Topic 6: Dopamine

Question 1

What are monoamines?

Answer 1

biogenic amines

a group of neurotransmitters/hormones that share a common single amine functional group

dopamine, norepinephrine, epinephrine, serotonin

Question 2

What are catecholamines?

Answer 2

dopamine, norepinephrine, epinephrine

catecholamine neurotransmitters have common structure (with individual variations)

Question 3

What is the process of dopamine synthesis?

Answer 3

tyrosine hydroxylase (TH) converts dietary L-tyrosine into L-DOPA

DOPA decarboxylase converts L-DOPA into dopamine

Question 4

What is VMAT?

Answer 4

VMAT is the transporter that loads dopamine into synaptic vesicles

Question 5

What is reserpine?

Answer 5

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

Question 6

How is dopamine broken down by MAO?

Answer 6

intracellularly breakdown starts with MAO first

dopamine is converted into DOPAC by MAO

DOPAC is then converted into homovanillic acid (HVA) by COMT

Question 7

How is dopamine broken down by COMT?

Answer 7

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

Question 8

How do cocaine and amphetamines affect the dopamine transporter (DAT)?

Answer 8

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

Question 9

What are the features of the dopaminergic synapse?

Answer 9

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

Question 10

What is the D1 family of dopamine receptors?

Answer 10

D1 and D5

G-protein coupled receptors signaling through Gs alpha to increase cAMP

excitatory

Question 11

What is the D2 family of dopamine receptors?

Answer 11

D2, D3, and D4

G-protein coupled receptors signaling through Gi alpha to decrease cAMP inhibitory

Question 12

What are dopaminergic terminals?

Answer 12

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

Question 13

What is the nigrostriatal system?

Answer 13

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

Question 14

What is the tuberoinfundibular system?

Answer 14

projects from the hypothalamus to the emdical eminence to stimulate the pituitary

prolactin secretion

Question 15

What is the mesolimbic/mesocortical system?

Answer 15

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

Question 16

What are dopaminergic lesions?

Answer 16

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

Question 17

What is the impact of degeneration of nigrostriatal dopaminergic pathways?

Answer 17

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

Question 18

What occurs after a DAT knockout in animal studies?

Answer 18

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

Question 19

What are the mesolimbic dopaminergic pathways?

Answer 19

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)

Question 20

How are schizophrenia and psychotic disorders related to dopaminergic signaling?

Answer 20

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

Question 21

How is the nucleus accumbens involved in schizophrenia?

Answer 21

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

Question 22

What are the therapeutic effects of antipsychotics?

Answer 22

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

Question 23

What are the extrapyramidal side effects of antipsychotics?

Answer 23

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

Question 24

What are the tuberofundibular side effects of antipsychotics?

Answer 24

hyperprolactinaemia can result from antipsychotic treatment

amenorrhea, infertility, sexual dysfunction, hypogonadism, spontaneous lactation

Question 25

What is the dopamine activity in schizophrenia?

Answer 25

dopamine levels in post-mortem SCZ brains are elevated in the striatum

PET and SPECT imaging of dopamine receptors show increased basal levels of dopamine

basal dopamine levels are predictive of responsiveness to antipsychotic therapy BUT hypoactivity of dopamine seen in cortex

typical antipsychotics targeting dopamine only address positive symptoms

Question 26

How is mesolimbic dopamine involved in addictions?

Answer 26

all drugs end with increased dopamine at nucleus succumbus

addictive behavior is linked to impulsive traits in humans: high correlation to impulsive disorders (e.g., ADHD, antisocial personality disorder)

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

Question 27

What is the animal model of testing impulse control with cocaine?

Answer 27

operant task for impulsivity testing in rats

nose poke results in food reward with a predictable delay between subsequent trials

premature responding resets the timer (slightly punitive) and is recorded as impulsive behavior

rats who are more impulsive are more likely to become addicted to cocaine, also chose to have more cocaine

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 behavior (cocaine self-administration)

Question 28

What is the relationship between addictions and schizophrenia?

Answer 28

SCZ patients have very high comorbidity with addictions
smoking (nicotine abuse) estimated as high as 75%
alcohol and/or drug abuse as high as 50%

substance abuse can be a precipitating event in SCZ

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