Conditioned avoidance response test#Test of other drug effects

There are several variations of the CAR test.{{cite book | last1=Castagné | first1=Vincent | last2=Moser | first2=Paul C. | last3=Porsolt | first3=Roger D. | title=Advances in Pharmacology | chapter=Preclinical Behavioral Models for Predicting Antipsychotic Activity | publisher=Elsevier | year=2009 | volume=57 | issn=1054-3589 | doi=10.1016/s1054-3589(08)57010-4 | pages=381–418| pmid=20230767 | isbn=978-0-12-378642-5 }} The most common form of the test is the two-way active avoidance test (also known as the two-way discriminated shuttle box procedure). Other variations of the test include the one-way active avoidance test (also known as the one-way discriminated pole jump procedure or the pole-jumping test) and the non-discriminated operant continuous avoidance procedure (also known as the continuous avoidance test, the Sidman avoidance test, or simply the Sidman procedure).

In the two-way active avoidance test, an animal is placed in a two-compartment shuttle box with an open doorway. Then, the animal is trained to avoid an aversive stimulus (unconditioned stimulus), usually an electric footshock, on presentation of a neutral stimulus (conditioned stimulus), usually an auditory or visual stimulus like a tone or light, that shortly precedes it.{{cite journal | vauthors = Forrest AD, Coto CA, Siegel SJ | title = Animal Models of Psychosis: Current State and Future Directions | journal = Curr Behav Neurosci Rep | volume = 1 | issue = 2 | pages = 100–116 | date = June 2014 | pmid = 25215267 | doi = 10.1007/s40473-014-0013-2 | pmc = 4157659 | url = }} The animal does this by performing a specific behavioral response, like moving to the other compartment of the box, and this response is referred to as "avoidance" or "conditioned avoidance". If the animal is late in performing the avoidance, the aversive stimulus is presented until the animal responds by moving to the compartment. This is referred to as "escape". If the animal does not escape within a certain amount of time, it is designated "escape failure". As such, there are three variables that can be measured in the CAR test: avoidance, escape, and escape failure.

Drugs that are considered to show antipsychotic-like effects selectively suppress the avoidance response without affecting escape behavior. Conversely, drugs that are not considered to have antipsychotic-like effects either have no effect in the CAR test or suppress both avoidance behavior and escape behavior at the same doses. Examples of drugs that inhibit both avoidance and escape responses include sedatives like benzodiazepines, barbiturates, and meprobamate and antidepressants like many tricyclic antidepressants (TCAs).

The CAR test is considered to have high predictive validity in the identification of potential antipsychotics and is frequently used in drug development. However, its face validity and construct validity have been described as low or absent. Moreover, a described major limitation of the model is that drugs active in the test work by impairing a normal self-preservation function; that is, avoiding an unpleasant or painful stimulus.

Another limitation of the CAR test is that selective suppression of avoidance responses by drugs is procedure-specific. In procedures besides the one-way discriminated pole jump procedure and the two-way active avoidance test, such as the Sidman procedure, antipsychotics block avoidance behavior and escapes at almost the same doses. Conversely, benzodiazepines selectively suppress avoidance behavior without affecting escape behavior in the Sidman procedure. This is opposite to what is generally described as reflecting antipsychotic-like activity. Hence, selective suppression of avoidance responses is not a specific predictor of antipsychotic efficacy, or at best, selective suppression of avoidance responses as a predictor of antipsychotic activity is dependent on the specific CAR procedure employed.

The test can detect antipsychotic-like activity both in the case of dopamine D₂ receptor antagonists and in the case of drugs lacking D₂ receptor antagonism.{{cite journal | vauthors = Rowley M, Bristow LJ, Hutson PH | title = Current and novel approaches to the drug treatment of schizophrenia | journal = J Med Chem | volume = 44 | issue = 4 | pages = 477–501 | date = February 2001 | pmid = 11170639 | doi = 10.1021/jm0002432 | url = }} The occupancy of the D₂ receptor by antagonists of this receptor required to inhibit the CAR is around 65 to 80%, which is similar to the occupancy at which therapeutic antipsychotic effects occur in humans with these drugs. Both typical antipsychotics and atypical antipsychotics are active in the CAR test. Similarly to dopamine D₂ receptor antagonists, dopamine depleting agents like reserpine and tetrabenazine suppress conditioned avoidance responses and hence are active in the CAR test.

Selective serotonin 5-HT_2A receptor antagonists like volinanserin (MDL-100907) and ritanserin can enhance the suppression of conditioned avoidance responses by dopamine D₂ receptor antagonists. Serotonin 5-HT_1A receptor agonism, for instance with buspirone, 8-OH-DPAT, or antipsychotics with concomitant 5-HT_1A receptor agonism, may also enhance suppression of conditioned avoidance responses.{{cite journal | last1=Yocca | first1=Frank | last2=Altar | first2=C. Anthony | title=Partial agonism of dopamine, serotonin and opiate receptors for psychiatry | journal=Drug Discovery Today: Therapeutic Strategies | publisher=Elsevier BV | volume=3 | issue=4 | year=2006 | issn=1740-6773 | doi=10.1016/j.ddstr.2006.10.014 | pages=429–435}}{{cite journal | vauthors = Newman-Tancredi A, Kleven MS | title = Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties | journal = Psychopharmacology (Berl) | volume = 216 | issue = 4 | pages = 451–473 | date = August 2011 | pmid = 21394633 | doi = 10.1007/s00213-011-2247-y | url = }} Dopamine D₂ receptor partial agonists like aripiprazole, brexpiprazole, and bifeprunox suppress conditioned avoidance responses in the CAR test similarly to dopamine D₂ receptor antagonists.{{cite journal | vauthors = Aftab A, Gao K | title = The preclinical discovery and development of brexpiprazole for the treatment of major depressive disorder | journal = Expert Opin Drug Discov | volume = 12 | issue = 10 | pages = 1067–1081 | date = October 2017 | pmid = 28718334 | doi = 10.1080/17460441.2017.1354849 | url = }}

Other drugs that may produce or enhance suppression of conditioned avoidance responses include serotonin 5-HT_2C receptor agonists like CP-809101, WAY-163909, and meta-chlorophenylpiperazine (mCPP); α₁-adrenergic receptor antagonists like prazosin; α₂-adrenergic receptor antagonists like idazoxan; norepinephrine reuptake inhibitors like reboxetine;{{cite journal | vauthors = Linnér L, Wiker C, Wadenberg ML, Schalling M, Svensson TH | title = Noradrenaline reuptake inhibition enhances the antipsychotic-like effect of raclopride and potentiates D2-blockage-induced dopamine release in the medial prefrontal cortex of the rat | journal = Neuropsychopharmacology | volume = 27 | issue = 5 | pages = 691–698 | date = November 2002 | pmid = 12431844 | doi = 10.1016/S0893-133X(02)00350-0 | url = }} acetylcholinesterase inhibitors (and hence indirect cholinergics) like galantamine;{{cite journal | vauthors = Wadenberg ML, Fjällström AK, Federley M, Persson P, Stenqvist P | title = Effects of adjunct galantamine to risperidone, or haloperidol, in animal models of antipsychotic activity and extrapyramidal side-effect liability: involvement of the cholinergic muscarinic receptor | journal = Int J Neuropsychopharmacol | volume = 14 | issue = 5 | pages = 644–654 | date = June 2011 | pmid = 20701827 | doi = 10.1017/S1461145710000921 | url = }} the muscarinic acetylcholine receptor agonist xanomeline (used clinically as xanomeline/trospium);{{cite journal | vauthors = Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC | title = Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia | journal = Am J Psychiatry | volume = 179 | issue = 9 | pages = 611–627 | date = September 2022 | pmid = 35758639 | doi = 10.1176/appi.ajp.21101083 | url = }}{{cite journal | vauthors = Mirza NR, Peters D, Sparks RG | title = Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists | journal = CNS Drug Rev | volume = 9 | issue = 2 | pages = 159–186 | date = 2003 | pmid = 12847557 | doi = 10.1111/j.1527-3458.2003.tb00247.x | pmc = 6741650 | url = }} κ-opioid receptor agonists like spiradoline;{{cite journal | last=Wadenberg | first=M-L. G. | title=A Review of the Properties of Spiradoline: A Potent and Selective k-Opioid Receptor Agonist | journal=CNS Drug Reviews | publisher=Wiley | volume=9 | issue=2 | year=2003 | issn=1080-563X | doi=10.1111/j.1527-3458.2003.tb00248.x | doi-access=free | pages=187–198| pmid=12847558 | pmc=6741666 }} AMPA receptor antagonists like GYKI-52466 and tezampanel (LY-326325); metabotropic glutamate mGlu₂ and mGlu₃ receptor agonists like pomaglumetad (LY-404039); and phosphodiesterase inhibitors like the PDE4 inhibitor rolipram and the PDE10A inhibitors papaverine, mardepodect (PF-2545920), and balipodect (TAK-063).{{cite journal | vauthors = Svensson TH | title = Dysfunctional brain dopamine systems induced by psychotomimetic NMDA-receptor antagonists and the effects of antipsychotic drugs | journal = Brain Res Brain Res Rev | volume = 31 | issue = 2–3 | pages = 320–329 | date = March 2000 | pmid = 10719159 | doi = 10.1016/s0165-0173(99)00048-x | url = }}{{cite journal | vauthors = Neef J, Palacios DS | title = Progress in mechanistically novel treatments for schizophrenia | journal = RSC Med Chem | volume = 12 | issue = 9 | pages = 1459–1475 | date = September 2021 | pmid = 34671731 | doi = 10.1039/d1md00096a | pmc = 8459322 | url = }}

Dopamine D₁ receptor antagonists have either shown no effect in the CAR, for instance ecopipam (SCH-39166), or have inhibited both avoidance and escape responses at the same doses, such as SCH-23390. However, different findings have also been reported, for instance ecopipam being effective in the CAR test.{{cite journal | vauthors = Barnett A, McQuade RD, Tedford C | title = Highlights of D1 dopamine receptor antagonist research | journal = Neurochem Int | volume = 20 Suppl | issue = | pages = 119S–122S | date = March 1992 | pmid = 1365409 | doi = 10.1016/0197-0186(92)90223-e | url = }} In contrast to dopamine D₂ receptor antagonists, clinical trials of dopamine D₁ receptor antagonists, including ecopipam and NNC 01-0687, have found that they were ineffective in the treatment of psychosis.{{cite journal | vauthors = Fleischhacker WW | title = New drugs for the treatment of schizophrenic patients | journal = Acta Psychiatr Scand Suppl | volume = 388 | issue = | pages = 24–30 | date = 1995 | pmid = 7604735 | doi = 10.1111/j.1600-0447.1995.tb05941.x | url = }}{{cite journal | vauthors = Arnt J, Skarsfeldt T | title = Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence | journal = Neuropsychopharmacology | volume = 18 | issue = 2 | pages = 63–101 | date = February 1998 | pmid = 9430133 | doi = 10.1016/S0893-133X(97)00112-7 | url = }}

Various antidepressants, like tricyclic antidepressants (TCAs) as well as the selective serotonin reuptake inhibitor (SSRI) fluoxetine, reduce both avoidance and escape responses in the CAR test and hence are not considered to be active since they are not selective for avoidance responses.{{cite journal | vauthors = Lucki I, Nobler MS | title = The acute effects of antidepressant drugs on the performance of conditioned avoidance behavior in rats | journal = Pharmacol Biochem Behav | volume = 22 | issue = 2 | pages = 261–264 | date = February 1985 | pmid = 3983218 | doi = 10.1016/0091-3057(85)90388-0 | url = }}

Dopaminergic agents, like the dopamine precursor levodopa (L-DOPA), the dopamine releasing agents amphetamine and methamphetamine, the dopamine reuptake inhibitors methylphenidate, bupropion, and nomifensine, the non-selective dopamine receptor agonist apomorphine, and the indirect dopaminergic agent amantadine, can all markedly reverse the effects of drugs like reserpine that are active in the CAR test and restore conditioned avoidance responses.{{cite journal | vauthors = Nakagawa T, Ukai K, Ohyama T, Gomita Y, Okamura H | title = Effects of dopaminergic agents on reversal of reserpine-induced impairment in conditioned avoidance response in rats | journal = Pharmacol Biochem Behav | volume = 58 | issue = 4 | pages = 829–836 | date = December 1997 | pmid = 9408183 | doi = 10.1016/s0091-3057(97)98984-x | hdl = 20.500.14094/D2002397 | url = | hdl-access = free }}{{cite journal | last1=Voith | first1=K. | last2=Herr | first2=F. | title=The effect of various antidepressant drugs upon the tetrabenazine-suppressed conditioned avoidance response in rats | journal=Psychopharmacologia | publisher=Springer Science and Business Media LLC | volume=20 | issue=3 | year=1971 | issn=0033-3158 | doi=10.1007/bf00402101 | pages=253–265| pmid=5565256 }} Selective dopamine D₁ receptor agonists. like SKF-38,393, and selective dopamine D₂ receptor agonists, like quinpirole, are only weakly effective in reversing the effects of reserpine in suppressing conditioned avoidance responses when given individually. However, they are synergistic and robustly effective when administered in combination. Similarly, anticholinergics like atropine and scopolamine increase rates of conditioned avoidance responses. In contrast to dopaminergic agents, non-dopaminergic antidepressants, like many tricyclic antidepressants (TCAs), are generally ineffective in antagonizing agents that are active in the test.

The effects of drugs that are active in the CAR test, suppression of conditioned avoidance responses without affecting escape behavior, are thought to be mediated specifically by modulation of signaling in the nucleus accumbens shell or ventral striatum, part of the mesolimbic pathway.{{cite journal | vauthors = Tang J, Yang C, Shi M, Chen W | title = Activation of dopamine D2 receptors in the shell of nucleus accumbens triggers conditioned avoidance responses in rats | journal = Behav Brain Res | volume = 422 | issue = | pages = 113759 | date = March 2022 | pmid = 35051488 | doi = 10.1016/j.bbr.2022.113759 | url = }} This area of the brain plays a major role in behavioral activation and in appetitive and aversive motivational processes.{{cite book | vauthors = Salamone JD, Pardo M, Yohn SE, López-Cruz L, SanMiguel N, Correa M | title = Behavioral Neuroscience of Motivation | chapter = Mesolimbic Dopamine and the Regulation of Motivated Behavior | series = Current Topics in Behavioral Neurosciences | volume = 27 | pages = 231–257 | date = 2016 | pmid = 26323245 | doi = 10.1007/7854_2015_383 | isbn = 978-3-319-26933-7 | chapter-url = }}{{cite journal | vauthors = Salamone JD, Correa M | title = The Neurobiology of Activational Aspects of Motivation: Exertion of Effort, Effort-Based Decision Making, and the Role of Dopamine | journal = Annu Rev Psychol | volume = 75 | issue = | pages = 1–32 | date = January 2024 | pmid = 37788571 | doi = 10.1146/annurev-psych-020223-012208 | url = | hdl = 10234/207207 | hdl-access = free }}{{cite journal | vauthors = Salamone JD, Correa M, Ferrigno S, Yang JH, Rotolo RA, Presby RE | title = The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation | journal = Pharmacol Rev | volume = 70 | issue = 4 | pages = 747–762 | date = October 2018 | pmid = 30209181 | doi = 10.1124/pr.117.015107 | pmc = 6169368 | url = }}{{cite journal | vauthors = Salamone JD, Correa M | title = The mysterious motivational functions of mesolimbic dopamine | journal = Neuron | volume = 76 | issue = 3 | pages = 470–485 | date = November 2012 | pmid = 23141060 | doi = 10.1016/j.neuron.2012.10.021 | pmc = 4450094 | url = }} Drugs active in the CAR test may work by dampening behavioral responses to motivationally salient stimuli.{{cite journal | vauthors = Kapur S, Agid O, Mizrahi R, Li M | title = How antipsychotics work-from receptors to reality | journal = NeuroRx | volume = 3 | issue = 1 | pages = 10–21 | date = January 2006 | pmid = 16490410 | doi = 10.1016/j.nurx.2005.12.003 | pmc = 3593357 | url = }}

Some academics, such as Joanna Moncrieff and David Healy, maintain that antipsychotics do not actually directly treat psychotic symptoms or delusions, but rather simply induce a state of psychic indifference or blunted emotions and resultant behavioral suppression (e.g., of agitation), thereby helping to reduce the functional consequences of psychotic symptoms.{{cite journal | vauthors = Thompson J, Stansfeld JL, Cooper RE, Morant N, Crellin NE, Moncrieff J | title = Experiences of taking neuroleptic medication and impacts on symptoms, sense of self and agency: a systematic review and thematic synthesis of qualitative data | journal = Soc Psychiatry Psychiatr Epidemiol | volume = 55 | issue = 2 | pages = 151–164 | date = February 2020 | pmid = 31875238 | doi = 10.1007/s00127-019-01819-2 | url = | doi-access = free }}{{cite book | last1=Belmaker | first1=Robert Haim | last2=Lichtenberg | first2=Pesach | title=Psychopharmacology Reconsidered: A Concise Guide Exploring the Limits of Diagnosis and Treatment | chapter=Antipsychotic Drugs: Do They Define Schizophrenia or Do They Blunt All Emotions? | publisher=Springer International Publishing | publication-place=Cham | date=2023 | isbn=978-3-031-40370-5 | doi=10.1007/978-3-031-40371-2_6 | pages=63–84}}{{cite book | last = Moncrieff | first = Joanna | chapter = What Do Neuroleptics Really Do? A Drug-Centred Account | pages = 100–117 | title = The Myth of the Chemical Cure: A Critique of Psychiatric Drug Treatment | date = 2007 | publisher = Palgrave Macmillan London | isbn = 978-0-230-57431-1 | doi = 10.1007/978-0-230-58944-5_7 | doi-broken-date = 1 November 2024 | url = }}{{cite book | last=Moncrieff | first=Joanna | title=The Bitterest Pills | chapter=The Patient's Dilemma: Other Evidence on the Effects of Antipsychotics | publisher=Palgrave Macmillan UK | publication-place=London | date=2013 | isbn=978-1-137-27743-5 | doi=10.1057/9781137277442_7 | pages=113–131}}{{cite journal | vauthors = Moncrieff J, Cohen D, Mason JP | title = The subjective experience of taking antipsychotic medication: a content analysis of Internet data | journal = Acta Psychiatr Scand | volume = 120 | issue = 2 | pages = 102–111 | date = August 2009 | pmid = 19222405 | doi = 10.1111/j.1600-0447.2009.01356.x | url = }}{{cite journal | vauthors = Healy D | title = Neuroleptics and psychic indifference: a review | journal = J R Soc Med | volume = 82 | issue = 10 | pages = 615–619 | date = October 1989 | pmid = 2572700 | pmc = 1292340 | doi = 10.1177/014107688908201018 | url = }} This interpretation is notably consistent with the behavioral effects of antipsychotics in the CAR test, in which treated animals lose their interest or motivation in preemptively avoiding an unpleasant stimulus.{{cite journal | last=Healy | first=David | title=Schizophrenia: Basic, release, reactive and defect processes | journal=Human Psychopharmacology: Clinical and Experimental | publisher=Wiley | volume=5 | issue=2 | year=1990 | issn=0885-6222 | doi=10.1002/hup.470050203 | pages=105–121 | quote = Arguably, indeed, the fact that neuroleptics reduced agitation in schizophrenic subjects is the best evidence against a malfunctioning of dopamine systems in schizophrenia. That this effect is therapeutically useful in schizophrenia does not imply an abnormality of dopamine systems in schizophrenia, but rather that the behavioural state induced can be put to therapeutic use in this illness. Such a behavioural effect is consistent with the known effects of neuroleptics on conditioned avoidance paradigms in experimental animals, where they appear to inhibit the engagement of motor responses or operant behaviour with learned associations (Beninger, 1983; Mason, 1984), leading to extinction-like effects in learning paradigms (Beninger, 1983; Crow and Deakin, 1985; Gallistel, 1986). These effects, unlike clinical recovery, correlate closely with potency in blocking D2 receptors. They are also of acute onset and are consistent with the induction of a state of psychic indifference in humans.}}

The CAR test was developed in the 1950s soon after the discovery of antipsychotics.{{cite journal | last=Willner | first=Paul | title=Animal models for Clinical Psychopharmacology: Depression, Anxiety, Schizophrenia | journal=International Review of Psychiatry | publisher=Informa UK Limited | volume=2 | issue=3–4 | year=1990 | issn=0954-0261 | doi=10.3109/09540269009026601 | pages=253–276}} It is one of the oldest and most classical tests of antipsychotic-like activity. The test was originally performed as the one-way active avoidance or pole-jumping test, but subsequently the two-way active avoidance test was introduced and became more commonly used. By 1998, the popularity of the CAR test had declined somewhat, but it continues to be frequently employed.

{{See also|Tetrabenazine#Animal model of motivational dysfunction|Motivation-enhancing drug|Animal models of depression}}

The CAR test can additionally be used to assess behavioral activity or drive and associated learning.{{cite journal | vauthors = Knoll J | title = Enhancer regulation/endogenous and synthetic enhancer compounds: a neurochemical concept of the innate and acquired drives | journal = Neurochem Res | volume = 28 | issue = 8 | pages = 1275–1297 | date = August 2003 | pmid = 12834268 | doi = 10.1023/a:1024224311289 | url = }}{{cite book | vauthors = Healy D |author-link1=David Healy (psychiatrist)| title=The Psychopharmacologists, Vol. III: Interviews |publisher=Arnold |location=London |year=2000 |pages=81–110 |doi=10.4324/9781003058892-3|isbn=978-0-340-76110-6 |chapter=The Psychopharmacology of Life and Death. Interview with Joseph Knoll. | chapter-url=https://books.google.com/books?id=NJEBEAAAQBAJ&pg=PT109}}{{cite journal | vauthors = Miklya I | title = The significance of selegiline/(-)-deprenyl after 50 years in research and therapy (1965-2015) | journal = Mol Psychiatry | volume = 21 | issue = 11 | pages = 1499–1503 | date = November 2016 | pmid = 27480491 | doi = 10.1038/mp.2016.127 | url = }} The dopamine depleting agent tetrabenazine can strongly and almost completely inhibit acquisition of conditioned avoidance responses in the shuttle box and also results in a very high rate of escape failures.{{cite journal | vauthors = Knoll J | title = Antiaging compounds: (-)deprenyl (selegeline) and (-)1-(benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective highly potent enhancer of the impulse propagation mediated release of catecholamine and serotonin in the brain | journal = CNS Drug Rev | volume = 7 | issue = 3 | pages = 317–345 | date = 2001 | pmid = 11607046 | doi = 10.1111/j.1527-3458.2001.tb00202.x | pmc = 6494119 | url = }} Dopaminergic agents, like the catecholaminergic activity enhancers selegiline, phenylpropylaminopentane (PPAP), and benzofuranylpropylaminopentane (BPAP), can reverse the effects of tetrabenazine and enhance learning in this test.{{cite journal | vauthors = Gaszner P, Miklya I | title = Major depression and the synthetic enhancer substances, (-)-deprenyl and R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane | journal = Prog Neuropsychopharmacol Biol Psychiatry | volume = 30 | issue = 1 | pages = 5–14 | date = January 2006 | pmid = 16023777 | doi = 10.1016/j.pnpbp.2005.06.004 | url = }}

In addition, the CAR test, by testing the capacity of drugs to enhance escape responses and thereby reverse learned helplessness, has been used as a test of antidepressant-like activity.{{cite journal | vauthors = Shirayama Y, Chaki S | title = Neurochemistry of the nucleus accumbens and its relevance to depression and antidepressant action in rodents | journal = Curr Neuropharmacol | volume = 4 | issue = 4 | pages = 277–291 | date = October 2006 | pmid = 18654637 | doi = 10.2174/157015906778520773 | pmc = 2475798 | url = }}{{cite journal | vauthors = Shirayama Y, Ishida H, Iwata M, Hazama GI, Kawahara R, Duman RS | title = Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant-like effects | journal = J Neurochem | volume = 90 | issue = 5 | pages = 1258–1268 | date = September 2004 | pmid = 15312181 | doi = 10.1111/j.1471-4159.2004.02589.x | url = }} κ-Opioid receptor antagonists like norbinaltorphimine have been found to be active in this test.

Acquisition of conditioned avoidance responses has been used as a test of anxiolytic and anxiogenic drug effects.{{cite journal | vauthors = Fernández-Teruel A, Escorihuela RM, Núñez JF, Zapata A, Boix F, Salazar W, Tobeña A | title = The early acquisition of two-way (shuttle-box) avoidance as an anxiety-mediated behavior: psychopharmacological validation | journal = Brain Res Bull | volume = 26 | issue = 1 | pages = 173–176 | date = January 1991 | pmid = 1673080 | doi = 10.1016/0361-9230(91)90205-x | url = }}

Since there is a learning (acquisition) phase, there have also been attempts to use the CAR test to assess activity of drugs in enhancing learning and memory. However, there have been no consistent data for this use. In addition, the CAR test may be inducing more of a behavioral reflex rather than involving higher-order memory associated with areas like the prefrontal cortex.

Other animal tests used to evaluate antipsychotic-like activity of drugs include inhibition of drug-induced stereotypy, inhibition of drug-induced hyperlocomotion or climbing behavior, and reversal of drug-induced prepulse inhibition or startle response deficits. Drugs that induce such effects include dopaminergic agents like amphetamine and apomorphine and NMDA receptor antagonists like dizocilpine (MK-801). Another test of antipsychotic-like activity is restoration of latent inhibition.

• Animal model of schizophrenia
• Dopamine hypothesis of schizophrenia

{{Reflist}}

Category:Animal testing techniques

Category:Neuroscience of schizophrenia

Category:Psychology experiments

Category:Schizophrenia research