Neurotransmitter - Dopamine

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Neurotransmitter - Dopamine

  1. 1. Neurotransmitters: Dopamine Sankar Alagapan Nov 2 2009 BME 6938 Special Neurobiology Topics for Biomedical Engineers
  2. 2. Overview <ul><li>Introduction </li></ul><ul><li>Biochemistry </li></ul><ul><li>Dopamine receptors </li></ul><ul><li>Dopaminergic pathways </li></ul><ul><li>Dopamine and Reward Signaling (Learning) </li></ul><ul><li>Dopamine and Addiction </li></ul><ul><li>Pathologies associated with dopamine system </li></ul><ul><li>Summary </li></ul>
  3. 3. Introduction <ul><li>Dopamine belongs to the family of catecholamines </li></ul><ul><li>Hormones Epinephrine and Norepinephrine (other catecholamines) are derived from Dopamine </li></ul><ul><li>Significant role in learning, goal-directed behavior, regulation of hormones, motor control </li></ul>
  4. 4. Introduction <ul><li>Not a simple excitatory or inhibitory neurotransmitter; neuromodulator that modulates the response of target neurons and alters the synaptic plasticity </li></ul>
  5. 5. History <ul><li>Synthesized by George Barger and James Ewens in 1910 </li></ul><ul><li>Was considered as just a precursor to Epinephrine and Norepinephrine </li></ul><ul><li>Function as neurotransmitter discovered by Arvid Carlsson in 1958 </li></ul>
  6. 6. Synthesis <ul><li>DOPA is converted so rapidly into Dopamine that DOPA levels are negligible in the brain </li></ul><ul><li>Rate of synthesis is regulated by </li></ul><ul><ul><li>Catecholamine acting as inhibitor of TH </li></ul></ul><ul><ul><li>Availability of BH 4 </li></ul></ul><ul><ul><li>Presynaptic DA receptors </li></ul></ul><ul><ul><li>Amount of activity in nigrostriatal pathway </li></ul></ul>Rate Limiting Step
  7. 7. Metabolism <ul><li>In rats – DOPAC major metabolite </li></ul><ul><li>In primates and human – HVA major metabolite </li></ul><ul><li>Accumulation of HVA in brain or CSF used as index of function of dopaminergic neurons </li></ul>
  8. 8. Dopamine Transporter <ul><li>High affinity DA-uptake sites – terminating transmitter action and homeostasis </li></ul><ul><li>619 amino acid protein </li></ul><ul><li>Uses energy provided by Na + gradient generated by Na + K + transporting ATPase </li></ul><ul><li>Recaptures DA soon after its release, modulating the concentration in the synapse </li></ul>
  9. 9. Dopamine Receptors <ul><li>Metabotropic G-protein coupled receptors </li></ul><ul><li>D 1 – like family: </li></ul><ul><ul><li>Includes subtypes D 1 and D 5 </li></ul></ul><ul><ul><li>Activation is coupled to G α s ; activates adenylyl cylcase which leads to increase in concentration of cAMP </li></ul></ul><ul><li>D 2 – like family: </li></ul><ul><ul><li>Includes D 2 , D 3 and D 4 </li></ul></ul><ul><ul><li>Activation is coupled to G α i ; inhibits adenylyl cyclase leading to decrease in concentration of cAMP </li></ul></ul>
  10. 10. Dopamine Receptors
  11. 11. Dopamine Receptors
  12. 12. Dopamine Receptors
  13. 13. Dopamine Receptors
  14. 14. Dopamine Receptors <ul><li>Postsynaptic Receptors: </li></ul><ul><ul><li>D 1 - like and D 2 – like found in cells postsynaptic to dopamine releasing cells </li></ul></ul><ul><ul><li>Provides a mechanism for feedback between striatum and substantia nigra </li></ul></ul><ul><li>Autoreceptors: </li></ul><ul><ul><li>D 2 - like found in soma, dendrites and nerve terminals </li></ul></ul><ul><ul><li>Stimulation of somatodendritic autoreceptors slows the firing rate while stimulation of those in nerve terminals inhibits dopamine release and synthesis </li></ul></ul><ul><ul><li>Synthesis-modulating, release-modulating and impulse-modulating </li></ul></ul>
  15. 15. Dopaminergic Neurons <ul><li>From Jasmin and Ohara lab (UCSF) </li></ul>
  16. 16. Dopaminergic Pathways <ul><li>Mesolimbic Pathway </li></ul><ul><li>Mesocortical Pathway </li></ul><ul><li>Nigrostriatal Pathway </li></ul><ul><li>Tuberoinfundibular Pathway </li></ul><ul><li>Incertohypothalamic Pathway </li></ul><ul><li>Medullary Periventricular </li></ul><ul><li>Retinal </li></ul><ul><li>Olfactory bulb </li></ul>
  17. 17. Dopaminergic Pathways Moore et al. 1978
  18. 18. Significance of Dopaminergic Pathways <ul><li>Mesolimbic Pathway </li></ul><ul><ul><li>Associated with pleasure, reward and goal directed behavior </li></ul></ul><ul><li>Mesocortical Pathway </li></ul><ul><ul><li>Associated with motivational and emotional responses </li></ul></ul><ul><li>Nigrostriatal Pathway </li></ul><ul><ul><li>Involved in coordination of movement (part of basal ganglia motor loop) </li></ul></ul><ul><li>Tuberoinfundibular Pathway </li></ul><ul><ul><li>Regulates secretion of prolactin by pituitary gland and involved in maternal behavior </li></ul></ul>
  19. 19. Dopamine and Reward Signaling <ul><li>Behavior studies show that dopamine projections to striatum and frontal cortex play important role in effect of rewards on learning </li></ul><ul><li>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 </li></ul>
  20. 20. Dopamine and Reward Signaling Schultz 2002
  21. 21. Dopamine and Reward Signaling <ul><li>The dopamine reward prediction error signal </li></ul><ul><ul><li>Dopamine neurons encode rewards relative to prediction as opposed to the unconditional encoding of actual rewards </li></ul></ul>Dopamine Response = Reward Occurred – Reward Predicted
  22. 22. Dopamine and Reward Signaling <ul><li>Human subjects treated with L-Dopa had a greater propensity to choose most rewarding action than those treated with haloperidol showing dopamine-dependent modulation can account for improving human decisions </li></ul>Pessiglione et al 2006 Roborats
  23. 23. Dopamine and Addiction <ul><li>The dopaminergic projection to ventral striatum has often been implicated in the mechanisms for addiction </li></ul><ul><li>Increased locomotor activity and stereotypy caused due to psychostimulant involve dopamine release in striatum </li></ul><ul><li>Psychostimulants such as Cocaine and Amphetamine are known to alter dopamine activity in brain </li></ul>
  24. 24. <ul><li>Cocaine binds to DAT (at a different site) preventing the reuptake of dopamine by the cells leading to an increased extracellular levels of dopamine </li></ul><ul><li>Homeostatic mechanisms tend to reduce the level of dopamine synthesis leading to reduced dopamine level </li></ul>Effect of Cocaine
  25. 25. Effect of Cocaine <ul><li>Evidences also show that D 1 -antagonists prevent the behavioral response than D 2 - antagonists implicating cocaine affinity to D 1 receptor </li></ul><ul><li>Suppresses the firing of Nucleus Accumbens neurons by enhancing extracellular dopamine concentration which alters the ion channels leading to less excitability </li></ul>
  26. 26. Effect of Amphetamine <ul><li>Amphetamine acts as a false substrate and is transported into the cytoplasm and results in reverse transport of dopamine from cytoplasm to the extracellular space. </li></ul><ul><li>Mice on Meth </li></ul><ul><li>&quot;There is a moment of regret, followed by vast sadness. Then comes a tidal wave of euphoria that sweeps away every negative thought in my head. I've never felt so alive, so hopeful -- and I've never felt such energy.&quot; </li></ul>
  27. 27. Parkinson’s Disease <ul><li>Substantial loss of Dopamine in the striatum (70 – 80%) </li></ul><ul><li>Loss of dopamine neurons in other systems also (mesolimbic, mesocortical and hypothalamic systems) </li></ul><ul><li>Treatment strategy includes increasing dopamine levels by administering L-Dopa, nerve grafting with dopamine containing cells and deep brain stimulation </li></ul>
  28. 28. Schizophrenia <ul><li>Defective dopamine neurotransmission – relative excess of central dopaminergic activity </li></ul><ul><li>An increase in DA function in the mesolimbic system and a decreased function in the mesocortical DA systems </li></ul><ul><li>Behavior similar to the behavioral effects of psychostimulants </li></ul><ul><li>Antipsychotics such as chlorpromazine, bind to D 2 dopamine receptors and reduced positive psychotic symptoms </li></ul>
  29. 29. Dopamine and Monogamy <ul><li>In prairie voles, partner preference is established after initial mating via D2-like receptors </li></ul><ul><li>There is an upregulation of D1-like receptors which results in maintaining the bond </li></ul>
  30. 30. Summary <ul><li>Neurotransmitter that acts as a modulator </li></ul><ul><li>2 family of receptors for dopamine </li></ul><ul><li>3 main pathways of action </li></ul><ul><li>Involved in reward signaling providing a reward prediction error signal </li></ul><ul><li>Implicated with addiction – psychostimulants act as agonists of dopamine </li></ul>

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