Chemistry:Dopaminergic pathways

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Short description: Projection neurons in the brain that synthesize and release dopamine
The main dopaminergic pathways of the human brain

Dopaminergic pathways (dopamine pathways, dopaminergic projections) in the human brain are involved in both physiological and behavioral processes including movement, cognition, executive functions, reward, motivation, and neuroendocrine control.[1] Each pathway is a set of projection neurons, consisting of individual dopaminergic neurons.

The four major dopaminergic pathways are the mesolimbic pathway, the mesocortical pathway, the nigrostriatal pathway, and the tuberoinfundibular pathway. The mesolimbic pathway and the mesocortical pathway form the mesocorticolimbic system. Two other dopaminergic pathways to be considered are the hypothalamospinal tract and the incertohypothalamic pathway.

Parkinson's disease, attention deficit hyperactivity disorder (ADHD), substance use disorders (addiction), and restless legs syndrome (RLS) can be attributed to dysfunction in specific dopaminergic pathways.

The dopamine neurons of the dopaminergic pathways synthesize and release the neurotransmitter dopamine.[2][3] Enzymes tyrosine hydroxylase and dopa decarboxylase are required for dopamine synthesis.[4] These enzymes are both produced in the cell bodies of dopamine neurons. Dopamine is stored in the cytoplasm and vesicles in axon terminals. Dopamine release from vesicles is triggered by action potential propagation-induced membrane depolarization.[4] The axons of dopamine neurons extend the entire length of their designated pathway.

Pathways

Major

Six of the dopaminergic pathways are listed below.[5][6][7]

Pathway name Description Associated processes Associated disorders
Mesocorticolimbic
system
Mesolimbic
pathway
 The mesolimbic pathway transmits dopamine from the ventral tegmental area (VTA), which is located in the midbrain, to the ventral striatum, which includes both the nucleus accumbens and olfactory tubercle.[5][6] The "meso" prefix in the word "mesolimbic" refers to the midbrain, or "middle brain", since "meso" means "middle" in Greek.
  • reward-related cognition
    • incentive salience ("wanting")
    • pleasure ("liking") response from certain stimuli
    • positive reinforcement
  • aversion-related cognition
Mesocortical
pathway
 The mesocortical pathway transmits dopamine from the VTA to the prefrontal cortex. The "meso" prefix in "mesocortical" refers to the VTA, which is located in the midbrain, and "cortical" refers to the cortex.
  • executive functions
Nigrostriatal pathway The nigrostriatal pathway transmits dopaminergic neurons from the zona compacta of the substantia nigra[8] to the caudate nucleus and putamen.

The substantia nigra is located in the midbrain, while both the caudate nucleus and putamen are located in the dorsal striatum.

  • motor function
  • reward-related cognition
  • associative learning
  • addiction
  • chorea
  • Huntington's disease
  • Schizophrenia
  • ADHD
  • Tourette's Syndrome
  • Parkinson's disease
Tuberoinfundibular pathway The tuberoinfundibular pathway transmits dopamine from the hypothalamus to the pituitary gland.

This pathway controls the secretion of certain hormones, including prolactin, from the pituitary gland.[9]

"Infundibular" in the word "tuberoinfundibular" refers to the cup or infundibulum, out of which the pituitary gland develops.

  • regulation of prolactin secretion[10]
Hypothalamospinal tract The tuberoinfundibular pathway not only regulates hormonal balance but also influences locomotor networks in the brainstem and spinal cord. Modulating motor control and coordination, showcasing the interconnected nature of neural circuits in the brain.
  • motor function.
Incertohypothalamic pathway This pathway from the zona incerta influences the hypothalamus and locomotor centers in the brainstem.
  • visceral and sensorimotor activities.
  • tremor

Minor

Hypothalamospinal
Incertohypothalamic
VTA → Hippocampus[6]
VTA → Cingulate cortex[6]
VTA → Olfactory bulb[6]
SNc → Subthalamic nucleus[11]

Function

Mesocorticolimbic system

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 system (mesocorticolimbic circuit) refers to both the mesocortical and mesolimbic pathways.[3][12] 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.[13] 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.[14] Both pathways of the mesocorticolimbic system are associated with ADHD, schizophrenia and addiction.[15][16][17][18]

Mesocortical pathway

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.[19] 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.[20] Dysregulation of the neurons in this pathway has been connected to ADHD.[16]

Mesolimbic pathway

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).[17] When a reward is anticipated, the firing rate of dopamine neurons in the mesolimbic pathway increases.[21] The mesolimbic pathway is involved with incentive salience, motivation, reinforcement learning, fear and other cognitive processes.[6][16][22] 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).[21] Research is ongoing to determine the role of the mesolimbic pathway in the perception of pleasure.[23][24][25][26]

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.[27][28] 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[29] while schizophrenia and ADHD are affected by reward and motivation functioning. This pathway also regulates associated learning such as classical conditioning and operant conditioning.[30]

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.[31] 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.[32]

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.[33][34] 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.[citation needed] 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 nigrostiatal 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.[35]

These models of the basal ganglia are thought to be relevant to the study of OCD,[36][37] 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.[35]

Regulation

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-HT1A receptors that exert a biphasic effects on firing, with low doses of 5-HT1A receptor agonists eliciting an increase in firing rate, and higher doses suppressing activity. The 5-HT2A receptors expressed on dopaminergic neurons increase activity, while 5-HT2C receptors elicit a decrease in activity.[38] 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.[39] 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.[40] Noradrenergic inputs deriving from the locus coeruleus have excitatory and inhibitory effects on the dopaminergic neurons that project out of the VTA and SNc.[41][42] The excitatory orexinergic inputs to the VTA originate in the lateral hypothalamus and may regulate the baseline firing of VTA dopaminergic neurons.[43][44]

Inputs to the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc)
Neurotransmitter Origin Type of Connection Sources
Glutamate Excitatory projections into the VTA and SNc [41]
GABA
  • rostromedial tegmental nucleus
  • striatum
  • local GABAergic inputs
 Inhibitory projections into the VTA and SNc [41]
Serotonin Modulatory effect, depending on receptor subtype
Produces a biphasic effect on VTA neurons 		[41]
Norepinephrine
  • locus coeruleus
  • other noradrenergic nuclei
 Modulatory effect, depending on receptor subtype
The excitatory and inhibitory effects of the LC on the VTA and SNc are time-dependent 		[41][42]
Endocannabinoids Excitatory effect on dopaminergic neurons from inhibiting GABAergic inputs
Inhibitory effect on dopaminergic neurons from inhibiting glutamatergic inputs
May interact with orexins via CB1–OX1 receptor heterodimers to regulate neuronal firing 		[40][41][43][45]
Acetylcholine
  • pedunculopontine nucleus
  • laterodorsal tegmental nuclei
 Modulatory effect, depending on receptor subtype [41]
Orexin Excitatory effect on dopaminergic neurons via signaling through orexin receptors (OX1 and OX2)
Increases both tonic and phasic firing of dopaminergic neurons in the VTA
May interact with endocannabinoids via CB1–OX1 receptor heterodimers to regulate neuronal firing 		[43][44][45]

See also

Notes

  1. ↑ 1.0 1.1 At a chemical synapse, neurotransmitters are normally released from the presynaptic axon terminal and signal through receptors that are located on the dendrites of the postsynaptic neuron; however, in retrograde neurotransmission, the dendrites of the postsynaptic neuron release neurotransmitters that signal through receptors that are located on the axon terminal of the presynaptic neuron.[43]
    Endocannabinoids signal between neurons through retrograde neurotransmission at synapses;[43] consequently, the dopaminergic neurons that project out of the VTA and SNc release endocannabinoids from their dendrites onto the axon terminals of their inhibitory GABAergic and excitatory glutamatergic inputs to inhibit their effects on dopamine neuronal firing.[40][43]

References

  1. ↑ "Behavioral functions of the mesolimbic dopaminergic system: an affective neuroethological perspective". Brain Research Reviews 56 (2): 283–321. December 2007. doi:10.1016/j.brainresrev.2007.07.014. PMID 17905440. 
  2. ↑ "Beyond the Reward Pathway". Learn Genetics. University of Utah. http://learn.genetics.utah.edu/content/addiction/reward/pathways.html. 
  3. ↑ 3.0 3.1 "Mesocorticolimbic Dopaminergic Neurons: Functional and Regulatory Roles". Psychopharmacology: the fourth generation of progress. New York: Raven Press. 1995. ISBN 978-0-7817-0166-2. http://www.acnp.org/g4/gn401000025/ch025.html. 
  4. ↑ 4.0 4.1 "Dopamine and the Dopaminergic Systems of the Brain". Handbook of Neurochemistry and Molecular Neurobiology. Boston, MA: Springer US. 2008. pp. 149–170. doi:10.1007/978-0-387-30382-6_7. ISBN 978-0-387-30351-2. 
  5. ↑ 5.0 5.1 "Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory". Neuroscience and Biobehavioral Reviews 35 (2): 129–50. November 2010. doi:10.1016/j.neubiorev.2010.02.001. PMID 20149820. "Recent studies on intracranial self-administration of neurochemicals (drugs) found that rats learn to self-administer various drugs into the mesolimbic dopamine structures–the posterior ventral tegmental area, medial shell nucleus accumbens and medial olfactory tubercle. ... In the 1970s it was recognized that the olfactory tubercle contains a striatal component, which is filled with GABAergic medium spiny neurons receiving glutamatergic inputs form cortical regions and dopaminergic inputs from the VTA and projecting to the ventral pallidum just like the nucleus accumbens". 
    Figure 3: The ventral striatum and self-administration of amphetamine
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. 2009. pp. 147–148, 154–157. ISBN 9780071481274. "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." 
  7. ↑ "Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. 2009. p. 249. ISBN 9780071481274. "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." 
  8. ↑ "Male Sexual Behavior". Hormones, Brain and Behavior. Elsevier. 2017. pp. 1–57. doi:10.1016/b978-0-12-803592-4.00001-8. ISBN 9780128036082. 
  9. ↑ "Acetylcholine ☆". Reference Module in Neuroscience and Biobehavioral Psychology. Elsevier. 2017. doi:10.1016/b978-0-12-809324-5.00464-8. ISBN 9780128093245. 
  10. ↑ 10.0 10.1 "Antipsychotic drugs". Neurobiology of Psychiatric Disorders. Handbook of Clinical Neurology. 106. Elsevier. 2012. pp. 657–667. doi:10.1016/b978-0-444-52002-9.00039-5. ISBN 9780444520029. 
  11. ↑ "Synaptic release of dopamine in the subthalamic nucleus". The European Journal of Neuroscience 20 (7): 1788–802. October 2004. doi:10.1111/j.1460-9568.2004.03629.x. PMID 15380000. 
  12. ↑ "Potential substrates for nicotine and alcohol interactions: a focus on the mesocorticolimbic dopamine system". Biochemical Pharmacology 86 (8): 1181–93. October 2013. doi:10.1016/j.bcp.2013.07.007. PMID 23876345. 
  13. ↑ "Mesocorticolimbic glutamatergic pathway". The Journal of Neuroscience 31 (23): 8476–90. June 2011. doi:10.1523/JNEUROSCI.1598-11.2011. PMID 21653852. 
  14. ↑ "Differential contributions of striatal dopamine D1 and D2 receptors to component processes of value-based decision making". Neuropsychopharmacology 44 (13): 2195–2204. December 2019. doi:10.1038/s41386-019-0454-0. PMID 31254972. 
  15. ↑ "Chapter 13: Higher Cognitive Function and Behavioral Control". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. 2009. pp. 313–321. ISBN 9780071481274. " • Executive function, the cognitive control of behavior, depends on the prefrontal cortex, which is highly developed in higher primates and especially humans.
     • 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."     
  16. ↑ 16.0 16.1 16.2 "Dopaminergic and noradrenergic contributions to functionality in ADHD: the role of methylphenidate". Current Neuropharmacology 6 (4): 322–8. December 2008. doi:10.2174/157015908787386069. PMID 19587853. 
  17. ↑ 17.0 17.1 "New insights into the roles of microRNAs in drug addiction and neuroplasticity". Genome Medicine 2 (12): 92. December 2010. doi:10.1186/gm213. PMID 21205279. 
  18. ↑ "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews. Neuroscience 12 (11): 623–37. October 2011. doi:10.1038/nrn3111. PMID 21989194. 
  19. ↑ Keyser, J. De (1990). "The mesoneocortical dopamine neuron system". Neurology 40 (11): 1660-1660. https://doi.org/10.1212/WNL.40.11.1660. 
  20. ↑ Floresco, Stan B.; Magyar, Orsolya (2006). "Mesocortical dopamine modulation of executive functions: beyond working memory". Psychopharmacology 188: 567-585. https://doi.org/10.1007/s00213-006-0404-5. 
  21. ↑ 21.0 21.1 "The mysterious motivational functions of mesolimbic dopamine". Neuron 76 (3): 470–85. November 2012. doi:10.1016/j.neuron.2012.10.021. PMID 23141060. 
  22. ↑ "Mesolimbic dopaminergic pathways in fear conditioning". Progress in Neurobiology 74 (5): 301–20. December 2004. doi:10.1016/j.pneurobio.2004.09.004. PMID 15582224. 
  23. ↑ "Pleasure systems in the brain". Neuron 86 (3): 646–64. May 2015. doi:10.1016/j.neuron.2015.02.018. PMID 25950633. "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.". 
  24. ↑ "Neuroscience of affect: brain mechanisms of pleasure and displeasure". Current Opinion in Neurobiology 23 (3): 294–303. June 2013. doi:10.1016/j.conb.2013.01.017. PMID 23375169. 
  25. ↑ Molecular neuropharmacology a foundation for clinical neuroscience. Paul J. Kenny, Scott J. Russo, Anne, MD Schaefer (Fourth ed.). New York. 2020. ISBN 978-1-260-45691-2. OCLC 1191071328. https://www.worldcat.org/oclc/1191071328. 
  26. ↑ "Pleasure systems in the brain". Neuron 86 (3): 646–64. May 2015. doi:10.1016/j.neuron.2015.02.018. PMID 25950633. 
  27. ↑ "The role of the dorsal striatum in reward and decision-making". The Journal of Neuroscience 27 (31): 8161–8165. August 2007. doi:10.1523/JNEUROSCI.1554-07.2007. PMID 17670959. 
  28. ↑ "Physiological and Functional Basis of Dopamine Receptors and Their Role in Neurogenesis: Possible Implication for Parkinson's disease". Journal of Experimental Neuroscience 12: 1179069518779829. 2018. doi:10.1177/1179069518779829. PMID 29899667. 
  29. ↑ "Meta-Analysis of Parkinson's Disease Transcriptome Data Using TRAM Software: Whole Substantia Nigra Tissue and Single Dopamine Neuron Differential Gene Expression". PLOS ONE 11 (9): e0161567. 2016-09-09. doi:10.1371/journal.pone.0161567. PMID 27611585. Bibcode: 2016PLoSO..1161567M. 
  30. ↑ "Learning and Memory in Addiction". Learning and Memory: A Comprehensive Reference. Elsevier. 2017. pp. 523–538. doi:10.1016/b978-0-12-809324-5.21101-2. ISBN 9780128052914. https://escholarship.org/uc/item/9ww1p0g8. 
  31. ↑ "Perioperative pain management and outcomes in patients who -discontinued or continued pre-existing buprenorphine therapy". Journal of Opioid Management 17 (7): 33–41. 2021-08-01. doi:10.5055/jom.2021.0640. PMID 34520024. 
  32. ↑ Russell, John A.; Douglas, Alison J.; Ingram, Colin D. (2001). "Brain preparations for maternity—adaptive changes in behavioral and neuroendocrine systems during pregnancy and lactation. An overview.". Progress in brain research 133: 1-38. https://doi.org/10.1016/S0079-6123(01)33002-9. 
  33. ↑ "The neurocircuitry of illicit psychostimulant addiction: acute and chronic effects in humans". Substance Abuse and Rehabilitation 4: 29–43. 2013. doi:10.2147/SAR.S39684. PMID 24648786. 
  34. ↑ "The ins and outs of the striatum: role in drug addiction". Neuroscience 301: 529–41. August 2015. doi:10.1016/j.neuroscience.2015.06.033. PMID 26116518. 
  35. ↑ 35.0 35.1 "From reinforcement learning models to psychiatric and neurological disorders". Nature Neuroscience 14 (2): 154–62. February 2011. doi:10.1038/nn.2723. PMID 21270784. 
  36. ↑ "Abnormally high degree connectivity of the orbitofrontal cortex in obsessive-compulsive disorder". JAMA Psychiatry 70 (6): 619–29. June 2013. doi:10.1001/jamapsychiatry.2013.173. PMID 23740050. 
  37. ↑ "The neural bases of obsessive-compulsive disorder in children and adults". Development and Psychopathology 20 (4): 1251–83. 1 January 2008. doi:10.1017/S0954579408000606. PMID 18838041. 
  38. ↑ "Serotonin interaction with other transmitter systems.". Handbook of Behavioral Neuroscience. 21. London: Academic. January 2010. pp. 259-276 (262–264). ISBN 978-0-12-374634-4. 
  39. ↑ "Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens". Proceedings of the National Academy of Sciences of the United States of America 112 (26): 8124–9. June 2015. doi:10.1073/pnas.1508846112. PMID 26080439. Bibcode: 2015PNAS..112.8124S. 
  40. ↑ 40.0 40.1 40.2 "Endocannabinoid signaling in midbrain dopamine neurons: more than physiology?". Current Neuropharmacology 5 (4): 268–77. December 2007. doi:10.2174/157015907782793612. PMID 19305743. "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.".     
  41. ↑ 41.0 41.1 41.2 41.3 41.4 41.5 41.6 "Dynamic regulation of midbrain dopamine neuron activity: intrinsic, synaptic, and plasticity mechanisms". Neuroscience 198: 95–111. December 2011. doi:10.1016/j.neuroscience.2011.08.023. PMID 21872647. 
  42. ↑ 42.0 42.1 "New perspectives on catecholaminergic regulation of executive circuits: evidence for independent modulation of prefrontal functions by midbrain dopaminergic and noradrenergic neurons". Frontiers in Neural Circuits 8: 53. 2014. doi:10.3389/fncir.2014.00053. PMID 24904299. "It has been shown that electrical stimulation of LC results in an excitation followed by a brief inhibition of midbrain dopamine (DA) neurons through an α1 receptor dependent mechanism (Grenhoff et al., 1993).". 
  43. ↑ 43.0 43.1 43.2 43.3 43.4 43.5 "Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far". Frontiers in Neuroscience 7: 256. December 2013. doi:10.3389/fnins.2013.00256. PMID 24391536. "Direct CB1-HcrtR1 interaction was first proposed in 2003 (Hilairet et al., 2003). Indeed, a 100-fold increase in the potency of hypocretin-1 to activate the ERK signaling was observed when CB1 and HcrtR1 were co-expressed ... In this study, a higher potency of hypocretin-1 to regulate CB1-HcrtR1 heteromer compared with the HcrtR1-HcrtR1 homomer was reported (Ward et al., 2011b). These data provide unambiguous identification of CB1-HcrtR1 heteromerization, which has a substantial functional impact. ... The existence of a cross-talk between the hypocretinergic and endocannabinoid systems is strongly supported by their partially overlapping anatomical distribution and common role in several physiological and pathological processes. However, little is known about the mechanisms underlying this interaction. ... Acting as a retrograde messenger, endocannabinoids modulate the glutamatergic excitatory and GABAergic inhibitory synaptic inputs into the dopaminergic neurons of the VTA and the glutamate transmission in the NAc. Thus, the activation of CB1 receptors present on axon terminals of GABAergic neurons in the VTA inhibits GABA transmission, removing this inhibitory input on dopaminergic neurons (Riegel and Lupica, 2004). Glutamate synaptic transmission in the VTA and NAc, mainly from neurons of the PFC, is similarly modulated by the activation of CB1 receptors (Melis et al., 2004).". 
     • Figure 1: Schematic of brain CB1 expression and orexinergic neurons expressing OX1 (HcrtR1) or OX2 (HcrtR2)
     • Figure 2: Synaptic signaling mechanisms in cannabinoid and orexin systems
     • Figure 3: Schematic of brain pathways involved in food intake
  44. ↑ 44.0 44.1 "Lateral hypothalamic orexin/hypocretin neurons: A role in reward-seeking and addiction". Brain Research 1314: 74–90. February 2010. doi:10.1016/j.brainres.2009.09.106. PMID 19815001. 
  45. ↑ 45.0 45.1 "Human orexin/hypocretin receptors form constitutive homo- and heteromeric complexes with each other and with human CB1 cannabinoid receptors". Biochemical and Biophysical Research Communications 445 (2): 486–90. March 2014. doi:10.1016/j.bbrc.2014.02.026. PMID 24530395. "Orexin receptor subtypes readily formed homo- and hetero(di)mers, as suggested by significant BRET signals. CB1 receptors formed homodimers, and they also heterodimerized with both orexin receptors. ... In conclusion, orexin receptors have a significant propensity to make homo- and heterodi-/oligomeric complexes. However, it is unclear whether this affects their signaling. As orexin receptors efficiently signal via endocannabinoid production to CB1 receptors, dimerization could be an effective way of forming signal complexes with optimal cannabinoid concentrations available for cannabinoid receptors.". 



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