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Dopaminergic pathways

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Dopaminergic pathways(dopamine pathways,dopaminergic projections) in thehuman brainare involved in both physiological and behavioral processes includingmovement,cognition,executive functions,reward,motivation,andneuroendocrine control.[1]Each pathway is a set ofprojection neurons,consisting of individual dopaminergic neurons.

The main dopaminergic pathways of thehuman brain

The four major dopaminergic pathways are themesolimbic pathway,themesocortical pathway,thenigrostriatal pathway,and thetuberoinfundibular pathway.The mesolimbic pathway and the mesocortical pathway form the mesocorticolimbic system. Two other dopaminergic pathways to be considered are thehypothalamospinal tractand theincertohypothalamic pathway.

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

The dopamine neurons of the dopaminergic pathways synthesize and release theneurotransmitterdopamine.[2][3]Enzymestyrosine hydroxylaseanddopa decarboxylaseare required for dopamine synthesis.[4]These enzymes are both produced in thecell bodiesof 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]Theaxonsof dopamine neurons extend the entire length of their designated pathway.

Pathways

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Major

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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 theventral tegmental area(VTA), which is located in themidbrain,to theventral striatum,which includes both thenucleus accumbensandolfactory tubercle.[5][6]The "meso"prefixin the word "mesolimbic" refers to the midbrain, or "middle brain", since "meso" means "middle" inGreek.
Mesocortical
pathway
 The mesocortical pathway transmits dopamine from the VTA to theprefrontal cortex.The "meso" prefix in "mesocortical" refers to the VTA, which is located in the midbrain, and "cortical" refers to the cortex.
Nigrostriatal pathway The nigrostriatal pathway transmits dopaminergic neurons from the zona compacta of the substantia nigra[8]to thecaudate nucleusandputamen.

Thesubstantia nigrais located in the midbrain, while both the caudate nucleus and putamen are located in thedorsal striatum.

Tuberoinfundibular pathway The tuberoinfundibular pathway transmits dopamine from thehypothalamusto thepituitary gland.

This pathway controls the secretion of certainhormones,includingprolactin,from the pituitary gland.[9]

"Infundibular" in the word "tuberoinfundibular" refers to the cup orinfundibulum,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 thezona incertainfluences the hypothalamus and locomotor centers in the brainstem.
  • visceral and sensorimotor activities.

Minor

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

Function

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Mesocorticolimbic system

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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.

Themesocorticolimbic system(mesocorticolimbic circuit) refers to both themesocorticalandmesolimbicpathways.[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 andnegative feedback.[14]Both pathways of the mesocorticolimbic system are associated withADHD,schizophreniaandaddiction.[15][16][17][18]

Mesocortical pathway

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Themesocortical pathwayprojects from the ventral tegmental area to the prefrontal cortex (VTA→Prefrontal cortex). This pathway is involved in cognition and the regulation ofexecutive 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

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Referred to as the reward pathway,mesolimbic pathwayprojects from the ventral tegmental area to the ventral striatum (VTA →Ventral striatum[nucleus accumbensandolfactory tubercle]).[17]When a reward is anticipated, the firing rate of dopamine neurons in the mesolimbic pathway increases.[21]The mesolimbic pathway is involved withincentive 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

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Thenigrostriatal pathwayis involved in behaviors relating to movement and motivation. The transmission of dopaminergic neurons to thedorsal striatumparticularly 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

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Thetuberoinfundibular pathwaytransmits dopamine from thehypothalamusto thepituitary 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

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The dopaminergic pathways that project from thesubstantia nigra pars compacta(SNc) andventral tegmental area(VTA) into thestriatum(i.e., the nigrostriatal and mesolimbic pathways, respectively) form one component of a sequence of pathways known as thecortico-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 theglobus pallidus,before carrying on to the thalamus, or into thesubthalamic nucleusbefore heading into thethalamus.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.[35]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.[36]

These models of the basal ganglia are thought to be relevant to the study ofOCD,[37][38]ADHD,Tourette syndrome,Parkinson's disease,schizophrenia,andaddiction.For example,Parkinson's diseaseis 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.[36]

Regulation

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Theventral tegmental areaandsubstantia nigra pars compactareceive inputs from other neurotransmitters systems, includingglutaminergicinputs,GABAergicinputs, cholinergic inputs, and inputs from other monoaminergic nuclei. The VTA contains5-HT1Areceptorsthat exert a biphasic effects onfiring,with low doses of 5-HT1Areceptor agonists eliciting an increase in firing rate, and higher doses suppressing activity. The5-HT2Areceptorsexpressed on dopaminergic neurons increase activity, while5-HT2Creceptorselicit a decrease in activity.[39]The mesolimbic pathway, which projects from the VTA to the nucleus accumbens, is also regulated bymuscarinic acetylcholine receptors.In particular, the activation ofmuscarinic acetylcholine receptor M2andmuscarinic acetylcholine receptor M4inhibits dopamine release, whilemuscarinic acetylcholine receptor M1activation increases dopamine release.[40]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.[41]Noradrenergicinputs deriving from thelocus coeruleushave excitatory and inhibitory effects on the dopaminergic neurons that project out of the VTA and SNc.[42][43]The excitatoryorexinergicinputs to the VTA originate in thelateral hypothalamusand may regulate the baselinefiringof VTA dopaminergic neurons.[44][45]

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 [42]
GABA Inhibitory projections into the VTA and SNc [42]
Serotonin Modulatory effect, depending on receptor subtype
Produces a biphasic effect on VTA neurons 		[42]
Norepinephrine Modulatory effect, depending on receptor subtype
The excitatory and inhibitory effects of theLCon the VTA and SNc are time-dependent 		[42][43]
Endocannabinoids Excitatory effect on dopaminergic neurons from inhibiting GABAergic inputs
Inhibitory effect on dopaminergic neurons from inhibiting glutamatergic inputs
May interact with orexins viaCB1–OX1receptor heterodimersto regulate neuronal firing 		[41][42][44][46]
Acetylcholine Modulatory effect, depending on receptor subtype [42]
Orexin Excitatory effect on dopaminergic neurons via signaling throughorexin receptors(OX1andOX2)
Increases both tonic and phasic firing of dopaminergic neurons in the VTA
May interact with endocannabinoids viaCB1–OX1receptor heterodimersto regulate neuronal firing 		[44][45][46]

See also

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Notes

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  1. ^abAt achemical synapse,neurotransmitters are normally released from the presynapticaxon terminaland signal through receptors that are located on thedendritesof the postsynaptic neuron; however, inretrograde neurotransmission,the dendrites of the postsynaptic neuron release neurotransmitters that signal through receptors that are located on the axon terminal of the presynaptic neuron.[44]
    Endocannabinoids signal between neurons through retrograde neurotransmission at synapses;[44]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.[41][44]

References

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    Figure 3: The ventral striatum and self-administration of amphetamine
  6. ^abcdefgMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience(2nd ed.). New York: McGraw-Hill Medical. pp. 147–148, 154–157.ISBN9780071481274.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.
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    • 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.
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  42. ^abcdefgMorikawa H, Paladini CA (December 2011)."Dynamic regulation of midbrain dopamine neuron activity: intrinsic, synaptic, and plasticity mechanisms".Neuroscience.198:95–111.doi:10.1016/j.neuroscience.2011.08.023.PMC3221882.PMID21872647.
  43. ^abChandler DJ, Waterhouse BD, Gao WJ (2014)."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.doi:10.3389/fncir.2014.00053.PMC4033238.PMID24904299.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).
  44. ^abcdefFlores A, Maldonado R, Berrendero F (December 2013)."Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far".Frontiers in Neuroscience.7:256.doi:10.3389/fnins.2013.00256.PMC3868890.PMID24391536.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
  45. ^abAston-Jones G, Smith RJ, Sartor GC, Moorman DE, Massi L, Tahsili-Fahadan P, Richardson KA (February 2010)."Lateral hypothalamic orexin/hypocretin neurons: A role in reward-seeking and addiction".Brain Research.1314:74–90.doi:10.1016/j.brainres.2009.09.106.PMC2819557.PMID19815001.
  46. ^abJäntti MH, Mandrika I, Kukkonen JP (March 2014). "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.doi:10.1016/j.bbrc.2014.02.026.PMID24530395.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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