Topic 6: Dopamine Flashcards
What are monoamines?
biogenic amines
a group of neurotransmitters/hormones that share a common single amine functional group
dopamine, norepinephrine, epinephrine, serotonin
What are catecholamines?
dopamine, norepinephrine, epinephrine
catecholamine neurotransmitters have common structure (with individual variations)
What is the process of dopamine synthesis?
tyrosine hydroxylase (TH) converts dietary L-tyrosine into L-DOPA
DOPA decarboxylase converts L-DOPA into dopamine
What is VMAT?
VMAT is the transporter that loads dopamine into synaptic vesicles
What is reserpine?
inhibits VMAT and depletes DA and NE as cytosolic catecholamines are rapidly degraded
end up getting less effect of monoamines
reserpine treatment causes sedation in animals and induces depression in humans
How is dopamine broken down by MAO?
intracellularly breakdown starts with MAO first
dopamine is converted into DOPAC by MAO
DOPAC is then converted into homovanillic acid (HVA) by COMT
How is dopamine broken down by COMT?
extracellularly broke down in the synapse by COMT
dopamine is converted into 3-methoxytyramine (3-MT) by COMT
3-MT is converted into homovanillic acid (HVA) by MAO
How do cocaine and amphetamines affect the dopamine transporter (DAT)?
cocaine and amphetamine affect DAT function
cocaine and amphetamines inhibits DAT preventing dopamine reuptake: increases dopamine in the synapse, prolongs dopamine signaling, hyperactivity of dopaminergic circuits
What are the features of the dopaminergic synapse?
presynaptic cell rich in anabolic enzymes (TH, DOPA decarboxylase)
VMAT expressed on vesicles for loading dopamine
dopamine receptors in postsynaptic membrane
autoreceptors in presynaptic membrane for feedback inhibition
dopamine transporter (DAT) responsible for reuptake
What is the D1 family of dopamine receptors?
D1 and D5
G-protein coupled receptors signaling through Gs alpha to increase cAMP
excitatory
What is the D2 family of dopamine receptors?
D2, D3, and D4
G-protein coupled receptors signaling through Gi alpha to decrease cAMP inhibitory
What are dopaminergic terminals?
unlike classical synapses, dopamine can often synapse onto the neck of dendritic spines
this allows dopamine to modulate the activity of the synapse
dopamine can gate the signals at dendritic spines - increasing or decreasing signal transmission
What is the nigrostriatal system?
projects from substantia nigra and ventral tegmental area to striatum (caudate and putamen)
projects to the striatum
involved in motor control
D1 and D2 family receptors
degradation in Parkinson’s leads to motor symptoms: treatment includes L-DOPA, precursor to dopamine)
MPTP is a neurotoxin that degrades dopaminergic neurons in the substantia nigra and produces Parkinson’s symptoms: resistant to L-DOPA treatment
What is the tuberoinfundibular system?
projects from the hypothalamus to the emdical eminence to stimulate the pituitary
prolactin secretion
What is the mesolimbic/mesocortical system?
projects from the ventral tegmental area to the limbic system, nucleus accumbens, mesial frontal, anterior cingulate, and entorhinal cortex
What are dopaminergic lesions?
6-hydroxydopamine (6-OHDA) is a selective neurotoxin
BBB impermeable, taken up by catecholaminergic neurons (after injection using a stereotactic apparatus)
bilateral nigrostriatal lesion - sensory neglect, motivational deficits, motor impairment
unilateral lesion of nigrostriatal pathway results in postural asymmetry and turning
What is the impact of degeneration of nigrostriatal dopaminergic pathways?
degeneration of dopaminergic neurons in the nigrostriatal system central to the pathophysiology of Parkinson’s disease
tremors, rigidity, forward-flexed posture and shuffling steps, bradykinesia (slowed movement)
targets enriched with D1 and D2 receptors in the basal ganglia
What occurs after a DAT knockout in animal studies?
genetic modification of dopamine function induces locomotor effects
DAT knockout causes hyperactivity: decreased re-uptake prologs DA signaling at the synapse
cocaine (inhibiting DAT activity) has comparable effects on locomotion to DAT knockout
D1 receptor knockout ablates cocaine’s hyperlocomotion
What are the mesolimbic dopaminergic pathways?
targets enriched in D1, D2 family receptors
limbic connections are proposed to mediate memory, learning, and affect
the nucleus accumbens is proposed to act to modify salience of information flow, implicated in motivation & addictions (motivational salience) and psychosis (sensory salience)
How are schizophrenia and psychotic disorders related to dopaminergic signaling?
exists along a spectrum of severity with combinations of symptoms
psychosis proposed to result from altered dopaminergic signaling
hyperactivity in mesolimbic system leads to positive symptoms
How is the nucleus accumbens involved in schizophrenia?
mesolimbic dopamine is proposed to mediate salience
motivational salience: addictions
sensory salience: sensory gating
excess dopamine activity leads the patient to perceive voices, sounds, and imagery as inappropriately salient
false significance assigned to internal and external stimuli are interpreted as delusions ad hallucinations
What are the therapeutic effects of antipsychotics?
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
What are the extrapyramidal side effects of antipsychotics?
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
What are the tuberofundibular side effects of antipsychotics?
hyperprolactinaemia can result from antipsychotic treatment
amenorrhea, infertility, sexual dysfunction, hypogonadism, spontaneous lactation
