Neurotransmitter - Dopamine
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Neurotransmitter - Dopamine






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    Neurotransmitter - Dopamine Neurotransmitter - Dopamine Presentation Transcript

    • Neurotransmitters: Dopamine Sankar Alagapan Nov 2 2009 BME 6938 Special Neurobiology Topics for Biomedical Engineers
    • Overview
      • Introduction
      • Biochemistry
      • Dopamine receptors
      • Dopaminergic pathways
      • Dopamine and Reward Signaling (Learning)
      • Dopamine and Addiction
      • Pathologies associated with dopamine system
      • Summary
    • 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
    • Introduction
      • Not a simple excitatory or inhibitory neurotransmitter; neuromodulator that modulates the response of target neurons and alters the synaptic plasticity
    • History
      • Synthesized by George Barger and James Ewens in 1910
      • Was considered as just a precursor to Epinephrine and Norepinephrine
      • Function as neurotransmitter discovered by Arvid Carlsson in 1958
    • Synthesis
      • DOPA is converted so rapidly into Dopamine that DOPA levels are negligible in the brain
      • Rate of synthesis is regulated by
        • Catecholamine acting as inhibitor of TH
        • Availability of BH 4
        • Presynaptic DA receptors
        • Amount of activity in nigrostriatal pathway
      Rate Limiting Step
    • Metabolism
      • In rats – DOPAC major metabolite
      • In primates and human – HVA major metabolite
      • Accumulation of HVA in brain or CSF used as index of function of dopaminergic neurons
    • Dopamine Transporter
      • High affinity DA-uptake sites – terminating transmitter action and homeostasis
      • 619 amino acid protein
      • Uses energy provided by Na + gradient generated by Na + K + transporting ATPase
      • Recaptures DA soon after its release, modulating the concentration in the synapse
    • Dopamine Receptors
      • 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
    • Dopamine Receptors
    • Dopamine Receptors
    • Dopamine Receptors
    • Dopamine Receptors
    • Dopamine Receptors
      • Postsynaptic Receptors:
        • D 1 - like and D 2 – like found in cells postsynaptic to dopamine releasing cells
        • Provides a mechanism for feedback between striatum and substantia nigra
      • Autoreceptors:
        • D 2 - like found in soma, dendrites and nerve terminals
        • Stimulation of somatodendritic autoreceptors slows the firing rate while stimulation of those in nerve terminals inhibits dopamine release and synthesis
        • Synthesis-modulating, release-modulating and impulse-modulating
    • Dopaminergic Neurons
      • From Jasmin and Ohara lab (UCSF)
    • Dopaminergic Pathways
      • Mesolimbic Pathway
      • Mesocortical Pathway
      • Nigrostriatal Pathway
      • Tuberoinfundibular Pathway
      • Incertohypothalamic Pathway
      • Medullary Periventricular
      • Retinal
      • Olfactory bulb
    • Dopaminergic Pathways Moore et al. 1978
    • Significance of Dopaminergic Pathways
      • Mesolimbic Pathway
        • Associated with pleasure, reward and goal directed behavior
      • Mesocortical Pathway
        • Associated with motivational and emotional responses
      • Nigrostriatal Pathway
        • Involved in coordination of movement (part of basal ganglia motor loop)
      • Tuberoinfundibular Pathway
        • Regulates secretion of prolactin by pituitary gland and involved in maternal behavior
    • 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
    • Dopamine and Reward Signaling Schultz 2002
    • Dopamine and Reward Signaling
      • The dopamine reward prediction error signal
        • Dopamine neurons encode rewards relative to prediction as opposed to the unconditional encoding of actual rewards
      Dopamine Response = Reward Occurred – Reward Predicted
    • Dopamine and Reward Signaling
      • 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
      Pessiglione et al 2006 Roborats
    • Dopamine and Addiction
      • 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
      • Cocaine binds to DAT (at a different site) preventing the reuptake of dopamine by the cells leading to an increased extracellular levels of dopamine
      • Homeostatic mechanisms tend to reduce the level of dopamine synthesis leading to reduced dopamine level
      Effect of Cocaine
    • Effect of Cocaine
      • Evidences also show that D 1 -antagonists prevent the behavioral response than D 2 - antagonists implicating cocaine affinity to D 1 receptor
      • Suppresses the firing of Nucleus Accumbens neurons by enhancing extracellular dopamine concentration which alters the ion channels leading to less excitability
    • Effect of Amphetamine
      • 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.
      • Mice on Meth
      • "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."
    • Parkinson’s Disease
      • Substantial loss of Dopamine in the striatum (70 – 80%)
      • Loss of dopamine neurons in other systems also (mesolimbic, mesocortical and hypothalamic systems)
      • Treatment strategy includes increasing dopamine levels by administering L-Dopa, nerve grafting with dopamine containing cells and deep brain stimulation
    • Schizophrenia
      • Defective dopamine neurotransmission – relative excess of central dopaminergic activity
      • An increase in DA function in the mesolimbic system and a decreased function in the mesocortical DA systems
      • Behavior similar to the behavioral effects of psychostimulants
      • Antipsychotics such as chlorpromazine, bind to D 2 dopamine receptors and reduced positive psychotic symptoms
    • Dopamine and Monogamy
      • In prairie voles, partner preference is established after initial mating via D2-like receptors
      • There is an upregulation of D1-like receptors which results in maintaining the bond
    • Summary
      • Neurotransmitter that acts as a modulator
      • 2 family of receptors for dopamine
      • 3 main pathways of action
      • Involved in reward signaling providing a reward prediction error signal
      • Implicated with addiction – psychostimulants act as agonists of dopamine