dopamine Flashcards by Cambell Meier

catecholamines

epinepherine, norepinepherine, dopamine

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epinepherine operates in the

PNS

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Catecholamine

neurotransmitters have common structure (with individual variations)

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dopamine synthesis

L-tyrosine – Tyrosine hydroxylase -> L-DOPA – DOPA decarboxylase -> dopamine

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when AMPT attaches to TH what does it do

inhibits the synthesis of dopamine, norepinepherine, epineperine

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VMAT

is the transporter that loads dopamine into synaptic vesicles

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Reserpine

Reserpine inhibits VMAT and depletes DA and NE as cytosolic catecholamines are rapidly degraded

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Reserpine treatment causes

sedation in animals and induces depression in humans

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intracellular pathway of dopamine

dopamine —MAO–> DOPAC — COMPT –> HVA

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Extracellular pathway of dopamine

dopamine —COMPT–> 3MT — MAO –> HVA

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Cocaine and amphetamine affect

DAT functions

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Cocaine & amphetamines inhibits

DAT preventing dopamine reuptake

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preventing dopamine uptake causes what ?

Increases dopamine in the synapse
Prolongs dopamine signalling
Hyperactivity of dopaminergic circuits

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Presynaptic cell rich in

anabolic enzymes (TH, DOPA decarboxylase)

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VMAT expressed on vesicles for

loading dopamine

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Dopamine receptors in

postsynaptic membrane

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Autoreceptors in

presynaptic membrane for feedback inhibition

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Dopamine transporter (DAT) responsible for

reuptake

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family [D1, D5] – G-protein coupled receptors signalling through Gsα to ↑cAMP (Excitatory)

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family [D2, D3, D4] – G-protein coupled receptors signalling through Giα to ↓ cAMP (Inhibitory)

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Unlike classical synapses, dopamine can often synapse onto the

neck of dendritic spines

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synapsing onto the neck of dendritic spines

allows dopamine to modulate the activity of the synapse

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Dopamine can gate the signals at dendritic spines –

– increasing or decreasing signal transmission

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Dopamine accounts for 90% of

catecholamine neurotransmission in the CNS

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Nigrostriatal system

projects from substantia nigra and ventral tegmental area to striatum (caudate and putamen)

Tuberoinfundibular system

projects from the hypothalamus to the medial eminence to stimulate the pituitary prolactin secretion

Mesolimbic/mesocortical system

Projects from the ventral tegmental area to the limbic system, nucleus accumbens, mesial frontal, anterior cingulate, and entorhinal cortex

Dopaminergic lesions Bilateral nigrostriatal lesion

sensory neglect, motivational deficits, motor impairment.

Unilateral lesion of nigrostriatal pathway results in

postural asymmetry and turning

6-hydroxydopamine (6-OHDA) is a

selective neurotoxin.

Nigrostriatal system

Projects to the striatum Involved in motor control D1 and D2 family receptors Degradation in Parkinson’s leads to motor symptoms

treatment of parkinsons disease includes

includes L-DOPA, precursor to dopamine

MPTP

) is a neurotoxin that degrades dopaminergic neurons in the Substantia nigra and produces Parkinson’s symptoms and is resistant to L-dopa treatment

Degeneration of dopaminergic neurons in the nigrostriatal system

central to the pathophysiology of Parkinson’s disease

target receptors in parkinsons

Targets enriched with D1 and D2 receptors in the basal ganglia

DAT knockout causes

hyperactivity - Decreased re-uptake prolongs DA signalling at the synapse

Cocaine (inhibiting DAT activity) has comparable effects on

locomotion to DAT knockout.

D1 receptor knockout removes

cocaine’s hyperlocomotion

Mesolimbic dopaminergic pathways Targets enriched in

D1, D2 family receptors

Mesolimbic dopaminergic pathways Limbic connections are proposed to

mediate memory, learning, and affect

Mesolimbic dopaminergic pathways The nucleus accumbens is proposed to act to modify

salience of information flow, implicated in motivation & addictions (motivational salience), and psychosis (sensory salience)

Schizophrenia and Psychotic disorders positive symptoms

Delusions Hallucinations Disorganized speech Grossly disorganized or catatonic motor behaviour

Schizophrenia and Psychotic disorders negative symptoms

Avolition Social deficits Flattened affect Cognitive deficits

Schizophrenia and Psychotic disorders Psychosis proposed to result from

altered dopaminergic signalling

Hyperactivity in mesolimbic system leads to

positive symptoms

Nucleus accumbens in SCZ Mesolimbic dopamine is proposed to mediate

salience

Motivational salience

addictions

Sensory salience

– sensory gating

Nucleus accumbens in SCZ Excess dopamine activity leads the patient to

perceive voices, sounds, and imagery as inappropriately salient

Nucleus accumbens in SCZ - False significance assigned to

internal and external stimuli are interpreted as delusions and hallucinations

Typical antipsychotics inhibit

D1 and D2 family dopamine receptors

Chlorpromazine

(first discovered neuroleptic)

Haloperidol

(still widely used front-line antipsychotic)

Antipsychotic efficacy is correlated with

D2 binding potential

Stimulants (esp. amphetamine) can induce

psychosis at sufficient dose

Extrapyramidal side effects (nigrostriatal):

akinesia, akathesia, acute dystonic reaction, Pseudoparkinsonism,

Akinesia

inability to initiate movement

Akathisia

inability to remain motionless

Acute dystonic reaction

– sustained muscle contraction, twisting and repetitive movements

Pseudoparkinsonism

– fixed (non-progressive) Parkinsonism without degeneration of dopaminergic neurons

Extrapyramidal side effects Tuberofundibular:

Hyperprolactinaemia

can result from antipsychotic treatment Amenorrhea (♀), infertility(♂/♀), sexual dysfunction (♂/♀), hypogonadism (♂), spontaneous lactation (♂/♀)

Dopamine levels in post-mortem SCZ brains are

are elevated in the striatum

SCZ - PET and SPECT imaging of dopamine receptors show

show increased basal levels of dopamine

Basal dopamine levels are predictive of

responsiveness to antipsychotic therapy

typical antipsychotics targeting dopamine only address

positive symptoms

in SCZ what is the dopamine activity in the cortex?

hypoactivity of dopamine seen in cortex

Gaba neuron is

inhibitory – take it away and we lose control

Addictive behaviour is linked to

impulsive traits in humans

Impulse control

is a manifestation of inhibitory control (component of executive function)

Impulse control Involves structures such as

anterior cingulate, dorsolateral prefrontal cortex, lateral orbital prefrontal cortex, and motor/premotor cortex

Inhibitory control can be considered a

gating event

Impulsive rats show increased premature responses and have

increased self-administration of cocaine than low impulsive rats (○)

PET imaging of a dopamine receptor D2/3 antagonist showed high

impulsive rats have reduced binding potential in the ventral striatum.

Reduced D2/3 binding potential correlates with high

impulsivity and addictive behaviour (cocaine self-administration).

SCZ patients have very high comorbidity with

addictions

Cannabis or amphetamine intoxication is a frequent precipitant of the first

episode of psychosis

Early substance use / abuse (teenage use) correlates with

SCZ onset and severity but is neither necessary nor sufficient