dopamine receptor pharmacology: what we …2017/pcod...dopamine receptor pharmacology: what we...

Dopamine Receptor Pharmacology: What We Clinicians Need to Know

Rakesh Jain, MD, MPHClinical ProfessorDepartment of Psychiatry Texas Tech Health Sciences Center School of MedicineMidland, 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-takingAppetite

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 other 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-dihydroxyphenylacetic acid; DBH = dopamine b hydroxylase; GTPCH = guanosine triphosphate Cyclohydrolase; H2NP2 = dihydroneopterintriphosphate; 3-MT = 3-methoxytyramine; PCD = pterin-4a-carbinolamine dehydratase; PLP = pyridoxal phosphate = PNMT = phenylethanolamineN-methyltransferase; TH = tyrosine hydroxylase; VMA = vanillylmandelic acid.

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

The signaling pathways in thepostsynaptic neuron are onlyrepresentative of D1-like receptorsignaling (which increases cAMP).D2-like receptors are known to haveopposite affects on cAMP activity,and thus slightly different downstreamsignaling cascades. Dopaminergicsignaling effects on ion channelsand membrane permeability.


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 disordersis that it may arise from a deficitor underactivity in the brain ofmonoamine signaling (DA, 5-HT,and/or NE)

• Deficiency in monoaminergic neuro-transmission may be in themonoamine levels themselves, orthrough disrupted receptor signaling

• Evidence supporting this hypothesisis that antidepressant therapieshave 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

AAC

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 (─)

NENE

+

+

─

NE

NE

─α2

LCNE

─

DA

DA

D2/3 (─)

DA

DA

D2

α2

α1

VTA DA ─

5HT

─

D2 DRN5HT

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

DopaminePleasure, reward, motivation/drive

NorepinephrineAlertness, concentration, energy

SerotoninObsessions,

compulsions,memory

AttentionMood,

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

InsomniaFatigue

(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 withinpars compacta (A8) and neighboring area(group A9) from SN project to striatum, thisprojection is involved in mostly the controlof voluntary movement.

Mesolimbic & Mesocortical pathway, which isthe projection from VTA, cell group A10, to theNAc, PFC, and other limbic areas. Theseneurons play a crucial role in reward-relatedbehaviors.

Tuberoinfundibular pathways, which are thecells fromarcuate nucleus (cell group A12) andperiventricular nucleus (cell group A14) of thehypothalamus, projecting to the pituitary. Thispathway is known to control the release andsynthesis of pituitary hormone, mostlyprolactin.

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

PHGparahippocampalgyrus

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 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.

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

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

Food and Food CravingsInteractions 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 foodstimuli activate VTA-NAc DA mesolimbic circuit with phenotypic importance of feeding behaviorstranslated through signaling in caudate putamen, DS, interacting with PFC for decision making andexecution of eating behaviors. As well, the homeostatic regulators such as leptin, insulin, and ghrelinexert their input to midbrain DA system for connection between homeostatic and hedonic system offood intake.

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

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 asimilar time of day, performing the same task on both days, 60 min after ingestion of either L-DOPA (150 mg of L-DOPA and37.5 mg of benserazide mixed in orange juice) or placebo (500 mg of ascorbic acid mixed in orange juice). All subjectsperformed 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 options chosen in trials involving potential gains

Boosting dopamine also increased happiness resulting from some rewards

Dopamine Receptor Classification and Its Diverse Pharmacology

Dopamine Receptor ClassificationIndividual 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 cortexD1, D2, D4, D5

StriatumD1, D2, D5

NAcD1, D2, D3, D5

HypothalamusD1, D2, D4, D5

HippocampusD1, D2, D4, D5

VTAD2, D3, D5

SND2, D3, D5

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


Dopamine D1 Family


• D1 dopamine receptors are expressed at a high level ofdensity in the nigrostriatal, mesolimbic, and mesocorticalareas, such as the caudate-putamen (striatum), NAc,SN, olfactory bulb, amygdala, and frontal cortex, as wellas at lower levels in the hippocampus, cerebellum, andthalamic areas

• D5 dopamine receptors are expressed at low levels inmultiple brain regions, including pyramidal neurons ofthe PFC, the premotor cortex, the cingulate cortex, theentorhinal cortex, SN, hypothalamus, the hippocampus,and the dentate gyrus

Dopamine D2 Family


• The highest levels of D2 dopamine receptors are found inthe striatum, the NAc, and the olfactory tubercle. D2receptors are also expressed at significant levels in the SN,VTA, hypothalamus, cortical areas, septum, amygdala, andhippocampus

• The D3 dopamine receptor has a more limited pattern ofdistribution, the highest level of expression being observedin the limbic areas, such as in the shell of the NAc

• The D4 dopamine receptor has the lowest level ofexpression in the brain, with documented expression in thefrontal cortex, amygdala, hippocampus, hypothalamus,globus pallidus, substantia nigra pars reticulata, andthalamus

Dopamine D2 Family (cont’d)


• Activation of brain dopamine receptors. D1, D2, and, to alesser degree, D3 dopamine receptors are critically involvedin reward and reinforcement mechanisms

• Both D1 and D2 dopamine receptors seem to be critical forlearning and memory mechanisms, such as workingmemory, that are mediated primarily by the PFC

• D3, D4, and, potentially, D5 dopamine receptors seem tohave a minor modulatory influence on some specificaspects of cognitive functions that are mediated byhippocampal areas

• D3 dopamine receptors exert some relatively minormodulatory influences on many of the functions generallyattributed 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) andthe short form (D2S). The 2 isoforms are generated from thesame gene by alternative splicing. D2L differs from D2S by theaddition of 29 amino acids in the third intracellular loop of itsprotein structure

• D2S and D2L may differentially contribute to the therapeuticactions and adverse effects of antipsychotic agents, andmay have implications for developing better antipsychoticagents

• In animal knock out mice model, deletion of D2L diminishesdrug-induced parkinsonism

• D2S has been shown to be mostly expressed presynapticallyand to be mostly involved in autoreceptor functions, whereasD2L 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 agonismhas the net effect of dampening DA neuronal firing,thus lowering psychosis or mania.

There may alsobe an associationwith increasedcortical statictone for alertnessand wakefulnessif the D3R isagonized.

Evidence amassed so far includes statistically andclinically significant improvements in positive symptomsof schizophrenia among subjects found to possessDRD3 polymorphisms for the D3R gene, and this D3

property may be implicated as a risk to developingschizophrenia symptoms.

Animal models have demonstrated thatnegative symptoms improve, includingcognition and social behavior, with D3R

agonism.

Notably, D3 receptors possess a highaffinity for DA (420-fold higher thanthat of D2 receptors) and, unlike D2

receptors, small changes in their numberor function may lead to dramatic effectson synaptic transmission, suggestingthat D3 receptors could be criticalmodulators of normal dopaminergicfunction and, despite their localization,also of cognition.

Dopamine D3 receptor expression andfunction are both down-regulated instress 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 DAergicreceptors. DA in the dorsal striatummodulates basal ganglia activity,by DAergic receptors mainlyexpressed on GABAergic mediumspiny neurons.

Locomotion

The mesolimbic DAergic pathwayplays a central role in theprocessing of reward-relatedstimuli, which mainly increaseextracellular DA levels in theNAc.

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.

D1RD1R family control working memory, behavioral flexibility, decision-making, andgoal-directed behaviors

D2R

D2R are highly expressed in striatum and hippocampus and moderately in layer 5of 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 inhibitingmesocortical DAergic activity and/or adjusting cortical Ach levels. Thus, D3R

inhibition improves attention, learning, memory and executive functions, whereasstriatal D3R modulate behavioral flexibility

D4R

D4R in PFC and hippocampus affect different cognitive tasks, including inhibitoryavoidance and object recognition memory being also involved in attention andexploratory 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 additionto blocking D3 receptors, alsoblock D2 receptors, in the striatumand NAc, causing motor sideeffects and interfering with thereward system, and in the PFC,interfering negatively with GABAneuron activity which may bedeleterious to the normalizationof the glutamate/GABA balance andtask-dependent neuronal activity,decision-making, effort-basedprocedures

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 oxidase 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 AgonistsADHD, Restless Leg Syndrome, Anorexigenic agents

Dopamine Antagonists/Partial Agonists Schizophrenia, Mood Disorders, etc.

Dopamine Degradation Inhibition MAOIs

Dopamine DepletersTardive 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

Dop

amin

e/N

orep

ine

phri

ne A

gent

s

Depressionwith Anxiety

Depression with Loss of 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

AntagonistBasal activity

Drug Concentration

Bio

log

ical

R

es

po

nse

(%

)

100

50

0

DrugsReceptors

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


160

11

6.3

4.8

3.57

1.3

1

0.49

0.34

0.3

0 20 40 60 80 100 120 140 160 180

Clozapine

Olanzapine

Iloperidone

Ziprasidone

Risperidone

Asenapine

Lurasidone

Cariprazine

Aripiprazole

BrexpiprazoleD2 More Affinity

Less Affinity

Select Atypicals and Their Effect on the D3 Receptor


1000

555

47

7.2

7.1

3.6

1.1

0.8

0.42

0.085

0 200 400 600 800 1000 1200

Lurasidone

Clozapine

Olanzapine

Ziprasidone

Iloperidone

Risperidone

Brexpiprazole

Aripiprazole

Asenapine

CariprazineD3 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 BodyIt’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 thepituitary D2 dopamine receptor-mediated regulation ofprolactin secretion)

• Kidney D1 dopamine receptor-mediated renin secretion

• Adrenal gland D2 dopamine receptor-mediated regulation ofaldosterone 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 andillness

• Its serves diverse roles in “brain/mind” and “body”functioning

• Dopamine receptor pharmacology is quite wellunderstood

• We clinicians would benefit from better understandingits physiological tasks, and its role in illnesses

• There are diverse means to pharmacologicallymanipulate dopamine and its receptors

• It behooves us to know dopamine and its receptorpharmacology well in order to serve our patient’s needsbetter

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