Dopaminergic pathways

Six of the dopaminergic pathways are listed below.{{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE | veditors = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | page = 249 | edition = 2nd | chapter = Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu | quote=Relationship of the hypothalamus and the pituitary gland. The anterior pituitary, or adenohypophysis, receives rich blood flow from the capillaries of the portal hypophyseal system. This system delivers factors released by hypothalamic neurons into portal capillaries at the median eminence. The figure shows one such projection, from the tuberal (arcuate) nuclei via the tuberoinfundibular tract to the median eminence.}}

{{clear}}

:Hypothalamospinal

:* Hypothalamus → Spinal cord

:Incertohypothalamic

:* Zona incerta → Hypothalamus

:* Zona incerta → Brainstem VTA → Amygdala (mesoamygdaloid pathway){{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE | veditors = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 147–148, 154–157 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin | quote=Neurons from the SNc densely innervate the dorsal striatum where they play a critical role in the learning and execution of motor programs. Neurons from the VTA innervate the ventral striatum (nucleus accumbens), olfactory bulb, amygdala, hippocampus, orbital and medial prefrontal cortex, and cingulate cortex. VTA DA neurons play a critical role in motivation, reward-related behavior, attention, and multiple forms of memory. ... Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus accumbens core region and dorsal striatum). ... DA has multiple actions in the prefrontal cortex. It promotes the "cognitive control" of behavior: the selection and successful monitoring of behavior to facilitate attainment of chosen goals. Aspects of cognitive control in which DA plays a role include working memory, the ability to hold information "on line" in order to guide actions, suppression of prepotent behaviors that compete with goal-directed actions, and control of attention and thus the ability to overcome distractions. ... Noradrenergic projections from the LC thus interact with dopaminergic projections from the VTA to regulate cognitive control.}}

:VTA → Hippocampus

:VTA → Cingulate cortex

:VTA → Olfactory bulb

:SNc → Subthalamic nucleus{{cite journal | vauthors = Cragg SJ, Baufreton J, Xue Y, Bolam JP, Bevan MD | title = Synaptic release of dopamine in the subthalamic nucleus | journal = The European Journal of Neuroscience | volume = 20 | issue = 7 | pages = 1788–802 | date = October 2004 | pmid = 15380000 | doi = 10.1111/j.1460-9568.2004.03629.x | s2cid = 14698708 | doi-access = free }}

File:Mesocorticolimbic Circuit.png

The mesocorticolimbic system (mesocorticolimbic circuit) refers to both the mesocortical and mesolimbic pathways.{{cite journal | vauthors = Doyon WM, Thomas AM, Ostroumov A, Dong Y, Dani JA | title = Potential substrates for nicotine and alcohol interactions: a focus on the mesocorticolimbic dopamine system | journal = Biochemical Pharmacology | volume = 86 | issue = 8 | pages = 1181–93 | date = October 2013 | pmid = 23876345 | pmc = 3800178 | doi = 10.1016/j.bcp.2013.07.007 }} Both pathways originate at the ventral tegmental area (VTA) which is located in the midbrain. Through separate connections to the prefrontal cortex (mesocortical) and ventral striatum (mesolimbic), the mesocorticolimbic projection has a significant role in learning, motivation, reward, memory and movement.{{cite journal | vauthors = Yamaguchi T, Wang HL, Li X, Ng TH, Morales M | title = Mesocorticolimbic glutamatergic pathway | journal = The Journal of Neuroscience | volume = 31 | issue = 23 | pages = 8476–90 | date = June 2011 | pmid = 21653852 | pmc = 6623324 | doi = 10.1523/JNEUROSCI.1598-11.2011 }} Dopamine receptor subtypes, D1 and D2 have been shown to have complementary functions in the mesocorticolimbic projection, facilitating learning in response to both positive and negative feedback.{{cite journal | vauthors = Verharen JP, Adan RA, Vanderschuren LJ | title = Differential contributions of striatal dopamine D1 and D2 receptors to component processes of value-based decision making | journal = Neuropsychopharmacology | volume = 44 | issue = 13 | pages = 2195–2204 | date = December 2019 | pmid = 31254972 | pmc = 6897916 | doi = 10.1038/s41386-019-0454-0 }} Both pathways of the mesocorticolimbic system are associated with ADHD, schizophrenia and addiction.{{cite book|title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience|vauthors=Malenka RC, Nestler EJ, Hyman SE|publisher=McGraw-Hill Medical|year=2009|isbn=9780071481274|veditors=Sydor A, Brown RY|edition=2nd|location=New York|pages=313–321|chapter=Chapter 13: Higher Cognitive Function and Behavioral Control|quote={{bull}} Executive function, the cognitive control of behavior, depends on the prefrontal cortex, which is highly developed in higher primates and especially humans.
{{bull}} Working memory is a short-term, capacity-limited cognitive buffer that stores information and permits its manipulation to guide decision-making and behavior. ...
These diverse inputs and back projections to both cortical and subcortical structures put the prefrontal cortex in a position to exert what is often called “top-down” control or cognitive control of behavior. ... The prefrontal cortex receives inputs not only from other cortical regions, including association cortex, but also, via the thalamus, inputs from subcortical structures subserving emotion and motivation, such as the amygdala (Chapter 14) and ventral striatum (or nucleus accumbens; Chapter 15). ...
In conditions in which prepotent responses tend to dominate behavior, such as in drug addiction, where drug cues can elicit drug seeking (Chapter 15), or in attention deficit hyperactivity disorder (ADHD; described below), significant negative consequences can result. ... ADHD can be conceptualized as a disorder of executive function; specifically, ADHD is characterized by reduced ability to exert and maintain cognitive control of behavior. Compared with healthy individuals, those with ADHD have diminished ability to suppress inappropriate prepotent responses to stimuli (impaired response inhibition) and diminished ability to inhibit responses to irrelevant stimuli (impaired interference suppression). ... Functional neuroimaging in humans demonstrates activation of the prefrontal cortex and caudate nucleus (part of the striatum) in tasks that demand inhibitory control of behavior. ... Early results with structural MRI show thinning of the cerebral cortex in ADHD subjects compared with age-matched controls in prefrontal cortex and posterior parietal cortex, areas involved in working memory and attention.}}{{cite journal | vauthors = Engert V, Pruessner JC | title = Dopaminergic and noradrenergic contributions to functionality in ADHD: the role of methylphenidate | journal = Current Neuropharmacology | volume = 6 | issue = 4 | pages = 322–8 | date = December 2008 | pmid = 19587853 | pmc = 2701285 | doi = 10.2174/157015908787386069 }}{{cite journal | vauthors = Dreyer JL | title = New insights into the roles of microRNAs in drug addiction and neuroplasticity | journal = Genome Medicine | volume = 2 | issue = 12 | pages = 92 | date = December 2010 | pmid = 21205279 | pmc = 3025434 | doi = 10.1186/gm213 | doi-access = free }}{{cite journal | vauthors = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nature Reviews. Neuroscience | volume = 12 | issue = 11 | pages = 623–37 | date = October 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 }}

The mesocortical pathway projects from the ventral tegmental area to the prefrontal cortex (VTA → Prefrontal cortex). This pathway is involved in cognition and the regulation of executive functions (e.g., attention, working memory, inhibitory control, planning, etc.) This intricate neural circuit serves as a crucial communication route within the brain, facilitating the transmission of dopamine, a neurotransmitter associated with reward, motivation, and cognitive control.{{Cite journal |last=Keyser |first=J. De |date=1990 |title=The mesoneocortical dopamine neuron system |url=https://doi.org/10.1212/WNL.40.11.1660 |journal=Neurology |volume=40 |issue=11 |pages=1660–1662|doi=10.1212/WNL.40.11.1660 |pmid=2234421 |s2cid=12241566 |url-access=subscription }} The prefrontal cortex, being a central hub for executive functions, relies on the input from the mesocortical pathway to modulate and fine-tune cognitive processes essential for goal-directed behavior and decision-making.{{Cite journal |last1=Floresco |first1=Stan B. |last2=Magyar |first2=Orsolya |date=2006 |title=Mesocortical dopamine modulation of executive functions: beyond working memory |url=https://doi.org/10.1007/s00213-006-0404-5 |journal=Psychopharmacology |volume=188 |issue=4 |pages=567–585 |doi=10.1007/s00213-006-0404-5 |pmid=16670842 |s2cid=24568869 |via=SpringerLink|url-access=subscription }} Dysregulation of the neurons in this pathway has been connected to ADHD.

Referred to as the reward pathway, mesolimbic pathway projects from the ventral tegmental area to the ventral striatum (VTA → Ventral striatum [nucleus accumbens and olfactory tubercle]). When a reward is anticipated, the firing rate of dopamine neurons in the mesolimbic pathway increases.{{cite journal | vauthors = Salamone JD, Correa M | title = The mysterious motivational functions of mesolimbic dopamine | journal = Neuron | volume = 76 | issue = 3 | pages = 470–85 | date = November 2012 | pmid = 23141060 | pmc = 4450094 | doi = 10.1016/j.neuron.2012.10.021 }} The mesolimbic pathway is involved with incentive salience, motivation, reinforcement learning, fear and other cognitive processes.{{cite journal | vauthors = Pezze MA, Feldon J | title = Mesolimbic dopaminergic pathways in fear conditioning | journal = Progress in Neurobiology | volume = 74 | issue = 5 | pages = 301–20 | date = December 2004 | pmid = 15582224 | doi = 10.1016/j.pneurobio.2004.09.004 | s2cid = 36091832 }} In animal studies, depletion of dopamine in this pathway, or lesions at its site of origin, decrease the extent to which an animal is willing to go to obtain a reward (e.g., the number of lever presses for nicotine or time searching for food). Research is ongoing to determine the role of the mesolimbic pathway in the perception of pleasure.{{cite journal | vauthors = Berridge KC, Kringelbach ML | title = Pleasure systems in the brain | journal = Neuron | volume = 86 | issue = 3 | pages = 646–64 | date = May 2015 | pmid = 25950633 | pmc = 4425246 | doi = 10.1016/j.neuron.2015.02.018 | quote = To summarize: the emerging realization that many diverse pleasures share overlapping brain substrates; better neuroimaging maps for encoding human pleasure in orbitofrontal cortex; identification of hotspots and separable brain mechanisms for generating ‘liking’ and ‘wanting’ for the same reward; identification of larger keyboard patterns of generators for desire and dread within NAc, with multiple modes of function; and the realization that dopamine and most ‘pleasure electrode’ candidates for brain hedonic generators probably did not cause much pleasure after all. }}{{cite journal | vauthors = Berridge KC, Kringelbach ML | title = Neuroscience of affect: brain mechanisms of pleasure and displeasure | journal = Current Opinion in Neurobiology | volume = 23 | issue = 3 | pages = 294–303 | date = June 2013 | pmid = 23375169 | pmc = 3644539 | doi = 10.1016/j.conb.2013.01.017 }}{{Cite book| vauthors = Nestler EJ |url=https://www.worldcat.org/oclc/1191071328|title=Molecular neuropharmacology a foundation for clinical neuroscience|date=2020|others=Paul J. Kenny, Scott J. Russo, Anne, MD Schaefer|isbn=978-1-260-45691-2|edition=Fourth |location=New York|oclc=1191071328}}{{cite journal | vauthors = Berridge KC, Kringelbach ML | title = Pleasure systems in the brain | journal = Neuron | volume = 86 | issue = 3 | pages = 646–64 | date = May 2015 | pmid = 25950633 | pmc = 4425246 | doi = 10.1016/j.neuron.2015.02.018 }}

File:Nigrostriatal Pathway.png

The nigrostriatal pathway is involved in behaviors relating to movement and motivation. The transmission of dopaminergic neurons to the dorsal striatum particularly plays a role in reward and motivation while movement is influenced by the transmission of dopaminergic neurons to the substantia nigra.{{cite journal | vauthors = Balleine BW, Delgado MR, Hikosaka O | title = The role of the dorsal striatum in reward and decision-making | journal = The Journal of Neuroscience | volume = 27 | issue = 31 | pages = 8161–8165 | date = August 2007 | pmid = 17670959 | pmc = 6673072 | doi = 10.1523/JNEUROSCI.1554-07.2007 }}{{cite journal | vauthors = Mishra A, Singh S, Shukla S | title = Physiological and Functional Basis of Dopamine Receptors and Their Role in Neurogenesis: Possible Implication for Parkinson's disease | journal = Journal of Experimental Neuroscience | volume = 12 | pages = 1179069518779829 | date = 2018 | pmid = 29899667 | pmc = 5985548 | doi = 10.1177/1179069518779829 }} The nigrostriatal pathway is associated with conditions such as Huntington's disease, Parkinson's disease, ADHD, Schizophrenia, and Tourette's Syndrome. Huntington's disease, Parkinson's disease, and Tourette's Syndrome are conditions affected by motor functioning{{cite journal | vauthors = Mariani E, Frabetti F, Tarozzi A, Pelleri MC, Pizzetti F, Casadei R | title = Meta-Analysis of Parkinson's Disease Transcriptome Data Using TRAM Software: Whole Substantia Nigra Tissue and Single Dopamine Neuron Differential Gene Expression | journal = PLOS ONE | volume = 11 | issue = 9 | pages = e0161567 | date = 2016-09-09 | pmid = 27611585 | pmc = 5017670 | doi = 10.1371/journal.pone.0161567 | bibcode = 2016PLoSO..1161567M | doi-access = free }} while schizophrenia and ADHD are affected by reward and motivation functioning. This pathway also regulates associated learning such as classical conditioning and operant conditioning.{{cite book | vauthors = Carmack SA, Koob GF, Anagnostaras SG |chapter=Learning and Memory in Addiction |date=2017 | doi = 10.1016/b978-0-12-809324-5.21101-2 |title=Learning and Memory: A Comprehensive Reference |pages=523–538 |publisher= Elsevier |isbn=9780128052914 |url=https://escholarship.org/uc/item/9ww1p0g8 }}

File:Tuberoinfundibular Pathway.png

The tuberoinfundibular pathway transmits dopamine from the hypothalamus to the pituitary gland. This neural circuit plays a pivotal role in the regulation of hormonal balance and, specifically, in modulating the secretion of prolactin from the pituitary gland, which is responsible for breast milk production in females. Hyperprolactinemia is an associated condition caused by an excessive amount of prolactin production that is common in pregnant women.{{cite journal | vauthors = Attaar A, Curran M, Meyenburg L, Bottner R, Johnston C, Roberts Mason K | title = Perioperative pain management and outcomes in patients who -discontinued or continued pre-existing buprenorphine therapy | journal = Journal of Opioid Management | volume = 17 | issue = 7 | pages = 33–41 | date = 2021-08-01 | pmid = 34520024 | doi = 10.5055/jom.2021.0640 | s2cid = 237507806 }} After childbirth, the tuberoinfundibular pathway resumes its role in regulating prolactin levels. The decline in estrogen levels postpartum contributes to the restoration of dopaminergic inhibition, preventing sustained hyperprolactinemia in non-pregnant and non-nursing individuals.{{Cite book |last1=Russell |first1=John A. |last2=Douglas |first2=Alison J. |last3=Ingram |first3=Colin D. |chapter=Chapter 1 Brain preparations for maternity — adaptive changes in behavioral and neuroendocrine systems during pregnancy and lactation. An overview |date=2001 |title=The Maternal Brain |url=https://doi.org/10.1016/S0079-6123(01)33002-9 |series=Progress in Brain Research |volume=133 |pages=1–38 |doi=10.1016/S0079-6123(01)33002-9 |pmid=11589124 |isbn=978-0-444-50548-4 |via=Elsevier}}

The dopaminergic pathways that project from the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) into the striatum (i.e., the nigrostriatal and mesolimbic pathways, respectively) form one component of a sequence of pathways known as the cortico-basal ganglia-thalamo-cortical loop.{{cite journal | vauthors = Taylor SB, Lewis CR, Olive MF | title = The neurocircuitry of illicit psychostimulant addiction: acute and chronic effects in humans | journal = Substance Abuse and Rehabilitation | volume = 4 | pages = 29–43 | year = 2013 | pmid = 24648786 | pmc = 3931688 | doi = 10.2147/SAR.S39684 | quote = | doi-access = free }}{{cite journal | vauthors = Yager LM, Garcia AF, Wunsch AM, Ferguson SM | title = The ins and outs of the striatum: role in drug addiction | journal = Neuroscience | volume = 301 | pages = 529–41 | date = August 2015 | pmid = 26116518 | pmc = 4523218 | doi = 10.1016/j.neuroscience.2015.06.033 | quote = }} The nigrostriatal component of the loop consists of the SNc, giving rise to both inhibitory and excitatory pathways that run from the striatum into the globus pallidus, before carrying on to the thalamus, or into the subthalamic nucleus before heading into the thalamus. The dopaminergic neurons in this circuit increase the magnitude of phasic firing in response to positive reward error, that is when the reward exceeds the expected reward. These neurons do not decrease phasic firing during a negative reward prediction (less reward than expected), leading to hypothesis that serotonergic, rather than dopaminergic neurons encode reward loss.{{Cite journal |last=Roberts |first=Angela C. |date=June 2011 |title=The Importance of Serotonin for Orbitofrontal Function |url=https://linkinghub.elsevier.com/retrieve/pii/S000632231100014X |journal=Biological Psychiatry |volume=69 |issue=12 |pages=1185–1191 |doi=10.1016/j.biopsych.2010.12.037 |issn=0006-3223|url-access=subscription }} Dopamine phasic activity also increases during cues that signal negative events, however dopaminergic neuron stimulation still induces place preference, indicating its main role in evaluating a positive stimulus. From these findings, two hypotheses have developed, as to the role of the basal ganglia and nigrostriatal dopamine circuits in action selection. The first model suggests a "critic" which encodes value, and an actor which encodes responses to stimuli based on perceived value. However, the second model proposes that the actions do not originate in the basal ganglia, and instead originate in the cortex and are selected by the basal ganglia. This model proposes that the direct pathway controls appropriate behavior and the indirect suppresses actions not suitable for the situation. This model proposes that tonic dopaminergic firing increases the activity of the direct pathway, causing a bias towards executing actions faster.{{cite journal | vauthors = Maia TV, Frank MJ | title = From reinforcement learning models to psychiatric and neurological disorders | journal = Nature Neuroscience | volume = 14 | issue = 2 | pages = 154–62 | date = February 2011 | pmid = 21270784 | pmc = 4408000 | doi = 10.1038/nn.2723 }}

These models of the basal ganglia are thought to be relevant to the study of OCD,{{cite journal | vauthors = Beucke JC, Sepulcre J, Talukdar T, Linnman C, Zschenderlein K, Endrass T, Kaufmann C, Kathmann N | display-authors = 6 | title = Abnormally high degree connectivity of the orbitofrontal cortex in obsessive-compulsive disorder | journal = JAMA Psychiatry | volume = 70 | issue = 6 | pages = 619–29 | date = June 2013 | pmid = 23740050 | doi = 10.1001/jamapsychiatry.2013.173 | doi-access = free }}{{cite journal | vauthors = Maia TV, Cooney RE, Peterson BS | title = The neural bases of obsessive-compulsive disorder in children and adults | journal = Development and Psychopathology | volume = 20 | issue = 4 | pages = 1251–83 | date = 1 January 2008 | pmid = 18838041 | pmc = 3079445 | doi = 10.1017/S0954579408000606 }} ADHD, Tourette syndrome, Parkinson's disease, schizophrenia, and addiction. For example, Parkinson's disease is hypothesized to be a result of excessive inhibitory pathway activity, which explains the slow movement and cognitive deficits, while Tourettes is proposed to be a result of excessive excitatory activity resulting in the tics characteristic of Tourettes.

The ventral tegmental area and substantia nigra pars compacta receive inputs from other neurotransmitters systems, including glutaminergic inputs, GABAergic inputs, cholinergic inputs, and inputs from other monoaminergic nuclei. The VTA contains 5-HT_1A receptors that exert a biphasic effects on firing, with low doses of 5-HT_1A receptor agonists eliciting an increase in firing rate, and higher doses suppressing activity. The 5-HT_2A receptors expressed on dopaminergic neurons increase activity, while 5-HT_2C receptors elicit a decrease in activity.{{cite book| vauthors = Adell A, Bortolozzi A, Díaz-Mataix L, Santana N, Celada P, Artigas F | chapter = Serotonin interaction with other transmitter systems. | veditors = Muller CP, Jacobs B | title = Handbook of Behavioral Neuroscience | date = January 2010 | volume = 21 | pages = 259-276 (262–264) |publisher=Academic|location=London|isbn=978-0-12-374634-4 }} The mesolimbic pathway, which projects from the VTA to the nucleus accumbens, is also regulated by muscarinic acetylcholine receptors. In particular, the activation of muscarinic acetylcholine receptor M2 and muscarinic acetylcholine receptor M4 inhibits dopamine release, while muscarinic acetylcholine receptor M1 activation increases dopamine release.{{cite journal | vauthors = Shin JH, Adrover MF, Wess J, Alvarez VA | title = Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 26 | pages = 8124–9 | date = June 2015 | pmid = 26080439 | pmc = 4491757 | doi = 10.1073/pnas.1508846112 | bibcode = 2015PNAS..112.8124S | doi-access = free }} GABAergic inputs from the striatum decrease dopaminergic neuronal activity, and glutaminergic inputs from many cortical and subcortical areas increase the firing rate of dopaminergic neurons. Endocannabinoids also appear to have a modulatory effect on dopamine release from neurons that project out of the VTA and SNc.{{cite journal | vauthors = Melis M, Pistis M | title = Endocannabinoid signaling in midbrain dopamine neurons: more than physiology? | journal = Current Neuropharmacology | volume = 5 | issue = 4 | pages = 268–77 | date = December 2007 | pmid = 19305743 | pmc = 2644494 | doi = 10.2174/157015907782793612 | quote = Thus, it is conceivable that low levels of CB1 receptors are located on glutamatergic and GABAergic terminals impinging on DA neurons [127, 214], where they can fine-tune the release of inhibitory and excitatory neurotransmitter and regulate DA neuron firing.
Consistently, in vitro electrophysiological experiments from independent laboratories have provided evidence of CB1 receptor localization on glutamatergic and GABAergic axon terminals in the VTA and SNc. }} Noradrenergic inputs deriving from the locus coeruleus have excitatory and inhibitory effects on the dopaminergic neurons that project out of the VTA and SNc.{{cite journal | vauthors = Morikawa H, Paladini CA | title = Dynamic regulation of midbrain dopamine neuron activity: intrinsic, synaptic, and plasticity mechanisms | journal = Neuroscience | volume = 198 | pages = 95–111 | date = December 2011 | pmid = 21872647 | pmc = 3221882 | doi = 10.1016/j.neuroscience.2011.08.023 }} The excitatory orexinergic inputs to the VTA originate in the lateral hypothalamus and may regulate the baseline firing of VTA dopaminergic neurons.

• Dopaminergic cell groups

{{reflist|group=note}}

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{{Neurotransmitter systems}}

Category:Central nervous system pathways

Category:Dopamine