Dopamine

Dopamine in psychiatry and its importance

1. H i s t o ry Synthesized by George Barger and James Ewens in 1910 W as c o n s id e r e d as j u s t a p r e c u r s o r t o E pin e ph r in e and Norepinephrine Function as neurotransmitter discovered by Arvid Carlsson in 1958

2. Introduction Dopamine belongs to the family of catecholamines H o r m o n e s : Epin e p h r in e and N o r e pin e ph r i n e ( catecholamines ) are derived from Dopamine Significant role in learning, goal-directed behavior, regulation of hormones, motor control

3. SYNTHESIS Site of synthesis- neural tissue adrenal medulla From AA- tyrosine Rate limiting enzyme Tyrosine Hydroxylase Reuptake Metabolised COMT MAO Homovanillic acid DEGRADATION

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5. DOPAMINE RECEPTORS  Metabotropic G-protein coupled receptors D 1 – like family: Includes subtypes D 1 and D 5 Activation is coupled to G 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 i ; inhibits adenylyl cyclase leading to decrease in concentration of cAMP 7

6. Dopaminergic Pathways Mesolimbic Pathway Mesocortical Pathway Nigrostriatal Pathway Tuberoinfundibular Pathway Incertohypothalamic Pathway Medullary Periventricular Retinal Olfactory bulb

7. MESOLIMBIC PATHWAY The mesolimbic dopamine pathway, which projects from the ventral tegmental area in the brainstem to the nucleus accumbens in the ventral striatum Involved in regulation of emotional behaviors Specifically, hyperactivity of this pathway is believed to account for delusions and hallucinations . This pathway is also involved in pleasure,reward, and reinforcing behavior, and many drugs of abuse interact here.

8. MESOCORTICAL PATHWAY Arising from cell bodies in the ventral tegmental area, but projecting to areas of the prefrontal cortex, is known as the mesocortical dopamine pathway Branches of this pathway into the dorsolateral prefrontal cortex are hypothesized to regulate cognition and executive functions whereas branches of this pathway into the v e n t r o m ed i al part s o f the p r e f r o n t al c or t e x a r e hypothesized to regulate emotions and affect

9. Hyperactivity of the mesolimbic dopamine pathway accounts for positive psychotic symptoms whether those symptoms are part of the illness of schizophrenia,or of drug-induced psychosis, or whether they are positive psychotic symptoms accompanying mania,depression, or dementia. Hyperactivity of mesolimbic dopamine neurons may also play a role in aggressive and hostile symptoms in schizophrenia and especially if serotonergic control of dopamine is aberrant in patients who lack impulse control.

10. Cognitive and some negative symptoms of schizophrenia may be due to a deficit of dopamine activity in mesocortical projections to dorsolateral prefrontal cortex whereas affective and other negative symptoms of schizophrenia may be due to a deficit of dopamine activity in mesocortical projections to ventromedial prefrontal cortex

11. DA & SCHIZOPHRENIA Mesoc o rt i c a l DLPFC- Cognitive and negative symptoms V M PFC- Cognitive and affective symptoms DOPAMINE HYPOTHESIS Mesolimbic +ve symptoms

12. ROLE OF DOPAMINE IN MOOD DISORDER Decreased mesocortical and mesolimbic dopamine activity has implications in cognitive and motor disturbances that are associated with depression While increased mesocortical and mesolimbic dopamine activity leads to mania

13. 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

14. Modulation of prefrontal cortical function,and therefore regulation of attention and behavior, relies on the optimum release of dopamine (DA) and norepinephrine(NE) If the systems are properly “tuned,”then D1 receptor stimulation can reduce the noise and α2A receptor stimulation can increase the signal to result in proper prefrontal cortex functioning. This will result inadequate guided attention , focus on a specific task, and adequate control of emotions and impulses.

15. In ADHD, imbalances in NE and DA circuits in the prefrontal cortex cause inefficient information processing in prefrontal circuits, and thus the symptoms of ADHD When there is low release of both DA and NE .It leads to low stimulation of both D1 and α2A receptors on the spines of these pyramidal neurons Deficient DA and NE input will lead to increased noise and decreased signal, respectively, thus preventing a coherent signal from being sent This could cause hyperactivity, inattention, impulsivity.

16. N I GROSTRIATAL PATHWAY Projects from dopaminergic cell bodies in the brainstem substantia nigra to the basal ganglia or striatum The nigrostriatal dopamine pathway is a part of the extrapyramidal nervous system and controls motor movements. Deficiencies in dopamine in this pathway cause movement disorders Dopamine deficiency in the basal ganglia also can produce akathisia (a type of restlessness), and dystonia(twisting movements especially of the face and neck). These movement disorders can be replicated by drugs that block D2 receptors in this pathway,

17. PARKINSONS DISEASE Substantial loss of Dopamine in the striatum (70 – 80%) characterized by rigidity, akinesia/bradykinesia (i.e., lack of movement or slowing of movement), and tremor T r e a t m e n t s t r a t e gy includes increasing dopamine levels by administering L-Dopa, nerve grafting with dopamine containing cells and deep brain stimulation

18. TUBEROINFUNDIBULAR PATHWAY The dopamine neurons that project from hypothalamus to anterior pituitary are part of the tuberoinfundibular dopamine pathway . These neurons are active and inhibit prolactin release. In the postpartum state, however, the activity of these dopamine neurons is decreased. Prolactin levels can therefore rise during breastfeeding so that lactation will occur. If the functioning of tuberoinfundibular dopamine neurons is disrupted by lesions or drugs, prolactin levels can also rise.

19. EATING DISORDERS Eating ,hunger and reward circuits Dopamine projections to mammillary body of Hypothalamus->extend to NA Hunger and reward circuits are interconnected IMPULSE CONTROL DISORDERS Linked to reward circuitry BPD Kleptomania Pyromania Sexual addictions paraphilias fetichism pedophilia

20. DOPAMINE AND ADDICTION The dopaminergic projection to ventral striatum has often been implicated in the mechanisms for addiction Increased loco - motor activity and stereotypy caused due to psych o- stimulant involve dopamine release in striatum

21. Nucleus Accumbens  Occurs due to increased release of dopamine caused by the psychotropic substances like  morphine  heroin  Cannabis  cocaine  nicotine

22. Cocaine binds to presynaptic dopamine transporter, thus inhibit dopamine reuptake Amphetamines not only inhibit dopamine uptake, but also reverse function of dopamine transporter Caffeine increases dopamine release in shell of nucleus accumbens Tetra hydro cannabinol also increase dopamine level in nucleus accumbens DOPAMINE AND DRUGS

23. D2 receptor blockade is associated with efficacy of antipsychotic drugs Longterm administration result in up regulation in the number of receptor → tardive dyskinesia. Serotonin Dopamine antagonist block 5HT.2 and lesser extend D2 receptors → decreased risk for parkinsonism → effective for +ve and –ve symptoms of schizophrenia. DOPAMINE AND DRUGS

24. Nicotine → Psychoactive ingredient Stimulate release of dopamine & glutamate Smokers – decreased risk of Parkinson disease, Alzheimers disease, ulcerativecolitis Dopamine transporter can be blocked by Buproprion. DOPAMINE AND DRUGS

25. Used to treat adverse effect of antipsychotic drugs Parkinsonism, EPS, akinesia, NMS, Focal perioral tremors, hyperprolactinemia galactorrhoea Bromocriptine, L Dopa & Carbi Dopa, Rapinirole, pramipexole, pergolide, apomorphine., DOPAMINE RECEPTOR AGONIST & PRECURSORS

26. Thankyou Avinav Gupta 140101146