Why Does Dopamine Matter and Why Devote Time to Understanding it Better? Mood Dopamine Receptor Pharmacology: Drive Cognition What We Clinicians Need to Know DOPAMINE Rakesh Jain, MD, MPH Well- Pleasure being Clinical Professor Department of Psychiatry Texas Tech Health Sciences Center School of Medicine Risk- Appetite taking Midland, Texas Knab AM, et al. Int J Biol Sci . 2010;6(2):133-150. Dopamine Sits at the Junction of Through its Main 4 Pathways, Dopamine Exerts Vast Control over Brain/Body Functioning Reward and Addiction (and So Much More) Mesolimbic & • Mesolimbic dopamine pathway Mesocortical – Involved in pleasurable sensations, reward, pathway , euphoria of drugs of abuse, and psychosis – Hyperactivity of dopamine neurons may which is the projection mediate positive symptoms from VTA, cell group • Mesocortical dopamine pathway A10, to NAc, PFC, and – Involved in cognition, executive function, and other limbic areas. These neurons play a regulation of emotion/affect crucial role in reward- – Hypoactivity in the mesocortical pathway may mediate cognitive, negative, and affective related behaviors. symptoms • Nigrostriatal pathway – Involved in control of motor movements – Plays significant role in EPS • Tuberoinfundibular pathway – Involved in neuroendocrine regulation – Plays significant role in neuroendocrine adverse effects (hyperprolactinemia) EPS = extrapyramidal symptoms. Beaulieu JM, et al. Pharmacol Rev . 2011;63(1):182-217. Stahl SM. Stahl’s Essential Psychopharmacology: NAc = nucleus accumbens; PFC = prefrontal cortex; VTA = ventral tegmental area. Neuroscientific Basis and Practical Applications . Fourth Edition. New York, NY: Cambridge University Press; 2013. Volkow ND, et al. N Engl J Med . 2016;374(4):363-371. Meltzer HY, et al. Schizophr Bull . 1976;2(1):19-76. A Quick Primer on Dopamine and Other Neurotransmitter Pathways AD = aldehyde dehydrogenase; DOPAC = 3,4- dihydroxyphenylaceti Dopamine – A Life Story c acid; DBH = dopamine b hydroxylase; GTPCH = guanosine triphosphate Cyclohydrolase; H2NP2 = dihydroneopterin triphosphate; 3-MT = 3-methoxytyramine; PCD = pterin-4a- carbinolamine dehydratase; PLP = pyridoxal phosphate = PNMT = phenylethanolamine N-methyltransferase; TH = tyrosine hydroxylase; VMA = vanillylmandelic acid. Ng J, et al. Paediatr Drugs . 2014;16(4):275-291.
Macro and Micro Understanding of Dopamine Neurons 1. Tonic DA release is dependent on slow, irregular spike activity of VTA DA neurons Fire in Both Tonic and Dopamine, Its Pathways, and Receptors 2. Is modulated by glutamatergic afferents Phasic Fashion from the PFC 3. Tonic DA releases low levels of DA (5–20 nM concentrations) into the extra synaptic space 4. Where it is subject to a limited degree of catabolism by COMT 5. Phasic DA transmission is evoked by behaviorally salient stimuli, and is triggered by burst firing of VTA neurons 6. Which release very high levels of DA into The signaling pathways in the the synaptic cleft, where it stimulates postsynaptic neuron are only postsynaptic D 2 -like DA receptors representative of D 1 -like receptor 7. Phasic DA is inactivated by removal from signaling (which increases cAMP). the synaptic cleft via rapid uptake by DAT D 2 -like receptors are known to have 8. Although tonic DA occurs in too low a opposite affects on cAMP activity, concentration to stimulate intrasynaptic D 2 - like DA receptors, it stimulates presynaptic and thus slightly different downstream D 2 -like DA autoreceptors signaling cascades. Dopaminergic 9. Which then inhibit phasic DA release signaling effects on ion channels and membrane permeability. COMT = catechol-O-methyltransferase; DA = dopamine; DAT = DA transporter. Knab AM, et al. Int J Biol Sci . 2010;6(2):133-150. Jarcho JM, et al. Pain . 2012;153(4):744-754. Dopamine Along with Other Monoamine Pathways Overlap in Monoamines is Involved in Several Areas of the Brain Various Mood Disorders Cerebral • One hypothesis of mood disorders Cortex is that it may arise from a deficit or underactivity in the brain of monoamine signaling (DA, 5-HT, AA and/or NE) C S • Deficiency in monoaminergic neuro- T transmission may be in the monoamine levels themselves, or PFC Hy through disrupted receptor signaling C Norepinephrine A • Evidence supporting this hypothesis Dopamine is that antidepressant therapies H have been shown to raise neuro- Substantia C Serotonin transmission tone of these neuro- nigra and VTA A1, A2, transmitters (5-HT, NE, and/or DA) A5, A7 Locus coeruleus and reduce depressive symptoms Raphe nuclei 5-HT = serotonin; NE = norepinephrine. Perović B, et al. Neuropsychiatr Dis Treat . 2010;6:343-364. Fuchs E, et al. Dialogues Clin Neurosci . 2004;6(2):171-183. Dopamine, Through its Receptors, Dopamine Serves as a Great Regulator/ Communicator in the Neural Circuitry of Monoamines Modulates Multiple Other Neurotransmitters Cortical Pyramidal Neurons Dopamine interacts with Β (+) α2A (─) D2/3 ( ─ ) the following Systems, Glu Glu through its multiple DA NE Receptors (DR1-5) + α1 NE LC VTA α2 ─ NE GABA DA D2 DA ─ ─ α2 Glutamate ─ DA Acetylcholine NE NE DA Histamine + + D2 DRN Serotonin 5HT Norepinephrine + = agonism or stimulatory effect; ─ = antagonism or inhibitory effect; ─ DRN = dorsal raphe nucleus; Glu = glutamate; LC = locus coeruleus. 5HT GABA = gamma-aminobutyric acid. Clarke R, et al. Neural Plast . 2015;2015:814567. El Mansari M, et al. CNS Neurosci Ther . 2010;16(3):e1-e17.
Dopamine May Be Particularly Important in Dopamine Pathways: Clinical Implications Addressing Residual Symptoms of Depression Many Symptoms Appear to be Influenced Most Common DSM-IV Residual Symptoms Of MDD Nigrostriatal pathway where DA cells within by Monoamine Signaling pars compacta (A8) and neighboring area (group A9) from SN project to striatum, this projection is involved in mostly the control Dopamine of voluntary movement. Pleasure, reward, motivation/drive Mesolimbic & Mesocortical pathway , which is the projection from VTA, cell group A10, to the Appetite, sex, Attention aggression NAc, PFC, and other limbic areas. These Mood, neurons play a crucial role in reward-related cognitive behaviors. function Norepinephrine Serotonin Alertness, Anxiety, Obsessions, concentration, Tuberoinfundibular pathways , which are the impulse, compulsions, energy irritability cells fromarcuate nucleus (cell group A12) and memory Brain Region PFC S NA Hy SC periventricular nucleus (cell group A14) of the Concentration, Fatigue Fatigue, Fatigue Symptom(s) interest, fatigue Insomnia hypothalamus, projecting to the pituitary. This (physical) energy (physical) (mental) pathway is known to control the release and Monoamine synthesis of pituitary hormone, mostly pathways NE/DA NE/DA NE/DA 5-HT/NE NE/DA implicated prolactin. S = striatum; NA = nucleus accumbens; Hy = hypothalamus; SC = spinal cord. SN = substantia nigra; HP = hypothalamus . Nutt D. J Clin Psychiatry . 2008;69 Suppl E1:4-7. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Baik JH. BMB Rep . 2013;46(11):519-526. Basis and Practical Applications . Fourth Edition. New York, NY: Cambridge University Press; 2013. Dopamine and Nucleus Accumbens: Deep Connections to Cognition, Emotion, and Pain Modulating Regions of the Brain primary sensory S1 cortex Functional Pharmacology of Dopamine primary motor M1 cortex supplementary SMA motor area PMC premotor cortex dorsolateral DLPFC prefrontal cortex anterior cingulate ACC cortex parahippocampal PHG gyrus NAc Alhourani A, et al. J Neurophysiol . 2015;114(4):2105-2117. Dopamine Impacts the Dopamine – Impacts Multiple Issues Pain / Insomnia / Mood Triad (Cognition, Affect, and Pain) Vulnerability model of tonic/phasic DA dysregulation. Solid arrows represent putative bidirectional pathways through which abnormalities in the homeostatic regulation of tonic and phasic DA contribute to the comorbid triad of insomnia, chronic pain, and depression. Dashed arrows represent putative moderators of DA function in this model. Finan PH, et al. Sleep Med Rev . 2013;17(3):173-183. Jarcho JM, et al. Pain . 2012;153(4):744-754.
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