2.5 - Dopamine

Catecholamines

- monoamines containing catechol w/ side chain amine (ex: dopamine, NE, epi)

- derived from Phe and Tyr

Adrenergic system

uses NE and epi as NT

Dopamine (DA)

- important in ANS and CNS activity

- first member of catecholamine NT class

Dopamine synthesis (in neurons)

- Tyr actively co-transported into cell (charged)

- hydroxylation of Tyr by tyrosine hydroxylase (rate limiting step)  → DOPA is converted to dopamine via DOPA decarboxylase

Dopamine transporter

- actively co-transported w// ions (exchange h+ for DA)

- after release 90% of DA is taken up by them into pre and post synaptic cells → terminates signaling

reserpine

inhibits VMAT protein

Amphetamine

inhibits VMAT

Dopamine reuptake fate

reused (presynaptic only) or metabolized into homovanillic acid and DOPAC by COMT and MAO enzymes

dopamine receptors

- all metabotropic 7 transmembrane GPCR-class receptors

- divided into 2 groups: D1-like and D2-like

D1-like receptors

- increase adenyl cyclase

- D1 and D5; excitatory

D2-like receptors

- decreases adenyl cyclase

- D2, D3, and D4; inhibitory

D2 receptors

- important in feedback inhibitory control and control mechanism

- inhibits release of NT from presynaptic cell

- binds to autoreceptor

autoreceptor

presynaptic receptors that respond to dopamine release by the same cell

Dopamine Pathways in the brain

Nigrostriatal, mesocorticolimbic, and tuberoinfundibular

Nigrostristal pathway

- substantia nigra to Striatum; ~75% of dopamine in brain

- regulates voluntary locomotor activity

- ex: Parkinson’s, Huntington’s, and Gilles de la Tourette

Parkinson’s disease

degeneration of substantia nigra dopamine neurons

Huntington’s chorea

excess dopamine → involuntary movement

Gilles de la Tourette syndrome

excess dopamine contributes to physical (motor) and vocal (phonic) tics

Mesocorticolimbic pathway

- originates in midbrain and projects to nucleus accumbent, limbic and frontal cortex

- regulates reward (signals natural reinforces; euphoria) and controls motivation

Tuberoinfundibular pathway

- originates in arcuate nucleus of hypothalamus. projects to pituitary gland

- inhibits secretion of prolactin

dopamine antagonists

cause hyperprolactinemia (↑ blood prolactin)

monoamine hypothesis

decreases catecholamine and serotonergic activity may underlie depression 

Tricyclic antidepressants (TCA)

- Ex: imipramine (Tofranil)

- block monoamine transporters

- prevent presynaptic neuron from reabsorbing catecholamines and serotonin from synaptic cleft after release

monoamine oxidase inhibitors (MOA-Is)

- ex: pheneizine (Nardil)

- block enzyme MAO, presynaptic terminal enzyme that metabolizes serotonin and catecholamines into inactive forms

- more NT available

dopamine hypothesis

schizophrenia results from excess activity at D2, D3, and D4 dopamine synapses

dopamine hypothesis support

- antipsychotic drugs strongly antagonize postsynaptic D2R

- drugs ↑ dopaminergic activity either aggravate schizophrenia or produce psychosis de novo

- mediate sexual behavior (↑ central DA = ↑ behavior) and vomiting (stimulation of D2R = ↑ vomiting)

opioid addiction

directly activates MOR; inhibits GABA-A, interneurons = ↑ DA in A10

psychostimulant addiction

- ex: cocaine, amphetamine

- increases DA by inhibiting dopamine transporter (DAT) = ↑ DA in synaptic cleft