Editing Dopaminergic pathways (section)

== Function ==

=== Mesocorticolimbic system ===
[[File:Mesocorticolimbic Circuit.png|thumb|The mesocorticolimbic pathway originates through the VTA and passes through the amygdala, nucleus accumbens, and hippocampus. These functions are relative to memory, emotional regulation, motivation, and reward.]]
The [[Mesocorticolimbic circuit|mesocorticolimbic system]] ([[mesocorticolimbic circuit]]) refers to both the [[mesocortical pathway|mesocortical]] and [[mesolimbic pathway|mesolimbic]] pathways.<ref name="projection" /><ref name="MEDRS-quality human review">{{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 }}</ref> 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.<ref>{{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 }}</ref> 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]].<ref>{{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 }}</ref> Both pathways of the mesocorticolimbic system are associated with [[ADHD]], [[schizophrenia]] and [[addiction]].<ref name="NHM-Cognitive Control">{{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.<br />{{bull}} Working memory is a short-term, capacity-limited cognitive buffer that stores information and permits its manipulation to guide decision-making and behavior.&nbsp;...<br /> 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.&nbsp;... 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).&nbsp;...<br />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.&nbsp;... 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).&nbsp;... <!--Inhibitory control brain structures-->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.&nbsp;... 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.}}</ref><ref name="ADHD 2008 paper">{{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 }}</ref><ref name=":0">{{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 }}</ref><ref>{{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 }}</ref>  

==== Mesocortical pathway ====

The [[mesocortical pathway]] projects from the ventral tegmental area to the prefrontal cortex ([[Ventral tegmental area|VTA]] → [[Prefrontal cortex]]). This pathway is involved in cognition and the regulation of [[executive function]]s (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.<ref>{{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 }}</ref> 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.<ref>{{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 }}</ref> Dysregulation of the neurons in this pathway has been connected to ADHD.<ref name="ADHD 2008 paper" />  

==== Mesolimbic pathway ====

Referred to as the reward pathway, [[mesolimbic pathway]] projects from the ventral tegmental area to the ventral striatum (VTA → [[Ventral striatum]] [<nowiki/>[[nucleus accumbens]] and [[olfactory tubercle]]]).<ref name=":0" /> When a reward is anticipated, the firing rate of dopamine neurons in the mesolimbic pathway increases.<ref name=":1">{{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 }}</ref> The mesolimbic pathway is involved with [[incentive salience]], [[motivation]], reinforcement learning, fear and other cognitive processes.<ref name="NHM pathways" /><ref name="ADHD 2008 paper" /><ref>{{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 }}</ref> 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).<ref name=":1" /> Research is ongoing to determine the role of the mesolimbic pathway in the perception of pleasure.<ref name="Pleasure system">{{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. }}</ref><ref>{{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 }}</ref><ref>{{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}}</ref><ref>{{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 }}</ref>
[[File:Nigrostriatal Pathway.png|thumb|The nigrostriatal pathway is involved in behaviors relating to movement and motivation.]]


=== Nigrostriatal pathway ===
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.<ref>{{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 }}</ref><ref>{{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 }}</ref> 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<ref>{{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 }}</ref> while schizophrenia and ADHD are affected by reward and motivation functioning. This pathway also regulates associated learning such as classical conditioning and operant conditioning.<ref>{{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 }}</ref> 

[[File:Tuberoinfundibular Pathway.png|thumb|The tuberoinfundibular pathway transmits dopamine the hypothalamus to the pituitary gland.]]

=== Tuberoinfundibular pathway ===
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.<ref>{{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 }}</ref> 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.<ref>{{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}}</ref>

=== Cortico-basal ganglia-thalamo-cortical loop ===

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]].<ref name="Reward system components and structure-specific functions">{{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 = <!--Regions of the basal ganglia, which include the dorsal and ventral striatum, internal and external segments of the globus pallidus, subthalamic nucleus, and dopaminergic cell bodies in the substantia nigra, are highly implicated not only in fine motor control but also in PFC function.43 Of these regions, the NAc (described above) and the DS (described below) are most frequently examined with respect to addiction. Thus, only a brief description of the modulatory role of the basal ganglia in addiction-relevant circuits will be mentioned here. The overall output of the basal ganglia is predominantly via the thalamus, which then projects back to the PFC to form cortico-striatal-thalamo-cortical (CSTC) loops. Three CSTC loops are proposed to modulate executive function, action selection, and behavioral inhibition. In the dorsolateral prefrontal circuit, the basal ganglia primarily modulate the identification and selection of goals, including rewards.44 The OFC circuit modulates decision-making and impulsivity, and the anterior cingulate circuit modulates the assessment of consequences.44 These circuits are modulated by dopaminergic inputs from the VTA to ultimately guide behaviors relevant to addiction, including the persistence and narrowing of the behavioral repertoire toward drug seeking, and continued drug use despite negative consequences.43–45--> | doi-access = free }}</ref><ref name="Striatal efferents, afferents, and colocalized receptors in dMSNs and iMSNs">{{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 striatum] receives dopaminergic inputs from the ventral tegmental area (VTA) and the substantia nigra (SNr) and glutamatergic inputs from several areas, including the cortex, hippocampus, amygdala, and thalamus (Swanson, 1982; Phillipson and Griffiths, 1985; Finch, 1996; Groenewegen et al., 1999; Britt et al., 2012). These glutamatergic inputs make contact on the heads of dendritic spines of the striatal GABAergic medium spiny projection neurons (MSNs) whereas dopaminergic inputs synapse onto the spine neck, allowing for an important and complex interaction between these two inputs in modulation of MSN activity&nbsp;... It should also be noted that there is a small population of neurons in the NAc that coexpress both D1 and D2 receptors, though this is largely restricted to the NAc shell (Bertran- Gonzalez et al., 2008).&nbsp;... Neurons in the NAc core and NAc shell subdivisions also differ functionally. The NAc core is involved in the processing of conditioned stimuli whereas the NAc shell is more important in the processing of unconditioned stimuli; Classically, these two striatal MSN populations are thought to have opposing effects on basal ganglia output. Activation of the dMSNs causes a net excitation of the thalamus resulting in a positive cortical feedback loop; thereby acting as a ‘go’ signal to initiate behavior. Activation of the iMSNs, however, causes a net inhibition of thalamic activity resulting in a negative cortical feedback loop and therefore serves as a ‘brake’ to inhibit behavior&nbsp;... there is also mounting evidence that iMSNs play a role in motivation and addiction (Lobo and Nestler, 2011; Grueter et al., 2013). For example, optogenetic activation of NAc core and shell iMSNs suppressed the development of a cocaine CPP whereas selective ablation of NAc core and shell iMSNs&nbsp;... enhanced the development and the persistence of an amphetamine CPP (Durieux et al., 2009; Lobo et al., 2010). These findings suggest that iMSNs can bidirectionally modulate drug reward.&nbsp;... Together these data suggest that iMSNs normally act to restrain drug-taking behavior and recruitment of these neurons may in fact be protective against the development of compulsive drug use.--> }}</ref> 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.<ref>{{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 }}</ref> 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.<ref name="pmid21270784">{{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 }}</ref>

These models of the basal ganglia are thought to be relevant to the study of [[OCD]],<ref>{{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 }}</ref><ref>{{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 }}</ref> [[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.<ref name="pmid21270784" />
<!--This "learning" is too nonspecific; most readers will assume this is the acquisition of new declarative memory when it really just refers to "reward prediction error", which was already covered in the first paragraph.  This paragraph needs to be merged into that one-->