Dopamine

Dopamine pharmacology, Advance pharmacology of Dopamine, Dopamine as neurotransmitter, Dopamine

1. DOPAMINE Presented by ruchi Yadav MPH:1

2. Introduction Dopamine belongs to the family of catecholamines Hormones Epinephrine and Norepinephrine (other catecholamines ) are derived from Dopamine Significant role in learning, goal-directed behavior, regulation of hormones, motor control

3. DA synthesis and metabolism L phenylalanine (amino acid from diet) phenyalanine hydroxylase L- Tyrosine Tyrosine hydroxylase RLS L Dopa Dopa decarboxylase Dopamine (DA) Monoamine oxidase (MAO) Catechol-O-methyl transferase (COMT) DOPAC + HVA

4. After synthesis, dopamine is packaged into synaptic vesicles via the vesicular monoamine transporter (VMAT2) and stored there until its release into the synapse during neurotransmission.

5. Dopamine Receptors

6. Metabotropic G-protein coupled receptors D 1 – like family: Includes subtypes D 1 and D 5 Activation is coupled to G α s ; activates adenylyl cylcase which leads to increase in concentration of cAMP D 2 – like family: Includes D 2 , D 3 and D 4 Activation is coupled to G α i ; inhibits adenylyl cyclase leading to decrease in concentration of cAMP

7. Receptor Locations Functions D1 Found in high concentration in mesolimbic, nigrostratal and mesocortical areas , such as substancia nigra , olfactory bulb, nucleus accumbens , cuadate , putamen, striatum, Expressed in low level in cerebellum, hippocampus, thalamus, hypothalamus, kidney Voluntary movements, regulate growth and development, regulations of feeding, affect, attentions, reward, sleep, impulse control, reproductive behaviors , working memory, learning, control of rennin in kidney D2 Expressed in high levels in as substancia nigra , olfactory bulb, cuadate , putamen, ventral tagemental area(VTA), nucleus accumbens Found in low level in hypothalamus, septum, kidney, cortex, heart, blood vessels, adrenal glands, gastrointestinal tract, sympathetic ganglia Involved in working memory, reward-motivation functions regulate blood pressure, renal functions, gastrointestinal motility, vasodilatations, regulate locomotion- presynatic receptors inhibit locomotion and post synaptic receptors activate locomotion D3 Expressed only in CNS and it is not found outside the CNS. Found in olfactory bulb, nucleus accumbens Involved in endocrine function cognitions, emotions, regulations oflocomotor functions and modulates endocrine functions D4 Substancia nigra , hippocampus, amygdala, thalamus, hypothalamus, kidney, frontal cortex, heart, blood vessels, adrenal glands, gastrointestinal tract, sympathetic ganglia, globus palidum , Lowest receptor found in CNS than all dopamine receptors Regulations of renal functions, gastrointestinal motility, vasodilatations, blood pressure, modulations of cognitive functions D5 Substancia nigra , hypothalamus, hippocampus, dental gyrus , kidney, heart, blood vessels, adrenal glands, gastrointestinal tract, sympathetic ganglia Involved in pain process, affective functions, endocrine functions of dopamine

8. Dopaminergic Pathways Mesolimbic Pathway Mesocortical Pathway Nigrostriatal Pathway Tuberoinfundibular Pathway Incertohypothalamic Pathway Medullary Periventricular Retinal

9. Functions Precursor NE  Epinephrine Neurotransmitter Neurohormone prolactin Pleasure Reward emotion Memory Attention Learning Locomotion smooth and controlled muscular movements Renal- vasodilation, diuresis, and natriuresis

10. Drugs and Diseases associated with Dopamine

11. Vomiting

12. Parkinson’s Disease

13. Drugs affecting brain dopaminergic system ( a) Dopamine precursor : Levodopa ( l-dopa ) ( b) Peripheral decarboxylase inhibitors : Carbidopa ,. ( c) Dopaminergic agonists: Bromocriptine , Ropinirole , Pramipexole ( d) MAO-B inhibitor: Selegiline (e) COMT inhibitors: Entacapone , Tolcapone (f) Dopamine facilitator: Amantadine

14. Dopamine and Reward Signaling

15. Dopamine and Reward Signaling Behavior studies show that dopamine projections to striatum and frontal cortex play important role in effect of rewards on learning Dopamine neurons in the basal ganglia show increase in activity when the animal receives an unexpected reward, or a cue that predicts a reward and a decrease in activity when an expected reward is not obtained

16. Addiction and drug abuse

17. The dopaminergic projection to ventral striatum has often been implicated in the mechanisms for addiction Increased locomotor activity and stereotypy caused due to psychostimulant involve dopamine release in striatum Psychostimulants such as Cocaine and Amphetamine are known to alter dopamine activity in brain

18. Impulsive cycle Occasional substance use is an impulse choice driven by positive reinforcement of the drug’s expected effect This teaches the brain to anticipate reward on subsequent exposure to the drug When the substance is taken, pleasure will be experienced again, usually followed by regret

19. Compulsive cycle With repeated exposure to the drug neurobiological changes occur in the brain leads to craving, reduced reward on drug exposure withdrawal during abstinence (negative reinforcement ) This leads to craving which is released by drug ingestion

20. Attention deficit hyperactivity disorder Decrease In Dopamine Level in Anterior frontal cortex An area associated with cognitive function such as Attention Concentration

21. Schizophrenia Defective dopamine neurotransmission – relative excess of central dopaminergic activity An increase in DA function in the mesolimbic system ( postive symptom) Decreased function in the mesocortical DA system (negative symptoms) Behavior similar to the behavioral effects of psychostimulants

22. ANTIPSYCHOTIC DRUGS 1 ) Phenothiazines Aliphatic side chain: Chlorpromazine Piperidine side chain: Thioridazine Piperazine side chain: Trifluoperazine Fluphenazine All antipsychotics (except clozapine-like atypical) have potent dopamine D2 receptor blocking action; antipsychotic potency has shown good correlation with their capacity to bind to D2 receptor. Phenothiazines and thioxanthenes also block D1, D3 and D4 receptors, but there is no correlation with antipsychotic potency. Blockade of dopaminergic projections to the temporal and prefrontal areas constituting the ‘limbic system’ and in mesocortical areas is probably responsible for the antipsychotic action.

23. Role of dopamine o prolactin secretion Inhibits secretion of prolactin by acting on D2 receptors. Treatment of hyperprolactinemia Ergot derivatives : bromocriptine , cabergoline , pergolide . Non ergot : Quinagolide

24. References Rang H.P. and Dale M.M;Antipsychotics;7 th edition; 39,45,49; 557 http://en.wikipedia.org/wiki/Dopamine