Kulkarni SK | title = 5-HT2A receptor antagonists block MK-801-induced stereotypy and hyperlocomotion | journal = Eur J Pharmacol | volume = 358 | issue = 2 | pages = 111–116 | date = October 1998 | pmid = 9808259 | doi = 10.1016/s0014-2999(98)00591-3 | url = }}{{cite journal | vauthors = McMahon LR, Cunningham KA | title = Antagonism of 5-hydroxytryptamine(2a) receptors attenuates the behavioral effects of cocaine in rats | journal = J Pharmacol Exp Ther | volume = 297 | issue = 1 | pages = 357–363 | date = April 2001 | pmid = 11259563 | doi = 10.1016/S0022-3565(24)29546-X| url = }}{{cite journal | vauthors = Herges S, Taylor DA | title = Involvement of serotonin in the modulation of cocaine-induced locomotor activity in the rat | journal = Pharmacol Biochem Behav | volume = 59 | issue = 3 | pages = 595–611 | date = March 1998 | pmid = 9512061 | doi = 10.1016/s0091-3057(97)00473-5 | url = }} Less-selective serotonin 5-HT_2A receptor antagonists, like trazodone, have been found to decrease locomotor and behavioral activity and to inhibit amphetamine-, cocaine-, and PCP-induced hyperactivity in animals similarly.{{cite journal | vauthors = Gleason SD, Shannon HE | title = Blockade of phencyclidine-induced hyperlocomotion by olanzapine, clozapine and serotonin receptor subtype selective antagonists in mice | journal = Psychopharmacology (Berl) | volume = 129 | issue = 1 | pages = 79–84 | date = January 1997 | pmid = 9122367 | doi = 10.1007/s002130050165 | url = }}{{cite journal | vauthors = Ayd FJ, Settle EC | title = Trazodone: a novel, broad-spectrum antidepressant | journal = Mod Probl Pharmacopsychiatry | series = Modern Trends in Pharmacopsychiatry | volume = 18 | issue = | pages = 49–69 | date = 1982 | pmid = 6124884 | doi = 10.1159/000406236 | isbn = 978-3-8055-3428-4 | url = }}{{cite journal | vauthors = Rawls WN | title = Trazodone (Desyrel, Mead-Johnson Pharmaceutical Division) | journal = Drug Intell Clin Pharm | volume = 16 | issue = 1 | pages = 7–13 | date = January 1982 | pmid = 7032872 | doi = 10.1177/106002808201600102 | url = }}{{cite journal | vauthors = Al-Yassiri MM, Ankier SI, Bridges PK | title = Trazodone--a new antidepressant | journal = Life Sci | volume = 28 | issue = 22 | pages = 2449–2458 | date = June 1981 | pmid = 7019617| doi = 10.1016/0024-3205(81)90586-5 | url = }}{{cite journal | vauthors = Baran L, Maj J, Rogóz Z, Skuza G | title = On the central antiserotonin action of trazodone | journal = Pol J Pharmacol Pharm | volume = 31 | issue = 1 | pages = 25–33 | date = 1979 | pmid = 482164 | doi = | url = }} Blockade of the serotonin 5-HT_2A receptor by atypical antipsychotics like clozapine and olanzapine contributes to the hypolocomotion they produce.{{cite journal | vauthors = McOmish CE, Lira A, Hanks JB, Gingrich JA | title = Clozapine-induced locomotor suppression is mediated by 5-HT2A receptors in the forebrain | journal = Neuropsychopharmacology | volume = 37 | issue = 13 | pages = 2747–2755 | date = December 2012 | pmid = 22871913 | pmc = 3499715 | doi = 10.1038/npp.2012.139 | url = }} In addition to serotonin 5-HT_2A receptor antagonists, serotonin 5-HT_2A receptor biased agonists that selectively activate the β-arrestin pathway but not the G_q pathway, like 25N-N1-Nap, have been found to antagonize PCP-induced locomotor hyperactivity in rodents.

Serotonin 5-HT_2B receptor antagonists by themselves do not appear to affect locomotor activity.{{cite journal | vauthors = Gleason SD, Lucaites VL, Shannon HE, Nelson DL, Leander JD | title = m-CPP hypolocomotion is selectively antagonized by compounds with high affinity for 5-HT(2C) receptors but not 5-HT(2A) or 5-HT(2B) receptors | journal = Behav Pharmacol | volume = 12 | issue = 8 | pages = 613–620 | date = December 2001 | pmid = 11856898 | doi = 10.1097/00008877-200112000-00005 | url = }} However, antagonists of the serotonin 5-HT_2B receptor decrease the locomotor hyperactivity of amphetamine, cocaine, and phencyclidine (PCP).{{cite book | last1=Cooper | first1=Ignatius Alvarez | last2=Beecher | first2=Kate | last3=Bartlett | first3=Selena E. | last4=Belmer | first4=Arnauld | title=5-HT2B Receptors | chapter=Role of the Serotonin 2B Receptor in the Reinforcing Effects of Psychostimulants | publisher=Springer International Publishing | publication-place=Cham | volume=35 | date=2021 | isbn=978-3-030-55919-9 | doi=10.1007/978-3-030-55920-5_18 | pages=309–322}}{{cite journal | vauthors = Wang Q, Zhou Y, Huang J, Huang N | title = Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor | journal = Pharmaceuticals | volume = 14 | issue = 2 | date = January 2021 | page = 76 | pmid = 33498477 | pmc = 7909583 | doi = 10.3390/ph14020076 | doi-access = free | url = }}{{cite journal | vauthors = Auclair AL, Cathala A, Sarrazin F, Depoortère R, Piazza PV, Newman-Tancredi A, Spampinato U | title = The central serotonin 2B receptor: a new pharmacological target to modulate the mesoaccumbens dopaminergic pathway activity | journal = J Neurochem | volume = 114 | issue = 5 | pages = 1323–1332 | date = September 2010 | pmid = 20534001 | doi = 10.1111/j.1471-4159.2010.06848.x | url = }}{{cite journal | vauthors = Devroye C, Cathala A, Di Marco B, Caraci F, Drago F, Piazza PV, Spampinato U | title = Central serotonin(2B) receptor blockade inhibits cocaine-induced hyperlocomotion independently of changes of subcortical dopamine outflow | journal = Neuropharmacology | volume = 97 | issue = | pages = 329–337 | date = October 2015 | pmid = 26116760 | doi = 10.1016/j.neuropharm.2015.06.012 | url = }}

The selective serotonin 5-HT_2C receptor antagonist SB-242084 has been found to produce modest hyperlocomotion at high doses in rodents.{{cite journal | vauthors = Manvich DF, Kimmel HL, Cooper DA, Howell LL | title = The serotonin 2C receptor antagonist SB 242084 exhibits abuse-related effects typical of stimulants in squirrel monkeys | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 342 | issue = 3 | pages = 761–769 | date = September 2012 | pmid = 22685342 | pmc = 3422522 | doi = 10.1124/jpet.112.195156 | quote = There is also evidence to support our finding that administration of SB 242084 alone induces stimulant-like effects, because administration of a high dose of SB 242084 (1.0 mg/kg) significantly increased basal locomotor activity in rats (Zaniewska et al., 2009). [...] This discrepancy may be accounted for by highlighting the tested dose range within each experiment. For example, the dose of SB 242084 used for reinstatement experiments in the previous rodent study (0.5 mg/kg) also failed to induce significant locomotor effects (Fletcher et al., 2002). However, increasing the dose of SB 242084 to 1.0 mg/kg did produce a modest, but significant, effect on locomotor activity in a separate study (Zaniewska et al., 2009). }}{{cite journal | vauthors = Zaniewska M, McCreary AC, Filip M | title = Interactions of serotonin (5-HT)2 receptor-targeting ligands and nicotine: locomotor activity studies in rats | journal = Synapse | volume = 63 | issue = 8 | pages = 653–661 | date = August 2009 | pmid = 19347958 | doi = 10.1002/syn.20645 | url = }} The drug has also been found to produce modest stimulant-like effects in squirrel monkeys. SB-242084 has additionally been found to enhance the hyperlocomotion of dextroamphetamine in rodents.{{cite journal | vauthors = Jensen NH, Cremers TI, Sotty F | title = Therapeutic potential of 5-HT2C receptor ligands | journal = ScientificWorldJournal | volume = 10 | issue = | pages = 1870–1885 | date = September 2010 | pmid = 20852829 | pmc = 5763985 | doi = 10.1100/tsw.2010.180 | doi-access = free | url = }} Similarly, it has been found to dose-dependently enhance the hyperlocomotion induced by dexfenfluramine in rodents.{{cite journal | vauthors = Higgins GA, Ouagazzal AM, Grottick AJ | title = Influence of the 5-HT(2C) receptor antagonist SB242,084 on behaviour produced by the 5-HT(2) agonist Ro60-0175 and the indirect 5-HT agonist dexfenfluramine | journal = Br J Pharmacol | volume = 133 | issue = 4 | pages = 459–466 | date = June 2001 | pmid = 11399662 | pmc = 1572804 | doi = 10.1038/sj.bjp.0704082 | url = }} It has also been found to enhance the hyperlocomotion induced by MDMA, fenfluramine, cocaine, and methylphenidate, to modestly enhance nicotine- and morphine-induced hyperactivity, and to not affect the hyperactivity induced by RU-24969 or citalopram.{{cite journal | vauthors = Fletcher PJ, Sinyard J, Higgins GA | title = The effects of the 5-HT(2C) receptor antagonist SB242084 on locomotor activity induced by selective, or mixed, indirect serotonergic and dopaminergic agonists | journal = Psychopharmacology (Berl) | volume = 187 | issue = 4 | pages = 515–525 | date = September 2006 | pmid = 16832658 | doi = 10.1007/s00213-006-0453-9 | url = }} The serotonin 5-HT_2C receptor antagonist SB-221284 has been found to augment the nucleus accumbens dopamine elevations and hyperlocomotion induced by NMDA receptor antagonists like phencyclidine (PCP) and dizocilpine (MK-801) in rodents.{{cite journal | vauthors = Hutson PH, Barton CL, Jay M, Blurton P, Burkamp F, Clarkson R, Bristow LJ | title = Activation of mesolimbic dopamine function by phencyclidine is enhanced by 5-HT(2C/2B) receptor antagonists: neurochemical and behavioural studies | journal = Neuropharmacology | volume = 39 | issue = 12 | pages = 2318–2328 | date = September 2000 | pmid = 10974315 | doi = 10.1016/s0028-3908(00)00089-7 | url = }}

Hyperlocomotion is induced by NMDA receptor antagonists and dissociative hallucinogens such as phencyclidine (PCP), ketamine, and dizocilpine (MK-801). These drugs likewise induce stereotypies.

Non-selective muscarinic acetylcholine receptor antagonists, or antimuscarinics, such as atropine, hyoscyamine, and scopolamine, produce robust hyperactivity in animals, but also produce deliriant effects such as amnesia and hallucinations in both animals and humans.{{cite journal | vauthors = Volgin AD, Yakovlev OA, Demin KA, Alekseeva PA, Kyzar EJ, Collins C, Nichols DE, Kalueff AV | title = Understanding Central Nervous System Effects of Deliriant Hallucinogenic Drugs through Experimental Animal Models | journal = ACS Chem Neurosci | volume = 10 | issue = 1 | pages = 143–154 | date = January 2019 | pmid = 30252437 | doi = 10.1021/acschemneuro.8b00433 | url = }}{{cite journal | vauthors = Lakstygal AM, Kolesnikova TO, Khatsko SL, Zabegalov KN, Volgin AD, Demin KA, Shevyrin VA, Wappler-Guzzetta EA, Kalueff AV | title = DARK Classics in Chemical Neuroscience: Atropine, Scopolamine, and Other Anticholinergic Deliriant Hallucinogens | journal = ACS Chem Neurosci | volume = 10 | issue = 5 | pages = 2144–2159 | date = May 2019 | pmid = 30566832 | doi = 10.1021/acschemneuro.8b00615 | url = }}

Tetrahydrocannabinol (THC) produces hypolocomotion in rodents.{{cite journal | vauthors = Calapai F, Cardia L, Calapai G, Di Mauro D, Trimarchi F, Ammendolia I, Mannucci C | title = Effects of Cannabidiol on Locomotor Activity | journal = Life (Basel) | volume = 12 | issue = 5 | date = April 2022 | page = 652 | pmid = 35629320 | pmc = 9144881 | doi = 10.3390/life12050652 | doi-access = free | bibcode = 2022Life...12..652C | url = }} Cannabidiol (CBD) does not appear to affect locomotor activity when administered by itself or when added to THC. However, in some studies, CBD augmented THC-induced hypolocomotion.

Classical opioids or μ-opioid receptor agonists like morphine and fentanyl stimulate locomotor activity in rodents.{{cite journal | vauthors = Steidl S, Wasserman DI, Blaha CD, Yeomans JS | title = Opioid-induced rewards, locomotion, and dopamine activation: A proposed model for control by mesopontine and rostromedial tegmental neurons | journal = Neurosci Biobehav Rev | volume = 83 | issue = | pages = 72–82 | date = December 2017 | pmid = 28951251 | pmc = 5730464 | doi = 10.1016/j.neubiorev.2017.09.022 | url = }}{{cite journal | vauthors = Fujita M, Ide S, Ikeda K | title = Opioid and nondopamine reward circuitry and state-dependent mechanisms | journal = Ann N Y Acad Sci | volume = 1451 | issue = 1 | pages = 29–41 | date = September 2019 | pmid = 29512887 | doi = 10.1111/nyas.13605 | bibcode = 2019NYASA1451...29F | url = }}{{cite journal | vauthors = Santos EJ, Banks ML, Negus SS | title = Role of Efficacy as a Determinant of Locomotor Activation by Mu Opioid Receptor Ligands in Female and Male Mice | journal = J Pharmacol Exp Ther | volume = 382 | issue = 1 | pages = 44–53 | date = July 2022 | pmid = 35489781 | pmc = 9341253 | doi = 10.1124/jpet.121.001045 | url = }} However, high doses of μ-opioid receptor agonists induce locomotor depression.{{cite journal | vauthors = Shaykin JD, Denehy ED, Martin JR, Chandler CM, Luo D, Taylor CE, Sunshine MD, Turner JR, Alilain WJ, Prisinzano TE, Bardo MT | title = Targeting α1- and α2-adrenergic receptors as a countermeasure for fentanyl-induced locomotor and ventilatory depression | journal = Environ Toxicol Pharmacol | volume = 110 | issue = | pages = 104527 | date = September 2024 | pmid = 39106924 | doi = 10.1016/j.etap.2024.104527 | pmc = 11423298 | pmc-embargo-date = September 1, 2025 | url = }} δ-Opioid receptor agonists like AZD-2327 likewise stimulate locomotor activity in rodents.{{cite journal | vauthors = Broom DC, Jutkiewicz EM, Rice KC, Traynor JR, Woods JH | title = Behavioral effects of delta-opioid receptor agonists: potential antidepressants? | journal = Jpn J Pharmacol | volume = 90 | issue = 1 | pages = 1–6 | date = September 2002 | pmid = 12396021 | doi = 10.1254/jjp.90.1 | url = | doi-access = free }}{{cite book | vauthors = Dripps IJ, Jutkiewicz EM | title = Delta Opioid Receptor Pharmacology and Therapeutic Applications | chapter = Delta Opioid Receptors and Modulation of Mood and Emotion | volume = 247 | pages = 179–197 | date = 2018 | pmid = 28993835 | doi = 10.1007/164_2017_42 | isbn = 978-3-319-95131-7 | series = Handbook of Experimental Pharmacology }}

The trace amine-associated receptor 1 (TAAR1) regulates the monoaminergic system and is a biological target for trace amines like β-phenethylamine and tyramine, the thyronamine 3-iodothyronamine, and drugs like amphetamines.{{cite journal | vauthors = Gainetdinov RR, Hoener MC, Berry MD | title = Trace Amines and Their Receptors | journal = Pharmacol Rev | volume = 70 | issue = 3 | pages = 549–620 | date = July 2018 | pmid = 29941461 | doi = 10.1124/pr.117.015305 | url = | doi-access = free }}{{cite journal | vauthors = Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME | title = In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1 | journal = J Pharmacol Exp Ther | volume = 357 | issue = 1 | pages = 134–144 | date = April 2016 | pmid = 26791601 | doi = 10.1124/jpet.115.229765 | url = https://web.archive.org/web/20250509235235/https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA}}

TAAR1 knockout mice show unchanged basal locomotor activity.{{cite journal | vauthors = Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, Bettler B, Wettstein JG, Borroni E, Moreau JL, Hoener MC | title = Trace amine-associated receptor 1 modulates dopaminergic activity | journal = J Pharmacol Exp Ther | volume = 324 | issue = 3 | pages = 948–956 | date = March 2008 | pmid = 18083911 | doi = 10.1124/jpet.107.132647 | url = }} However, they show enhanced hyperlocomotion with amphetamine, methamphetamine, and MDMA, as well as with β-phenethylamine.{{cite journal | vauthors = Halff EF, Rutigliano G, Garcia-Hidalgo A, Howes OD | title = Trace amine-associated receptor 1 (TAAR1) agonism as a new treatment strategy for schizophrenia and related disorders | journal = Trends Neurosci | volume = 46 | issue = 1 | pages = 60–74 | date = January 2023 | pmid = 36369028 | doi = 10.1016/j.tins.2022.10.010 | url = | quote = In addition to enhanced dopamine release, TAAR1-KO mice show enhanced hyperlocomotion in response to psychostimulant drugs including amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) [19,20,41,55], as well as to drugs that increase monoamine levels, such as MAO inhibitors [56]. By contrast, TAAR1-OE animals are hyposensitive to the stimulatory effects of amphetamine [54] in comparison to wild-type animals. [...] Three TAAR1 full agonists, RO5166017, RO5256390, and SEP-363856, were all able to prevent psychostimulant-induced hyperlocomotion in wild-type but not TAAR1-KO mice [47,78,79]. | doi-access = free }}{{cite journal | vauthors = Di Cara B, Maggio R, Aloisi G, Rivet JM, Lundius EG, Yoshitake T, Svenningsson P, Brocco M, Gobert A, De Groote L, Cistarelli L, Veiga S, De Montrion C, Rodriguez M, Galizzi JP, Lockhart BP, Cogé F, Boutin JA, Vayer P, Verdouw PM, Groenink L, Millan MJ | title = Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA) | journal = J Neurosci | volume = 31 | issue = 47 | pages = 16928–16940 | date = November 2011 | pmid = 22114263 | pmc = 6623861 | doi = 10.1523/JNEUROSCI.2502-11.2011 | url = }}{{cite journal | vauthors = Wolinsky TD, Swanson CJ, Smith KE, Zhong H, Borowsky B, Seeman P, Branchek T, Gerald CP | title = The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia | journal = Genes Brain Behav | volume = 6 | issue = 7 | pages = 628–639 | date = October 2007 | pmid = 17212650 | doi = 10.1111/j.1601-183X.2006.00292.x | url = | quote = Most notably, Caron & Gainetdinov (personal communication) have recently observed that group-housed TA1 KO mice show enhanced sensitivity to the locomotor stimulating effects of both amphetamine and b-PEA relative to group-housed WT littermates, as well as normal habituation to an open field. }} TAAR1 overexpression likewise is associated with unchanged basal locomotor activity.{{cite journal | vauthors = Pei Y, Asif-Malik A, Canales JJ | title = Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications | journal = Front Neurosci | volume = 10 | issue = | pages = 148 | date = 2016 | pmid = 27092049 | pmc = 4820462 | doi = 10.3389/fnins.2016.00148 | doi-access = free | url = }} However, overexpression of the TAAR1 results in only weak locomotor stimulation by amphetamine.{{cite journal | vauthors = Wu R, Li JX | title = Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders | journal = CNS Drugs | volume = 35 | issue = 12 | pages = 1239–1248 | date = December 2021 | pmid = 34766253 | pmc = 8787759 | doi = 10.1007/s40263-021-00871-4 | url = }}{{cite journal | vauthors = Revel FG, Meyer CA, Bradaia A, Jeanneau K, Calcagno E, André CB, Haenggi M, Miss MT, Galley G, Norcross RD, Invernizzi RW, Wettstein JG, Moreau JL, Hoener MC | title = Brain-specific overexpression of trace amine-associated receptor 1 alters monoaminergic neurotransmission and decreases sensitivity to amphetamine | journal = Neuropsychopharmacology | volume = 37 | issue = 12 | pages = 2580–2592 | date = November 2012 | pmid = 22763617 | pmc = 3473323 | doi = 10.1038/npp.2012.109 | url = }} The TAAR1 full agonists RO5256390, ulotaront (SEP-363856), and LK00764 have been found to suppress locomotion in mice.{{cite journal | vauthors = Shabani S, Houlton S, Ghimire B, Tonello D, Reed C, Baba H, Aldrich S, Phillips TJ | title = Robust aversive effects of trace amine-associated receptor 1 activation in mice | journal = Neuropsychopharmacology | volume = 48 | issue = 10 | pages = 1446–1454 | date = September 2023 | pmid = 37055488 | pmc = 10425385 | doi = 10.1038/s41386-023-01578-4 | url = }}{{cite journal | vauthors = Kuvarzin SR, Sukhanov I, Onokhin K, Zakharov K, Gainetdinov RR | title = Unlocking the Therapeutic Potential of Ulotaront as a Trace Amine-Associated Receptor 1 Agonist for Neuropsychiatric Disorders | journal = Biomedicines | volume = 11 | issue = 7 | date = July 2023 | page = 1977 | pmid = 37509616 | pmc = 10377193 | doi = 10.3390/biomedicines11071977 | doi-access = free | url = }} Conversely, the TAAR1 full agonist RO5166017{{cite journal | vauthors = Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, Durkin S, Zbinden KG, Norcross R, Meyer CA, Metzler V, Chaboz S, Ozmen L, Trube G, Pouzet B, Bettler B, Caron MG, Wettstein JG, Hoener MC | title = TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity | journal = Proc Natl Acad Sci U S A | volume = 108 | issue = 20 | pages = 8485–8490 | date = May 2011 | pmid = 21525407 | pmc = 3101002 | doi = 10.1073/pnas.1103029108 | doi-access = free | bibcode = 2011PNAS..108.8485R | url = }}{{cite journal | vauthors = Liu J, Wu R, Seaman R, Manz KM, Johnson B, Vu J, Huang Y, Zhang Y, Robison AJ, Neve R, Grueter BA, Dietz D, Li JX | title = TAAR1 regulates drug-induced reinstatement of cocaine-seeking via negatively modulating CaMKIIα activity in the NAc | journal = Mol Psychiatry | volume = 27 | issue = 4 | pages = 2136–2145 | date = April 2022 | pmid = 35079125 | pmc = 9829124 | doi = 10.1038/s41380-022-01448-3 | url = }} and the TAAR1 partial agonists RO5073012, RO5203648,{{cite journal | vauthors = Revel FG, Moreau JL, Gainetdinov RR, Ferragud A, Velázquez-Sánchez C, Sotnikova TD, Morairty SR, Harmeier A, Groebke Zbinden K, Norcross RD, Bradaia A, Kilduff TS, Biemans B, Pouzet B, Caron MG, Canales JJ, Wallace TL, Wettstein JG, Hoener MC | title = Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics | journal = Biol Psychiatry | volume = 72 | issue = 11 | pages = 934–942 | date = December 2012 | pmid = 22705041 | doi = 10.1016/j.biopsych.2012.05.014 | url = | quote = Psychostimulants like cocaine and d-amphetamine interact with the DA transporter (DAT) to elevate extracellular DA concentration. In rodents, this translates into excessive [locomotor activity (LMA)] (Figures 2A, B; Figure S3A, B in Supplement 1), the reversal of which can be used to predict the potential antipsychotic activity of drugs (22). RO5203648 given orally reduced hyperlocomotion in both rats and mice treated with cocaine (Figure 2A, B), although not at the highest dose in mice (10 mg/kg). RO5203648 reduced d-amphetamine-induced hyperlocomotion by one half at a high dose (30 mg/kg) in rats, whereas in mice it had no effect at the doses tested (Figure S3A, B in Supplement 1). }} and RO5263397 on their own did not affect basal locomotion in rodents.{{cite journal | vauthors = Thorn DA, Jing L, Qiu Y, Gancarz-Kausch AM, Galuska CM, Dietz DM, Zhang Y, Li JX | title = Effects of the trace amine-associated receptor 1 agonist RO5263397 on abuse-related effects of cocaine in rats | journal = Neuropsychopharmacology | volume = 39 | issue = 10 | pages = 2309–2316 | date = September 2014 | pmid = 24743376 | pmc = 4138753 | doi = 10.1038/npp.2014.91 | url = }}{{cite journal | vauthors = Jing L, Zhang Y, Li JX | title = Effects of the trace amine associated receptor 1 agonist RO5263397 on abuse-related behavioral indices of methamphetamine in rats | journal = Int J Neuropsychopharmacol | volume = 18 | issue = 4 | pages = pyu060| date = October 2014 | pmid = 25522401 | pmc = 4360231 | doi = 10.1093/ijnp/pyu060 | url = }}{{cite journal | vauthors = Black SW, Schwartz MD, Chen TM, Hoener MC, Kilduff TS | title = Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics | journal = Biol Psychiatry | volume = 82 | issue = 9 | pages = 623–633 | date = November 2017 | pmid = 27919403 | pmc = 5395352 | doi = 10.1016/j.biopsych.2016.10.012 | url = }} Similarly, the TAAR1 partial agonist RO5263397 did not affect locomotor activity in monkeys.{{cite journal | vauthors = Goonawardena AV, Morairty SR, Dell R, Orellana GA, Hoener MC, Wallace TL, Kilduff TS | title = Trace amine-associated receptor 1 agonism promotes wakefulness without impairment of cognition in Cynomolgus macaques | journal = Neuropsychopharmacology | volume = 44 | issue = 8 | pages = 1485–1493 | date = July 2019 | pmid = 30954024 | pmc = 6784974 | doi = 10.1038/s41386-019-0386-8 | url = }} The TAAR1 antagonist EPPTB does not affect basal locomotor activity in rodents.{{cite journal | vauthors = Raony Í, Domith I, Lourenco MV, Paes-de-Carvalho R, Pandolfo P | title = Trace amine-associated receptor 1 modulates motor hyperactivity, cognition, and anxiety-like behavior in an animal model of ADHD | journal = Prog Neuropsychopharmacol Biol Psychiatry | volume = 117 | issue = | pages = 110555 | date = July 2022 | pmid = 35346791 | doi = 10.1016/j.pnpbp.2022.110555 | url = }}

The TAAR1 full agonists RO5166017, RO5256390, and ulotaront all suppress psychostimulant-induced hyperlocomotion in mice.{{cite journal | vauthors = Dedic N, Dworak H, Zeni C, Rutigliano G, Howes OD | title = Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies | journal = Int J Mol Sci | volume = 22 | issue = 24 | date = December 2021 | page = 13185 | pmid = 34947997 | pmc = 8704992 | doi = 10.3390/ijms222413185 | doi-access = free | url = }}{{cite journal | vauthors = Liu JF, Li JX | title = TAAR1 in Addiction: Looking Beyond the Tip of the Iceberg | journal = Front Pharmacol | volume = 9 | issue = | pages = 279 | date = 2018 | pmid = 29636691 | pmc = 5881156 | doi = 10.3389/fphar.2018.00279 | doi-access = free | url = }} The TAAR1 partial agonists RO5073012, RO5203648, and RO5263397 suppress locomotor stimulation induced by cocaine.{{cite journal | vauthors = Jing L, Li JX | title = Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction | journal = Eur J Pharmacol | volume = 761 | issue = | pages = 345–352 | date = August 2015 | pmid = 26092759 | pmc = 4532615 | doi = 10.1016/j.ejphar.2015.06.019 | url = }}{{cite journal | vauthors = Revel FG, Moreau JL, Pouzet B, Mory R, Bradaia A, Buchy D, Metzler V, Chaboz S, Groebke Zbinden K, Galley G, Norcross RD, Tuerck D, Bruns A, Morairty SR, Kilduff TS, Wallace TL, Risterucci C, Wettstein JG, Hoener MC | title = A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight | journal = Mol Psychiatry | volume = 18 | issue = 5 | pages = 543–556 | date = May 2013 | pmid = 22641180 | doi = 10.1038/mp.2012.57 | url = }} The TAAR1 partial agonist RO5203648 suppressed dextroamphetamine-induced hyperlocomotion at the highest assessed dose in rats but did not affect dextroamphetamine-induced hyperactivity in mice. It showed complex effects on methamphetamine-induced hyperlocomotion in rats, reducing early but potentiating late methamphetamine-induced hyperlocomotion with acute administration and suppressing methamphetamine-induced hyperlocomotion with chronic administration.{{cite journal | vauthors = Cotter R, Pei Y, Mus L, Harmeier A, Gainetdinov RR, Hoener MC, Canales JJ | title = The trace amine-associated receptor 1 modulates methamphetamine's neurochemical and behavioral effects | journal = Front Neurosci | volume = 9 | issue = | pages = 39 | date = 2015 | pmid = 25762894 | doi = 10.3389/fnins.2015.00039 | doi-access = free | pmc = 4327507 | url = }} The dual TAAR1 full agonist and serotonin 5-HT₁ receptor modulator ulotaront did not affect dextroamphetamine-induced hyperlocomotion in rats.{{cite journal | vauthors = Begni V, Sanson A, Luoni A, Sensini F, Grayson B, Munni S, Neill JC, Riva MA | title = Towards Novel Treatments for Schizophrenia: Molecular and Behavioural Signatures of the Psychotropic Agent SEP-363856 | journal = Int J Mol Sci | volume = 22 | issue = 8 | date = April 2021 | page = 4119 | pmid = 33923479 | pmc = 8073823 | doi = 10.3390/ijms22084119 | doi-access = free | url = }} The TAAR1 weak partial agonist RO5073012 did not affect amphetamine-induced hyperlocomotion in mice but substantially restored the locomotor stimulation of amphetamine in mice with TAAR1 overexpression. In an unpublished study, EPPTB was reported to considerably reduce methamphetamine-induced hyperlocomotion in mice chronically exposed to methamphetamine, an effect that was absent in TAAR1 knockout mice.{{cite journal | vauthors = Grandy DK, Miller GM, Li JX | title = "TAARgeting Addiction"--The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference | journal = Drug Alcohol Depend | volume = 159 | issue = | pages = 9–16 | date = February 2016 | pmid = 26644139 | pmc = 4724540 | doi = 10.1016/j.drugalcdep.2015.11.014 | url = | quote = [...] EPPTB’s effect on the spontaneous locomotor activity in a familiar environment displayed by WT and taar1-deficient mice chronically exposed to 3 mg/kg METH (i.p.) over a range of doses was examined. The results of this study (Grandy, 2014; SfN abstracts) support the interpretation that EPPTB prevents to a significant degree METH-stimulated locomotor activity but only in WT mice with a history of chronic METH exposure. }}{{cite conference | vauthors=Grandy DK | title=A G protein-coupled receptor mechanism of action distinguishes methamphetamine from cocaine | conference=Neuroscience 2014 | date=16 November 2014 | url=https://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=5a1aaa25-ae71-43f4-9d64-2dbe6fd43285&cKey=1800b5d6-aafa-471d-9209-7ff2f00ab8c6&mKey=54c85d94-6d69-4b09-afaa-502c0e680ca7 | access-date=6 January 2025 | quote = The TAAR1-selective antagonist EPPTB blocked methamphetamine- and bupropion-stimulated chloride conductance in Xenopous oocytes co-expressing mouse TAAR1 and the human cystic fibrosis transmembrane conductance regulator in a concentration-dependent manner with IC50’s of 2.3±0.3nM and 4.3±0.7nM, respectively. [...] EPPTB displayed no affinity for mouse biogenic amine transporters nor did it produce a significant phenotype in wildtype or taar1-/- mice. In contrast, at the highest dose tested (100 mg/kg, i.p.) EPPTB inhibited approximately 70% of methamphetamine-stimulated (3 mg/kg, i.p.) activity in wildtype mice while having no effect on similarly treated [TAAR1] knockout mice. Intraperitoneal co-administration of methamphetamine (3 mg/kg) and bupropion (50 mg/kg) to wildtype mice produced greater activity than either drug alone, an effect absent from [TAAR1] knockout mice. [...] The existence of a methamphetamine-activated G protein-coupled receptor that is also activated by bupropion [...] }} The TAAR1 full agonists RO5166017, RO5256390, ulotaront, and LK00764 and the TAAR1 partial agonists RO5203648 and RO5263397 suppress the hyperlocomotion induced by NMDA receptor antagonists like phencyclidine (PCP), L-687,414, and dizocilpine (MK-801) in rodents.{{cite journal | vauthors = Dedic N, Jones PG, Hopkins SC, Lew R, Shao L, Campbell JE, Spear KL, Large TH, Campbell UC, Hanania T, Leahy E, Koblan KS | title = SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action | journal = J Pharmacol Exp Ther | volume = 371 | issue = 1 | pages = 1–14 | date = October 2019 | pmid = 31371483 | doi = 10.1124/jpet.119.260281 | url = | doi-access = free }}{{cite journal | vauthors = Krasavin M, Lukin A, Sukhanov I, Gerasimov AS, Kuvarzin S, Efimova EV, Dorofeikova M, Nichugovskaya A, Matveev A, Onokhin K, Zakharov K, Gureev M, Gainetdinov RR | title = Discovery of Trace Amine Associated Receptor 1 (TAAR1) Agonist 2-(5-(4'-Chloro-[1,1'-biphenyl]-4-yl)-4H-1,2,4-triazol-3-yl)ethan-1-amine (LK00764) for the Treatment of Psychotic Disorders | journal = Biomolecules | volume = 12 | issue = 11 | pages = | date = November 2022 | pmid = 36359001 | pmc = 9687812 | doi = 10.3390/biom12111650 | doi-access = free | url = }}

Many tricyclic antidepressants (TCAs) do not increase locomotion, and instead often actually show behavioral sedation.{{cite journal | vauthors = File SE, Tucker JC | title = Behavioral consequences of antidepressant treatment in rodents | journal = Neurosci Biobehav Rev | volume = 10 | issue = 2 | pages = 123–134 | date = 1986 | pmid = 3526203 | doi = 10.1016/0149-7634(86)90023-0 | url = }}

Light exposure has been found to increase locomotor activity and exploratory behavior in rodents.{{cite journal | vauthors = Amato D, Pum ME, Groos D, Lauber AC, Huston JP, Carey RJ, de Souza Silva MA, Müller CP | title = Neuropharmacology of light-induced locomotor activation | journal = Neuropharmacology | volume = 95 | issue = | pages = 243–251 | date = August 2015 | pmid = 25842246 | doi = 10.1016/j.neuropharm.2015.03.023 | url = | quote = It was found that visual stimulation of rats with white-light of 82 lux intensity induced locomotor activity and increased extracellular 5-HT and dopamine (DA) levels in the visual cortex (Müller et al., 2007a; Müller and Huston, 2007) and 5-HT in the medial prefrontal cortex (Pum et al., 2008). The 5-HT and DA increase were also seen in anesthetized animals (Pum et al., 2008). Cocaine, which induces serotonergic and dopaminergic activation (Izenwasser et al., 1990; Müller and Homberg, 2015), potentiates [light-induced locomotor activity (LIA)] (Pum et al., 2011). }}

Other similar behavioral measures include stereotypy, exploratory behavior, climbing behavior, and jumping behavior.{{cite book | vauthors = McCarson KE | title = Transgenic Mouse | chapter = Strategies for Behaviorally Phenotyping the Transgenic Mouse | series = Methods Mol Biol | volume = 2066 | pages = 171–194 | date = 2020 | pmid = 31512217 | doi = 10.1007/978-1-4939-9837-1_15 | isbn = 978-1-4939-9836-4 | chapter-url = }} Amphetamines, which are dopamine releasing agents (DRAs) induce stereotypies in addition to hyperlocomotion. The dopamine receptor agonist apomorphine induces stereotypy and climbing behavior. The dopamine precursor levodopa (L-DOPA) induces jumping behavior. These effects can all be reversed by antipsychotics, which are dopamine receptor antagonists.

• Open field (animal test)
• Conditioned avoidance response test
• Animal models of schizophrenia
• Dopamine hypothesis of schizophrenia

{{Reflist}}

{{Psychology}}

{{Pharmacology}}

Category:Animal testing techniques

Category:Neuroscience of schizophrenia

Category:Psychology experiments

Category:Schizophrenia research

Category:Symptoms and signs of mental disorders