Post on 07-May-2015
transcript
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
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
Introduction
• Not a simple excitatory or inhibitory neurotransmitter; neuromodulator that modulates the response of target neurons and alters the synaptic plasticity
4
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
5
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
6
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
7
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
8
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
9
Dopamine Receptors
10
Dopamine Receptors
11
Dopamine Receptors
12
Dopamine Receptors
13
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
14
Dopaminergic NeuronsFrom Jasmin and Ohara lab (UCSF)
15
Dopaminergic Pathways• Mesolimbic Pathway• Mesocortical Pathway• Nigrostriatal Pathway• Tuberoinfundibular
Pathway• Incertohypothalamic
Pathway• Medullary Periventricular• Retinal• Olfactory bulb
16
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
18
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
19
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
21
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
23
• 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
24
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
25
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."
26
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
27
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
28
Dopamine and Monogamy
29
• 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
30