Monoamines: Catecholamines

Question 1

What are monoamines?

Answer 1

Monoamines (biogenic amines) are a group of neurotransmitters / hormones that share a common single amine functional group.

• Includes epinephrine, norepinephrine, dopamine and serotonin

Question 2

What are catecholamines?

Answer 2

Catecholamine neurotransmitters have common structure (with individual variations)

• includes epinephrine, norepinephrine and dopamine

Question 3

what is VMAT?

Answer 3

VMAT is the transporter that loads
dopamine into synaptic vesicles

Question 4

What is reserpine?

Answer 4

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

Reserpine treatment causes sedation in animals and induces depression in humans

Question 5

How does
cocaine and amphetamine affect DAT function?

Answer 5

Cocaine and amphetamine affect DAT function

Cocaine & amphetamines inhibits
DAT preventing dopamine reuptake

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

Question 6

Describe dopaminergic synapse

Answer 6

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 7

What is the difference between D1 and D2 receptors?

Answer 7

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

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

Question 8

Describe dopaminergic terminals

Answer 8

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 9

Describe dopaminergic pathways

Answer 9

Dopamine accounts for 90% of catecholamine neurotransmission in the CNS

1. Nigrostriatal system

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

2. Tuberoinfundibular system

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

3. Mesolimbic/mesocortical system

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

Question 10

Describe dopaminergic lesions

Answer 10

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 11

Describe the nigrostriatal system

Answer 11

• 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 (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin that degrades dopaminergic neurons in the substantia nigra and produces
  Parkinson’s symptoms
• Resistant to L-DOPA treatment

Question 12

Describe nigrostriatal dopaminergic pathways

Answer 12

• 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
• Degradation of neurons in the substantia nigra in Parkinson’s disease

Question 13

Describe NIGROSTRIATAL DOPAMINE

Answer 13

• Genetic modification of dopamine function induces locomotor effects
• DAT knockout causes hyperactivity
• Decreased re-uptake prolongs DA signalling at the synapse

Question 14

What leads to cocaine’s hyper locomotion

Answer 14

• Cocaine (inhibiting DAT activity) has comparable effects on locomotion to DAT knockout.
• D1 receptor knockout ablates cocaine’s hyperlocomotion.

Question 15

Describe mesolimbic pathways

Answer 15

• 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 16

Describe schizophrenia and psychotic disorders

Answer 16

Exist along a spectrum of severity with combinations of symptoms:
Delusions
Hallucinations
Disorganized speech
Grossly disorganized or catatonic motor behaviour
Avolition
Social deficits Flattened affect Cognitive deficits

Psychosis proposed to result from altered dopaminergic signalling

Hyperactivity in mesolimbic system leads to positive symptoms

Question 17

Describe nucleus accumbens in SCZ

Answer 17

• 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 and hallucinations

Question 18

Describe therapeutic effects of antipsychotics

Answer 18

• 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 19

Describe adverse effects of antipsychotics

Answer 19

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

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

Question 20

Describe dopamine activity in SCZ

Answer 20

• 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 21

Describe dopamine and addictions

Answer 21

• Addictive behaviour 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 22

Describe operant task for impulsivity in rats

Answer 22

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 behaviour.

Question 23

Describe dopamine and impulsivity in the rat study

Answer 23

Impulsive rats (●) show increased premature responses and have increased self-administration of cocaine than low impulsive rats (○)

Question 24

Describe PET imaging

Answer 24

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).

Question 25

Describe addictions and SCZ

Answer 25

* 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