Dopamine Receptor Pharmacology: What We Clinicians Need to Know. Dopamine Sits at the Junction of Reward and Addiction (and So Much More)

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1 Why Does Dopamine Matter and Why Devote Time to Understanding it Better? Dopamine Receptor Pharmacology: What We Clinicians Need to Know Drive Mood Cognition Rakesh Jain, MD, MPH Clinical Professor Department of Psychiatry Texas Tech Health Sciences Center School of Medicine Midland, Texas Pleasure Appetite Knab AM, et al. Int J Biol Sci. 2010;6(2): DOPAMINE Wellbeing Risktaking Through its Main 4 Pathways, Dopamine Exerts Vast Control over Brain/Body Functioning Mesolimbic dopamine pathway Involved in pleasurable sensations, reward, euphoria of drugs of abuse, and psychosis Hyperactivity of dopamine neurons may mediate positive symptoms Mesocortical dopamine pathway Involved in cognition, executive function, and regulation of emotion/affect Hypoactivity in the mesocortical pathway may mediate cognitive, negative, and affective 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. Stahl SM. Stahl s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Fourth Edition. New York, NY: Cambridge University Press; Meltzer HY, et al. Schizophr Bull. 1976;2(1): Dopamine Sits at the Junction of Reward and Addiction (and So Much More) NAc = nucleus accumbens; PFC = prefrontal cortex; VTA = ventral tegmental area. Volkow ND, et al. N Engl J Med. 2016;374(4): Mesolimbic & Mesocortical pathway, which is the projection from VTA, cell group A10, to NAc, PFC, and other limbic areas. These neurons play a crucial role in rewardrelated behaviors. A Quick Primer on Dopamine and Other Neurotransmitter Pathways Dopamine A Life Story AD = aldehyde dehydrogenase; DOPAC = 3,4- dihydroxyphenylaceti c acid; DBH = dopamine b hydroxylase; GTPCH = guanosine triphosphate Cyclohydrolase; H2NP2 = dihydroneopterin triphosphate; 3-MT = 3-methoxytyramine; PCD = pterin-4acarbinolamine dehydratase; PLP = pyridoxal phosphate = PNMT = phenylethanolamine N-methyltransferase; TH = tyrosine hydroxylase; VMA = vanillylmandelic acid. Ng J, et al. Paediatr Drugs. 2014;16(4):

2 Macro and Micro Understanding of Dopamine, Its Pathways, and Receptors The signaling pathways in the postsynaptic neuron are only representative of D 1 -like receptor signaling (which increases camp). D 2 -like receptors are known to have opposite affects on camp activity, and thus slightly different downstream signaling cascades. Dopaminergic signaling effects on ion channels and membrane permeability. Knab AM, et al. Int J Biol Sci. 2010;6(2): Dopamine Neurons Fire in Both Tonic and Phasic Fashion 1. Tonic DA release is dependent on slow, irregular spike activity of VTA DA neurons 2. Is modulated by glutamatergic afferents 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 synaptic cleft, where it stimulates postsynaptic D 2 -like DA receptors 7. Phasic DA is inactivated by removal from the synaptic cleft via rapid uptake by DAT 8. Although tonic DA occurs in too low a concentration to stimulate intrasynaptic D 2 - like DA receptors, it stimulates presynaptic D 2 -like DA autoreceptors 9. Which then inhibit phasic DA release COMT = catechol-o-methyltransferase; DA = dopamine; DAT = DA transporter. Jarcho JM, et al. Pain. 2012;153(4): Dopamine Along with Other Monoamines is Involved in Various Mood Disorders One hypothesis of mood disorders is that it may arise from a deficit or underactivity in the brain of monoamine signaling (DA, 5-HT, and/or NE) Deficiency in monoaminergic neurotransmission may be in the monoamine levels themselves, or through disrupted receptor signaling Evidence supporting this hypothesis is that antidepressant therapies have been shown to raise neurotransmission tone of these neurotransmitters (5-HT, NE, and/or DA) and reduce depressive symptoms 5-HT = serotonin; NE = norepinephrine. Perović B, et al. Neuropsychiatr Dis Treat. 2010;6: Monoamine Pathways Overlap in Several Areas of the Brain PFC Substantia nigra and VTA Cerebral Cortex AA C Fuchs E, et al. Dialogues Clin Neurosci. 2004;6(2): S T Hy A C Norepinephrine H Dopamine C Serotonin A1, A2, A5, A7 Locus coeruleus Raphe nuclei Dopamine, Through its Receptors, Modulates Multiple Other Neurotransmitters Dopamine Serves as a Great Regulator/ Communicator in the Neural Circuitry of Monoamines Cortical Pyramidal Neurons Dopamine interacts with the following Systems, through its multiple Receptors (DR1-5) GABA Glutamate Acetylcholine Histamine Serotonin Norepinephrine Glu DA VTA DA DA D2/3 ( ) + α1 α2 D2 DA + = agonism or stimulatory effect; = antagonism or inhibitory effect; DRN = dorsal raphe nucleus; Glu = glutamate; LC = locus coeruleus. DA NE + D2 DRN 5HT 5HT + NE Β(+) NE LC NE NE α2a ( ) α2 Glu GABA = gamma-aminobutyric acid. Clarke R, et al. Neural Plast. 2015;2015: El Mansari M, et al. CNS Neurosci Ther. 2010;16(3):e1-e17.

3 Dopamine May Be Particularly Important in Addressing Residual Symptoms of Depression Many Symptoms Appear to be Influenced by Monoamine Signaling Dopamine Pleasure, reward, motivation/drive Appetite, sex, Attention aggression Mood, cognitive function Norepinephrine Alertness, Serotonin Anxiety, concentration, Obsessions, impulse, energy compulsions, irritability memory Most Common DSM-IV Residual Symptoms Of MDD Brain Region PFC S NA Hy SC Symptom(s) Monoamine pathways implicated Concentration, interest, fatigue (mental) Fatigue (physical) Fatigue, energy Insomnia S = striatum; NA = nucleus accumbens; Hy = hypothalamus; SC = spinal cord. Nutt D. J Clin Psychiatry. 2008;69 Suppl E1:4-7. Stahl SM. Stahl s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Fourth Edition. New York, NY: Cambridge University Press; Fatigue (physical) NE/DA NE/DA NE/DA 5-HT/NE NE/DA Dopamine Pathways: Clinical Implications SN = substantia nigra; HP = hypothalamus. Baik JH. BMB Rep. 2013;46(11): Nigrostriatal pathway where DA cells within pars compacta (A8) and neighboring area (group A9) from SN project to striatum, this projection is involved in mostly the control of voluntary movement. Mesolimbic & Mesocortical pathway, whichis the projection from VTA, cell group A10, to the NAc, PFC, and other limbic areas. These neurons play a crucial role in reward-related behaviors. Tuberoinfundibular pathways, which are the cells fromarcuate nucleus (cell group A12) and periventricular nucleus (cell group A14) of the hypothalamus, projecting to the pituitary. This pathway is known to control the release and synthesis of pituitary hormone, mostly prolactin. Functional Pharmacology of Dopamine Dopamine and Nucleus Accumbens: Deep Connections to Cognition, Emotion, and Pain Modulating Regions of the Brain S1 M1 SMA PMC DLPFC ACC PHG primary sensory cortex primary motor cortex supplementary motor area premotor cortex dorsolateral prefrontal cortex anterior cingulate cortex parahippocampal gyrus NAc Alhourani A, et al. J Neurophysiol. 2015;114(4): Dopamine Impacts the Pain / Insomnia / Mood Triad Dopamine Impacts Multiple Issues (Cognition, Affect, and Pain) Finan PH, et al. Sleep Med Rev. 2013;17(3): 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. Jarcho JM, et al. Pain. 2012;153(4):

4 Food and Food Cravings Interactions with Dopamine and Its Receptors How Dopamine and Its Various Receptors Affect Exercise Motivation Dopamine system can act in both an independent and dependent manner in regard to regulation of physical activity Food reward circuit involving DA system and D 2 receptors. As the drug addiction, it appears that food stimuli activate VTA-NAc DA mesolimbic circuit with phenotypic importance of feeding behaviors translated through signaling in caudate putamen, DS, interacting with PFC for decision making and execution of eating behaviors. As well, the homeostatic regulators such as leptin, insulin, and ghrelin exert their input to midbrain DA system for connection between homeostatic and hedonic system of food intake. DS = dorsal striatum. Baik JH. BMB Rep. 2013;46(11): Physical activity (ie, intensity and duration of exercise) can cause changes in neuronal signaling as well. Knab AM, et al. Int J Biol Sci. 2010;6(2): Dopamine and Music Music has existed in human societies since prehistory, perhaps because it allows expression and regulation of emotion and evokes pleasure. Dopamine: Risk-Taking and Well-Being Dopamine s influence on economic risk-taking and on subjective well-being This was a within-subject double-blind placebo controlled study. Subjects participated on 2 occasions, typically 1 week apart at a similar time of day, performing the same task on both days, 60 min after ingestion of either L-DOPA (150 mg of L-DOPA and 37.5 mg of benserazide mixed in orange juice) or placebo (500 mg of ascorbic acid mixed in orange juice). All subjects performed a 300-trial economic decision-making task with trials of three different types: gain trials, mixed trials, and loss trials. Boosting dopamine levels increased the number of risky options chosen in trials involving potential gains Dopamine, NAc, and Mesolimbic striatal systems are all activated by Familiar and Novel music and its involvement in reward, motivation, and pleasure Zatorre RJ, et al. Proc Natl Acad Sci U S A. 2013;110 Suppl 2: *P <.05. Rutledge RB, et al. J Neurosci. 2015;35(27): Boosting dopamine also increased happiness resulting from some rewards Dopamine Receptor Classification and Its Diverse Pharmacology Dopamine Receptor Classification Individual Receptors are Diverse and We Clinicians Need to Know the Differences D 1 Like Family Members are D 1 (coded by the DRD1 gene) D 5 (coded by DRD5 gene) Stimulation of these leads to increased camp D 2 Like Family Members are D 2 receptor (coded by DRD2 gene) D 3 receptor (coded by DRD3 gene) D 4 receptor (coded by DRD4 gene) Stimulation of these leads to decreased camp

5 The Dopamine Receptor Family Mediated by G proteincoupled receptors in 2 major groups D 1 -class (D 1 and D 5 ) Found primarily postsynaptically D 2 -class (D 2, D 3, D 4 ) Expressed pre- and postsynaptically D 2 is the high affinity binding site for virtually all antipsychotic agents Location, Location, Location Significant Differences in Dopamine Receptor Distribution Cerebral cortex D 1, D 2, D 4, D 5 Striatum D 1, D 2, D 5 NAc D 1, D 2, D 3, D 5 Hypothalamus D 1, D 2, D 4, D 5 VTA D 2, D 3, D 5 SN D 2, D 3, D 5 Hippocampus D 1, D 2, D 4, D 5 Stahl SM. Stahl s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Fourth Edition. New York, NY: Cambridge University Press; Beaulieu JM, et al. Pharmacol Rev. 2011;63(1): Brichta L, et al. Trends Neurosci. 2013;36(9): Basic Genetic, Structural, and Pharmacologic Properties of Dopamine Receptor Subtypes Dopamine D 1 Family D 1 dopamine receptors are expressed at a high level of density in the nigrostriatal, mesolimbic, and mesocortical areas, such as the caudate-putamen (striatum), NAc, SN, olfactory bulb, amygdala, and frontal cortex, as well as at lower levels in the hippocampus, cerebellum, and thalamic areas D 5 dopamine receptors are expressed at low levels in multiple brain regions, including pyramidal neurons of the PFC, the premotor cortex, the cingulate cortex, the entorhinal cortex, SN, hypothalamus, the hippocampus, and the dentate gyrus Dopamine D 2 Family The highest levels of D 2 dopamine receptors are found in the striatum, the NAc, and the olfactory tubercle. D 2 receptors are also expressed at significant levels in the SN, VTA, hypothalamus, cortical areas, septum, amygdala, and hippocampus The D 3 dopamine receptor has a more limited pattern of distribution, the highest level of expression being observed in the limbic areas, such as in the shell of the NAc The D 4 dopamine receptor has the lowest level of expression in the brain, with documented expression in the frontal cortex, amygdala, hippocampus, hypothalamus, globus pallidus, substantia nigra pars reticulata, and thalamus Dopamine D 2 Family (cont d) Activation of brain dopamine receptors. D 1,D 2, and, to a lesser degree, D 3 dopamine receptors are critically involved in reward and reinforcement mechanisms Both D 1 and D 2 dopamine receptors seem to be critical for learning and memory mechanisms, such as working memory, that are mediated primarily by the PFC D 3, D 4, and, potentially, D 5 dopamine receptors seem to have a minor modulatory influence on some specific aspects of cognitive functions that are mediated by hippocampal areas D 3 dopamine receptors exert some relatively minor modulatory influences on many of the functions generally attributed to D 2 dopamine receptors

6 Update on D 2 Receptor: Emergence of D 2 Subtypes D 2L and D 2S The D 2 receptor exists in 2 isoforms: the long form (D 2L ) and the short form (D 2S ). The 2 isoforms are generated from the same gene by alternative splicing. D 2L differs from D 2S by the addition of 29 amino acids in the third intracellular loop of its protein structure D 2S and D 2L may differentially contribute to the therapeutic actions and adverse effects of antipsychotic agents, and may have implications for developing better antipsychotic agents In animal knock out mice model, deletion of D 2L diminishes drug-induced parkinsonism D 2S has been shown to be mostly expressed presynaptically and to be mostly involved in autoreceptor functions, whereas D 2L seems to be predominantly a postsynaptic isoform Xu R, et al. Mol Psychiatry. 2002;7(10): Neve KA, et al. Neuroscience. 2013;248: D 3 Receptor Details In high DA areas of the brain, D 3R partial agonism has the net effect of dampening DA neuronal firing, thus lowering psychosis or mania. There may also be an association with increased cortical static tone for alertness and wakefulness if the D 3R is agonized. Evidence amassed so far includes statistically and clinicallysignificant improvements in positivesymptoms of schizophrenia among subjects found to possess DRD3 polymorphisms for the D 3R gene, and this D 3 property may be implicated as a risk to developing schizophrenia symptoms. Notably, D 3 receptors possess a high affinity for D A (420-fold higher than that of D 2 receptors) and, unlike D 2 receptors, small changes in their number or function may lead to dramatic effects on synaptic transmission, suggesting that D 3 receptors could be critical modulators of normal dopaminergic function and, despite their localization, also of cognition. Dopamine D 3 receptor expression and function are both down-regulated in stress and depression. Animal models have demonstrated that negative symptoms improve, including cognition and social behavior, with D 3R agonism. Frankel JS, et al. Ther Adv Psychopharmacol. 2017;7(1): Maramai S, et al. Front Neurosci. 2016;10:451. Leggio GM, et al. Eur J Pharmacol. 2013;719(1-3): Major Functions of Dopamine Receptors: Locomotion, Reward, Cognition Focus on the 3rd Major Function of Dopamine Receptors: Cognition Locomotion Locomotion represents a wellcharacterized function of DAergic receptors. DA in the dorsal striatum modulates basal ganglia activity, by DAergic receptors mainly expressed on GABAergic medium spiny neurons. D 1 and D 2 are main dopamine receptors involved Ledonne A, et al. Front Cell Neurosci. 2017;11:27. Reward The mesolimbic DAergic pathway plays a central role in the processing of reward-related stimuli, which mainly increase extracellular DA levels in the NAc. D 1, D 2, and D 3 are dopamine receptors involved Regulation of Cognitive Functions DA regulates essential cognitive functions through Dopamine receptors expressed in the PFC, striatum, and hippocampus. D D 1R family control working memory, behavioral flexibility, decision-making, and 1R goal-directed behaviors D 2R are highly expressed in striatum and hippocampus and moderately in layer 5 D 2R of PFC and regulate behavioral flexibility, goal-directed behaviors, and decisionmaking, also affecting working- and long-term memory D 3R indirectly modulate PFC-dependent cognitive functions, by inhibiting mesocortical DAergic activity and/or adjusting cortical Ach levels. Thus, D D 3R 3R inhibition improves attention, learning, memory and executive functions, whereas striatal D 3R modulate behavioral flexibility D 4R in PFC and hippocampus affect different cognitive tasks, including inhibitory D 4R avoidance and object recognition memory being also involved in attention and exploratory behavior Ledonne A, et al. Front Cell Neurosci. 2017;11:27. Dopamine and Its Complex Role in Cognition (Learning) A. Reference scenario B. Effect of phasic dopamine burst on learning Dopamine and Its Various Roles in Health and Illness C. Effect of phasic dopamine dip on learning D. Effect of dopamine increase during choice Maia TV, et al. Biol Psychiatry. 2017;81(1):52-66.

7 Dopamine: Glutamate Interactions in the Development of Psychosis Dopamine and Its Receptors, Deeply Involved in Inflammation (Macrophage Cell Interactions) Howes OD, et al. Biol Psychiatry. 2017;81(1):9-20. A. Catecholamines are recognized by α and β-adrenergic receptors (1). Signaling through α-adrenergic receptors is proinflammatory and promotes LPS-induced gene expression whereas β-adrenergic receptor signaling inhibits this and induces expression of anti-inflammatory cytokines (2). Cold temperature induces macrophage synthesis of catecholamines which act to increase white to beige adipose tissue conversion and energy expenditure (3). B. Sciatic and vagus nerve stimulation promotes dopamine synthesis (1). Dopamine receptor signaling enhances GPCR activity leading to increased viral entry and replication (2). Dopamine signaling also inhibits pro-inflammatory cytokine production (3). GPCR = G protein coupled receptors; LPS = lipopolysaccharide. Barnes MA, et al. Cytokine. 2015;72(2): Dopamine Receptors and Cytokines: Monocyte Deep Interactions D 3 Dopamine Receptor and Its Role in Modulating Inflammation All 5 dopamine receptors (DRs, DRD 1-DRD 5) have been found to be expressed in immune cells where they exert a complex regulation of immunity, both innate and adaptive immunity systems Macrophage Tissue migration Activation Cytokines Arreola R, et al. J Immunol Res. 2016;2016: DRD 3, which display the highest affinity by dopamine, has been strongly involved in inflammation Pacheco R. Oncotarget. 2017;8(5): D 3 Receptor Emerging Details in Cognition and Reward The D 3 receptor is expressed in brain regions controlling reward, emotions, and motivation Current antipsychotics, in addition to blocking D 3 receptors, also block D 2 receptors, in the striatum and NAc, causing motor side effects and interfering with the reward system, and in the PFC, interfering negatively with GABA neuron activity which may be deleterious to the normalization of the glutamate/gaba balance and task-dependent neuronal activity, decision-making, effort-based procedures Dopamine Release Triggered by Just Visualizing Cues (eg, Cocaine in Recreational Users) Simply watching a desired object releases dopamine in the dorsal striatum Sokoloff P, et al. Eur J Neurosci. 2017;45(1):2-19. Cox SML, et al. Sci Rep. 2017;7:46665.

8 Dopamine and Marijuana (and its individual ingredients THC and CBD) Interactions D 2 Receptor and How It Plays a Role in Tardive Dyskinesia Chronic antipsychotic treatment can result in D 2 receptor super-sensitivity (upregulation), as an increase in receptor number compensates for drug-induced receptor blockade Renard J, et al. Neurosci Biobehav Rev. 2017;75: Stahl SM. Stahl s Illustrated Antipsychotics: Treating Psychosis, Mania, and Depression. Second Edition. New York, NY: Cambridge University Press; Ginovart N, et al. Handb Exp Pharmacol. 2012;(212): Tuppurainen H, et al. Nord J Psychiatry. 2010;64(4): Dopamine System and Various Points of Clinical Interventions for Therapeutic Benefit Dopamine, Dopamine Receptors, and Clinical Interventions AADC = aromatic amino acid decarboxylase; B6 = pyridoxal phosphate; BH4 = tetrahydrobiopterin; D1 = post synaptic dopamine receptor type 1; D2 = postsynaptic dopamine receptor type 2; DAT = dopamine transporter; DTDS = dopamine transport deficiency syndrome; MAO = monoamine oxidase; MAO-B = monoamine oxidase type B; PITX3 = PITX3 gene; TH = tyrosine hydroxylase; VMAT2 = vesicular monoamine transporter 2. Ng J, et al. Paediatr Drugs. 2014;16(4): Dopamine System and Clinical Manipulations to Treat Various Disorders Dopamine Agonism Dopamine Receptor Agonists Dopamine Antagonists/Partial Agonists Dopamine Degradation Inhibition Dopamine Depleters Parkinson s Disease ADHD, Restless Leg Syndrome, Anorexigenic agents Schizophrenia, Mood Disorders, etc. MAOIs Tardive Dyskinesia, Tourette s Disorder, Huntington s Disease The Dopamine System and its Receptors are involved in multiple disorders and there are multiple means to impact them to treat various disorders ADHD = attention-deficit/hyperactivity disorder; MAOI = monoamine oxidase inhibitor. Jarcho JM, et al. Pain. 2012;153(4): Ng J, et al. Paediatr Drugs. 2014;16(4): A Multiple Targeted Approach May Be Needed to Treat Mood Disorders Dopamine s Importance (especially in Treatment-Resistant Depression) Do we often need 2 neurotransmitter systems when treating mood disorders? Loss of Positive Affect Dopamine/Norepinephrine Agents Nutt D. J Clin Psychiatry. 2008;69 Suppl E1:4-7. Loss of Pleasure/ Enjoyment Loss of Motivation Loss of Interest Depression with Loss of Interest and Energy Low mood Sadness Fear Anxiety Guilt Irritability Norepinephrine/Serotonin Agents Depression with Anxiety Negative Affect

9 Agonism, Partial Agonism, and Antagonism Appreciating the Differences in these 3 Separate Receptor Activities Biological Response (%) Basal activity Drug Concentration Full agonist Partial agonist Antagonist Stahl SM. Stahl s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Fourth Edition. New York, NY: Cambridge University Press; Bolonna AA, et al. Br J Psychiatry. 2005;186: Receptor Profiles of Some of the Atypicals: Significant Differences Exist (Section 12.2 Pharmacodynamics of FDA Package Insert) Drugs Receptors D2 D3 5-HT1A 5-HT2A 5-HT2C 5-HT7 α1a α2c H1 M1 Aripiprazole Clozapine Iloperidone Ziprasidone Lurasidone Risperidone Asenapine Olanzapine Brexpiprazole Cariprazine US Food and Drug Administration. Various Atypicals and Their Effect on the D 2 Receptor D 2 Brexpiprazole 0.3 Aripiprazole 0.34 Cariprazine 0.49 Lurasidone 1 Asenapine 1.3 Risperidone 3.57 Ziprasidone 4.8 Iloperidone 6.3 Olanzapine 11 More Affinity Less Affinity Clozapine Select Atypicals and Their Effect on the D 3 Receptor D 3 Cariprazine Asenapine 0.42 Aripiprazole 0.8 Brexpiprazole 1.1 Risperidone 3.6 Iloperidone 7.1 Ziprasidone 7.2 Olanzapine 47 Clozapine 555 More Affinity Less Affinity Lurasidone US Food and Drug Administration. US Food and Drug Administration. Examining Similarities and Dissimilarities Among the 3 Partial Agonists at the Dopamine Receptor Aripiprazole Brexpiprazole Cariprazine D D HT 1A HT 2A HT 2C HT H M 1 >1000 >1000 >1000 Dopamine Depletion: The Birth of a New Mechanism to Treat Tardive Dyskinesia VMAT2 Inhibitor VMAT1 is not widely widely distributed in the human brain VMAT2 is extensively distributed in the human cortex, striatum, and basal ganglia It is found in pre-synaptic neurons α Frankel JS, et al. Ther Adv Psychopharmacol. 2017;7(1): Meyer AC, et al. J Neurochem. 2013;127(2):

10 Dopamine and Hyperkinetic Disorders: Tardive Dyskinesia, Tourette s, Huntington s Disease Dopamine depletion a new approach to modulating Dopamine (through VMAT2 inhibition) Dopamine and Nucleus Accumbens: Deep Brain Stimulation Targeting both Refractory Anxiety and Mood Disorders Targeting NAc A Central player in HEDONIC DRIVE Selective VMAT2 Inhibitors Tetrabenazine Valbenazine Deutetrabenazine NAc contains a larger proportion of small cells with high concentrations of D 1 - and D 3 -receptors Jankovic J. Expert Opin Pharmacother. 2016;17(18): Alhourani A, et al. J Neurophysiol. 2015;114(4): Berridge KC, et al. Neuron. 2015;86(3): Dopamine in the Body It s a Central Player in Multiple Bodily Functions Functions mediated by dopamine receptors that are localized outside the CNS include: Olfaction, vision, and hormonal regulation (such as the pituitary D 2 dopamine receptor-mediated regulation of prolactin secretion) Kidney D 1 dopamine receptor-mediated renin secretion Adrenal gland D 2 dopamine receptor-mediated regulation of aldosterone secretion Sympathetic tone regulation D 1,D 2, and D 4 receptor mediated regulation of renal function Blood pressure regulation and vasodilation Gastrointestinal motility CNS = central nervous system. In Conclusion: Dopamine is a central neurotransmitter in health and illness Its serves diverse roles in brain/mind and body functioning Dopamine receptor pharmacology is quite well understood We clinicians would benefit from better understanding its physiological tasks, and its role in illnesses There are diverse means to pharmacologically manipulate dopamine and its receptors It behooves us to know dopamine and its receptor pharmacology well in order to serve our patient s needs better