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Dopamine Receptor Pharmacology: What We Clinicians Need to Know

Rakesh Jain, MD, MPH

Clinical Professor Department of Psychiatry Texas Tech Health Sciences Center School of Medicine Midland, Texas

Why Does Dopamine Matter and Why Devote Time to Understanding it Better?

Knab AM, et al. Int J Biol Sci. 2010;6(2):133-150.

Mood Cognition Well- being Risk- taking Appetite Pleasure Drive DOPAMINE

Through its Main 4 Pathways, Dopamine Exerts Vast Control over Brain/Body Functioning

EPS = extrapyramidal symptoms. Beaulieu JM, et al. Pharmacol Rev. 2011;63(1):182-217. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Fourth Edition. New York, NY: Cambridge University Press; 2013. Meltzer HY, et al. Schizophr Bull. 1976;2(1):19-76.

• 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)

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):363-371.

Mesolimbic & Mesocortical pathway,

which is the projection from VTA, cell group A10, to NAc, PFC, and

• ther limbic areas.

These neurons play a crucial role in reward- related behaviors.

Dopamine – A Life Story

A Quick Primer on Dopamine and Other Neurotransmitter Pathways

Ng J, et al. Paediatr Drugs. 2014;16(4):275-291.

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-4a- carbinolamine dehydratase; PLP = pyridoxal phosphate = PNMT = phenylethanolamine N-methyltransferase; TH = tyrosine hydroxylase; VMA = vanillylmandelic acid.

Macro and Micro Understanding of Dopamine, Its Pathways, and Receptors

The signaling pathways in the postsynaptic neuron are

• nly

representative of D1-like receptor signaling (which increases cAMP). D2-like receptors are known to have

• pposite 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):133-150.

Dopamine Neurons Fire in Both Tonic and Phasic Fashion

COMT = catechol-O-methyltransferase; DA = dopamine; DAT = DA transporter. Jarcho JM, et al. Pain. 2012;153(4):744-754.

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 D2-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 D2- like DA receptors, it stimulates presynaptic D2-like DA autoreceptors 9. Which then inhibit phasic DA release

Dopamine Along with Other Monoamines is Involved in Various Mood Disorders

5-HT = serotonin; NE = norepinephrine. Perović B, et al. Neuropsychiatr Dis Treat. 2010;6:343-364.

• One hypothesis of mood disorders

is that it may arise from a deficit

• r underactivity in the brain of

monoamine signaling (DA, 5-HT, and/or NE)

• Deficiency in monoaminergic neuro-

transmission 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 neuro- transmission tone of these neuro- transmitters (5-HT, NE, and/or DA) and reduce depressive symptoms

A1, A2, A5, A7 Locus coeruleus

Monoamine Pathways Overlap in Several Areas of the Brain

Fuchs E, et al. Dialogues Clin Neurosci. 2004;6(2):171-183. PFC AA C Hy T S A H C C Cerebral Cortex Substantia nigra and VTA

Dopamine Norepinephrine

Raphe nuclei

Serotonin

Dopamine, Through its Receptors, Modulates Multiple Other Neurotransmitters

GABA = gamma-aminobutyric acid. Clarke R, et al. Neural Plast. 2015;2015:814567.

Dopamine interacts with the following Systems, through its multiple Receptors (DR1-5)  GABA  Glutamate  Acetylcholine  Histamine  Serotonin  Norepinephrine

Dopamine Serves as a Great Regulator/ Communicator in the Neural Circuitry of Monoamines

+ = agonism or stimulatory effect; ─ = antagonism or inhibitory effect; DRN = dorsal raphe nucleus; Glu = glutamate; LC = locus coeruleus. El Mansari M, et al. CNS Neurosci Ther. 2010;16(3):e1-e17.

Glu Glu

Cortical Pyramidal Neurons

+ Β (+) α2A (─) NE NE + +

─

NE NE

─

α2

LC NE

─

DA DA D2/3 (─) DA DA D2 α2 α1

VTA DA

─

5HT

─

D2 DRN

5HT

Dopamine May Be Particularly Important in Addressing Residual Symptoms of Depression

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; 2013. Many Symptoms Appear to be Influenced by Monoamine Signaling Most Common DSM-IV Residual Symptoms Of MDD Dopamine Pleasure, reward, motivation/drive Norepinephrine Alertness, concentration, energy Serotonin Obsessions, compulsions, memory Attention Mood, cognitive function Appetite, sex, aggression Anxiety, impulse, irritability

Brain Region PFC S NA Hy SC Symptom(s) Concentration, interest, fatigue (mental) Fatigue (physical) Fatigue, energy Insomnia Fatigue (physical) Monoamine pathways implicated 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):519-526.

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

• f voluntary movement.

Mesolimbic & Mesocortical pathway, which is 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

• f

pituitary hormone, mostly prolactin.

Functional Pharmacology of Dopamine

Dopamine and Nucleus Accumbens:

Deep Connections to Cognition, Emotion, and Pain Modulating Regions of the Brain

Alhourani A, et al. J Neurophysiol. 2015;114(4):2105-2117.

NAc

S1

primary sensory cortex

M1

primary motor cortex

SMA

supplementary motor area

PMC

premotor cortex

DLPFC

dorsolateral prefrontal cortex

ACC

anterior cingulate cortex

PHG

parahippocampal gyrus

Dopamine Impacts the Pain / Insomnia / Mood Triad

Finan PH, et al. Sleep Med Rev. 2013;17(3):173-183.

Vulnerability model of tonic/phasic DA

• dysregulation. Solid

arrows represent putative bidirectional pathways through which abnormalities in the homeostatic regulation

• f 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.

Dopamine – Impacts Multiple Issues (Cognition, Affect, and Pain)

Jarcho JM, et al. Pain. 2012;153(4):744-754.

Food and Food Cravings

Interactions with Dopamine and Its Receptors

DS = dorsal striatum. Baik JH. BMB Rep. 2013;46(11):519-526. Food reward circuit involving DA system and D2 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.

How Dopamine and Its Various Receptors Affect Exercise Motivation

Knab AM, et al. Int J Biol Sci. 2010;6(2):133-150.

Dopamine system can act in both an independent and dependent manner in regard to regulation of physical activity Physical activity (ie, intensity and duration of exercise) can cause changes in neuronal signaling as well.

Dopamine and Music

Zatorre RJ, et al. Proc Natl Acad Sci U S A. 2013;110 Suppl 2:10430-10437.

“Music has existed in human societies since prehistory, perhaps because it allows expression and regulation of emotion and evokes pleasure.” Dopamine, NAc, and Mesolimbic striatal systems are all activated by

Familiar and Novel music and its involvement in reward, motivation, and pleasure

Dopamine: Risk-Taking and Well-Being

*P < .05. Rutledge RB, et al. J Neurosci. 2015;35(27):9811-9822.

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.

Dopamine’s influence on economic risk-taking and on subjective well-being

 Boosting dopamine levels increased the number of risky

• ptions chosen in trials

involving potential gains  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

Beaulieu JM, et al. Pharmacol Rev. 2011;63(1):182-217.

• D1 Like Family

– Members are

• D1 (coded by the DRD1 gene)
• D5 (coded by DRD5 gene)

– Stimulation of these leads to increased cAMP

• D2 Like Family

– Members are

• D2 receptor (coded by DRD2 gene)
• D3 receptor (coded by DRD3 gene)
• D4 receptor (coded by DRD4 gene)

– Stimulation of these leads to decreased cAMP

The Dopamine Receptor Family

Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Fourth Edition. New York, NY: Cambridge University Press; 2013. Beaulieu JM, et al. Pharmacol Rev. 2011;63(1):182-217.

• Mediated by G protein-

coupled receptors in 2 major groups

• D1-class (D1 and D5)

– Found primarily postsynaptically

• D2-class (D2, D3, D4)

– Expressed pre- and postsynaptically – D2 is the high affinity binding site for virtually all antipsychotic agents

Location, Location, Location…

Significant Differences in Dopamine Receptor Distribution

Brichta L, et al. Trends Neurosci. 2013;36(9):543-554.

Cerebral cortex D1, D2, D4, D5 Striatum D1, D2, D5 NAc D1, D2, D3, D5 Hypothalamus D1, D2, D4, D5 Hippocampus D1, D2, D4, D5 VTA D2, D3, D5 SN D2, D3, D5

Basic Genetic, Structural, and Pharmacologic Properties of Dopamine Receptor Subtypes

Beaulieu JM, et al. Pharmacol Rev. 2011;63(1):182-217.

Dopamine D1 Family

Beaulieu JM, et al. Pharmacol Rev. 2011;63(1):182-217.

• D1 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

• D5 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 D2 Family

Beaulieu JM, et al. Pharmacol Rev. 2011;63(1):182-217.

• The highest levels of D2 dopamine receptors are found in

the striatum, the NAc, and the olfactory tubercle. D2 receptors are also expressed at significant levels in the SN, VTA, hypothalamus, cortical areas, septum, amygdala, and hippocampus

• The D3 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

D4 dopamine receptor has the lowest level

• f

expression in the brain, with documented expression in the frontal cortex, amygdala, hippocampus, hypothalamus, globus pallidus, substantia nigra pars reticulata, and thalamus

Dopamine D2 Family (cont’d)

Beaulieu JM, et al. Pharmacol Rev. 2011;63(1):182-217.

• Activation of brain dopamine receptors. D1, D2, and, to a

lesser degree, D3 dopamine receptors are critically involved in reward and reinforcement mechanisms

• Both D1 and D2 dopamine receptors seem to be critical for

learning and memory mechanisms, such as working memory, that are mediated primarily by the PFC

• D3, D4, and, potentially, D5 dopamine receptors seem to

have a minor modulatory influence on some specific aspects

• f

cognitive functions that are mediated by hippocampal areas

• D3

dopamine receptors exert some relatively minor modulatory influences on many of the functions generally attributed to D2 dopamine receptors

Update on D2 Receptor:

Emergence of D2 Subtypes – D2L and D2S

Xu R, et al. Mol Psychiatry. 2002;7(10):1075-1082. Neve KA, et al. Neuroscience. 2013;248:479-487. Beaulieu JM, et al. Pharmacol Rev. 2011;63(1):182-217.

• The D2 receptor exists in 2 isoforms: the long form (D2L) and

the short form (D2S). The 2 isoforms are generated from the same gene by alternative splicing. D2L differs from D2S by the addition of 29 amino acids in the third intracellular loop of its protein structure

• D2S and D2L 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 D2L diminishes

drug-induced parkinsonism

• D2S has been shown to be mostly expressed presynaptically

and to be mostly involved in autoreceptor functions, whereas D2L seems to be predominantly a postsynaptic isoform

D3 Receptor Details

Frankel JS, et al. Ther Adv Psychopharmacol. 2017;7(1):29-41. Maramai S, et al. Front Neurosci. 2016;10:451. Leggio GM, et al. Eur J Pharmacol. 2013;719(1-3):25-33.

In high DA areas of the brain, D3R 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 D3R is agonized. Evidence amassed so far includes statistically and clinically significant improvements in positive symptoms

• f schizophrenia among subjects found to possess

DRD3 polymorphisms for the D3R gene, and this D3 property may be implicated as a risk to developing schizophrenia symptoms. Animal models have demonstrated that negative symptoms improve, including cognition and social behavior, with D3R agonism. Notably, D3 receptors possess a high affinity for DA (420-fold higher than that of D2 receptors) and, unlike D2 receptors, small changes in their number

• r function may lead to dramatic effects
• n synaptic transmission, suggesting

that D3 receptors could be critical modulators

• f

normal dopaminergic function and, despite their localization, also of cognition. Dopamine D3 receptor expression and function are both down-regulated in stress and depression.

3 Major Functions of Dopamine Receptors:

Locomotion, Reward, Cognition

Ledonne A, et al. Front Cell Neurosci. 2017;11:27.

Locomotion represents a well- characterized function of DAergic

• receptors. DA in the dorsal striatum

modulates basal ganglia activity, by DAergic receptors mainly expressed on GABAergic medium spiny neurons. Locomotion The mesolimbic DAergic pathway plays a central role in the processing

• f

reward-related stimuli, which mainly increase extracellular DA levels in the NAc. Reward D1 and D2 are main dopamine receptors involved D1, D2, and D3 are dopamine receptors involved

Focus on the 3rd Major Function of Dopamine Receptors: Cognition

Ledonne A, et al. Front Cell Neurosci. 2017;11:27.

Regulation of Cognitive Functions – DA regulates essential cognitive functions through Dopamine receptors expressed in the PFC, striatum, and hippocampus. D1R

D1R family control working memory, behavioral flexibility, decision-making, and goal-directed behaviors

D2R

D2R are highly expressed in striatum and hippocampus and moderately in layer 5

• f PFC and regulate behavioral flexibility, goal-directed behaviors, and decision-

making, also affecting working- and long-term memory

D3R

D3R indirectly modulate PFC-dependent cognitive functions, by inhibiting mesocortical DAergic activity and/or adjusting cortical Ach levels. Thus, D3R inhibition improves attention, learning, memory and executive functions, whereas striatal D3R modulate behavioral flexibility

D4R

D4R in PFC and hippocampus affect different cognitive tasks, including inhibitory avoidance and object recognition memory being also involved in attention and exploratory behavior

Dopamine and Its Various Roles in Health and Illness Dopamine and Its Complex Role in Cognition (Learning)

Maia TV, et al. Biol Psychiatry. 2017;81(1):52-66.

• A. Reference scenario
• B. Effect of phasic dopamine burst on learning
• C. Effect of phasic dopamine dip on learning
• D. Effect of dopamine increase during choice

Dopamine: Glutamate Interactions in the Development of Psychosis

Howes OD, et al. Biol Psychiatry. 2017;81(1):9-20.

Dopamine and Its Receptors, Deeply Involved in Inflammation (Macrophage Cell Interactions)

GPCR = G protein coupled receptors; LPS = lipopolysaccharide. Barnes MA, et al. Cytokine. 2015;72(2):210-219.

• A. Catecholamines are recognized by α and β-adrenergic receptors (1). Signaling through α-adrenergic receptors is pro-

inflammatory 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).

Dopamine Receptors and Cytokines: Deep Interactions

Arreola R, et al. J Immunol Res. 2016;2016:3160486. Monocyte

Activation Tissue migration

Macrophage Cytokines

D3 Dopamine Receptor and Its Role in Modulating Inflammation

Pacheco R. Oncotarget. 2017;8(5):7224-7225. All 5 dopamine receptors (DRs, DRD1-DRD5) have been found to be expressed in immune cells where they exert a complex regulation of immunity, both innate and adaptive immunity systems DRD3, which display the highest affinity by dopamine, has been strongly involved in inflammation

D3 Receptor – Emerging Details in Cognition and Reward

Sokoloff P, et al. Eur J Neurosci. 2017;45(1):2-19.

Current antipsychotics, in addition to blocking D3 receptors, also block D2 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

• f the glutamate/GABA balance and

task-dependent neuronal activity, decision-making, effort-based procedures The D3 receptor is expressed in brain regions controlling reward, emotions, and motivation

Dopamine Release Triggered by Just Visualizing Cues (eg, Cocaine in Recreational Users)

Cox SML, et al. Sci Rep. 2017;7:46665.

Simply watching a desired object releases dopamine in the dorsal striatum

Dopamine and Marijuana (and its individual

ingredients – THC and CBD) Interactions

Renard J, et al. Neurosci Biobehav Rev. 2017;75:157-165.

D2 Receptor and How It Plays a Role in Tardive Dyskinesia

Stahl SM. Stahl’s Illustrated Antipsychotics: Treating Psychosis, Mania, and Depression. Second

• Edition. New York, NY: Cambridge University Press; 2010. Ginovart N, et al. Handb Exp Pharmacol.

2012;(212):27-52. Tuppurainen H, et al. Nord J Psychiatry. 2010;64(4):233-238.

Chronic antipsychotic treatment can result in D2 receptor super-sensitivity (upregulation), as an increase in receptor number compensates for drug-induced receptor blockade

Dopamine, Dopamine Receptors, and Clinical Interventions

Dopamine System and Various Points of Clinical Interventions for Therapeutic Benefit

Ng J, et al. Paediatr Drugs. 2014;16(4):275-291.

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

• xidase type B; PITX3 =

PITX3 gene; TH = tyrosine hydroxylase; VMAT2 = vesicular monoamine transporter 2.

Dopamine System and Clinical “Manipulations” to Treat Various Disorders

ADHD = attention-deficit/hyperactivity disorder; MAOI = monoamine oxidase inhibitor. Jarcho JM, et al. Pain. 2012;153(4):744-754. Ng J, et al. Paediatr Drugs. 2014;16(4):275-291.

The Dopamine System and its Receptors are involved in multiple disorders and there are multiple means to impact them to treat various disorders Dopamine Agonism Parkinson’s Disease Dopamine Receptor Agonists ADHD, Restless Leg Syndrome, Anorexigenic agents Dopamine Antagonists/Partial Agonists Schizophrenia, Mood Disorders, etc. Dopamine Degradation Inhibition MAOIs Dopamine Depleters Tardive Dyskinesia, Tourette’s Disorder, Huntington’s Disease

A Multiple Targeted Approach May Be Needed to Treat Mood Disorders – Dopamine’s Importance

(especially in Treatment-Resistant Depression)

Nutt D. J Clin Psychiatry. 2008;69 Suppl E1:4-7.

Do we often need ≥ 2 neurotransmitter systems when treating mood disorders?

Low mood Sadness

Norepinephrine/Serotonin Agents Dopamine/Norepinephrine Agents Depression with Anxiety Depression with Loss

• f Interest and Energy

Loss of Positive Affect Negative Affect

Loss of Pleasure/ Enjoyment Loss of Motivation Loss of Interest Guilt Irritability Anxiety Fear

Agonism, Partial Agonism, and Antagonism

Appreciating the Differences in these 3 Separate Receptor Activities

Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Fourth

• Edition. New York, NY: Cambridge University Press; 2013. Bolonna AA, et al. Br J Psychiatry. 2005;186:7-10.

Full agonist Partial agonist Antagonist Basal activity Drug Concentration Biological Response (%) 100 50

Drugs

Receptors

D2 D3 5-HT1A 5-HT2A 5-HT2C 5-HT7 α1A α2C H1 M1 Aripiprazole

0.34 0.8 1.7 3.4 15 39 57 1000 61 1000

Clozapine

160 555 120 5.4 9.4 6.3 1.6 90 1.1 6.2

Iloperidone

6.3 7.1 168 5.6 1000 22 0.36 4.7 437 1000

Ziprasidone

4.8 7.2 0.4 4.8 7.2 1000 10 1000 47 1000

Lurasidone

1 1000 6.4 0.5 1000 0.5 1000 11 1000 1000

Risperidone

3.57 3.6 423 0.17 12 6.6 5 1.3 20.1 1000

Asenapine

1.3 0.42 2.5 0.07 0.03 0.11 1.2 1.2 1 1000

Olanzapine

11 47 7 4 11 1000 19 1000 7 73 Brexpiprazole 0.3 1.1 0.12 0.47 1000 1000 0.17 0.59 19 1000

Cariprazine

0.49 0.085 3 19 134 111 1000 1000 23 1000

Receptor Profiles of Some of the Atypicals: Significant Differences Exist

(Section 12.2 – Pharmacodynamics of FDA Package Insert)

US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/daf/.

Various Atypicals and Their Effect on the D2 Receptor

US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/daf/.

160 11 6.3 4.8 3.57 1.3 1 0.49 0.34 0.3

20 40 60 80 100 120 140 160 180

Clozapine Olanzapine Iloperidone Ziprasidone Risperidone Asenapine Lurasidone Cariprazine Aripiprazole Brexpiprazole D2

More Affinity Less Affinity

Select Atypicals and Their Effect on the D3 Receptor

US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/daf/.

1000 555 47 7.2 7.1 3.6 1.1 0.8 0.42 0.085

200 400 600 800 1000 1200

Lurasidone Clozapine Olanzapine Ziprasidone Iloperidone Risperidone Brexpiprazole Aripiprazole Asenapine Cariprazine D3

More Affinity Less Affinity

Examining Similarities and Dissimilarities Among the 3 Partial Agonists at the Dopamine Receptor

Frankel JS, et al. Ther Adv Psychopharmacol. 2017;7(1):29-41.

Aripiprazole Brexpiprazole Cariprazine D2 0.34 0.30 0.49 D3 0.8 1.1 0.085 5-HT1A 1.7 0.12 2.6 5-HT2A 3.4 0.47 18.8 5-HT2C 15 34 134 5-HT7 29 3.7 111 H1 61 19 23.2 M1 >1000 >1000 >1000 α1 57 3.8 155

Dopamine Depletion:

The Birth of a New Mechanism to Treat Tardive Dyskinesia

Meyer AC, et al. J Neurochem. 2013;127(2):187-198.

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 VMAT2 Inhibitor

Dopamine and “Hyperkinetic” Disorders:

Tardive Dyskinesia, Tourette’s, Huntington’s Disease

Jankovic J. Expert Opin Pharmacother. 2016;17(18):2461-2470.

Dopamine “depletion” – a new approach to modulating Dopamine (through VMAT2 inhibition)

Selective VMAT2 Inhibitors  Tetrabenazine  Valbenazine  Deutetrabenazine

Dopamine and Nucleus Accumbens:

Deep Brain Stimulation

Targeting both Refractory Anxiety and Mood Disorders

Alhourani A, et al. J Neurophysiol. 2015;114(4):2105-2117. Berridge KC, et al. Neuron. 2015;86(3):646- 664.

Targeting NAc – A Central player in HEDONIC DRIVE NAc contains a larger proportion of small cells with high concentrations of D1- and D3-receptors

Dopamine in the Body

It’s a Central Player in Multiple Bodily Functions

CNS = central nervous system. Beaulieu JM, et al. Pharmacol Rev. 2011;63(1):182-217.

Functions mediated by dopamine receptors that are localized outside the CNS include:

• Olfaction, vision, and hormonal regulation (such as the

pituitary D2 dopamine receptor-mediated regulation

• f

prolactin secretion)

• Kidney D1 dopamine receptor-mediated renin secretion
• Adrenal gland D2 dopamine receptor-mediated regulation of

aldosterone secretion

• Sympathetic tone regulation
• D1, D2, and D4 receptor mediated regulation of renal function
• Blood pressure regulation and vasodilation
• Gastrointestinal motility

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