Neurotransmitters: Dopamine

Sankar AlagapanNov 2 2009

BME 6938Special 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

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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

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Introduction

• Not a simple excitatory or inhibitory neurotransmitter; neuromodulator that modulates the response of target neurons and alters the synaptic plasticity

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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

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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 BH4

– Presynaptic DA receptors– Amount of activity in

nigrostriatal pathway

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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

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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

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Dopamine Receptors

• Metabotropic G-protein coupled receptors• D1 – like family:

– Includes subtypes D1 and D5

– Activation is coupled to Gαs ; activates adenylyl cylcase which leads to increase in concentration of cAMP

• D2 – like family: – Includes D2, D3 and D4

– Activation is coupled to Gαi ; inhibits adenylyl cyclase leading to decrease in concentration of cAMP

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Dopamine Receptors

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Dopamine Receptors

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Dopamine Receptors

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Dopamine Receptors

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Dopamine Receptors• Postsynaptic Receptors:

– D1 - like and D2 – like found in cells postsynaptic to dopamine releasing cells

– Provides a mechanism for feedback between striatum and substantia nigra

• Autoreceptors:– D2 - 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

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Dopaminergic NeuronsFrom Jasmin and Ohara lab (UCSF)

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Dopaminergic Pathways• Mesolimbic Pathway• Mesocortical Pathway• Nigrostriatal Pathway• Tuberoinfundibular

Pathway• Incertohypothalamic

Pathway• Medullary Periventricular• Retinal• Olfactory bulb

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Dopaminergic Pathways

17Moore 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

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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

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Dopamine and Reward Signaling

20Schultz 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

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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

22Pessiglione 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

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• 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

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Effect of Cocaine

• Evidences also show that D1-antagonists prevent the behavioral response than D2- antagonists implicating cocaine affinity to D1 receptor

• Suppresses the firing of Nucleus Accumbens neurons by enhancing extracellular dopamine concentration which alters the ion channels leading to less excitability

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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."

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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

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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 D2 dopamine receptors and reduced positive psychotic symptoms

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Dopamine and Monogamy

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• 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

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