Block 6: Week 2: Mechanism of Psychotropic Drug Action

what is the role of the nigrostriatal pathway?

dopaminergic - initiation and control of movement

what is the role of the mesolimbic pathway?

dopaminergic - reward and reinforcement

what is the role of the mesocorticol pathway?

dopaminergic - cognition, planning, motivation

what is the role of the “tubero-infunibular” pathway?

hypothalamus to pituitary dopaminergic - inhibits release of prolactin hormone from pituitary gland

what is the role of noradrenaline?

released by neurons from locus coerulus in brainstem,

project widely influencing sleep, wakefulness, attention and feeding behaviour.

what is the role of serotonin?

released from neurons in ralphe nuclei, influences mood, emotional behaviour, satiety and sleep.

what is the role of GABA?

released by inhibitory neurons throughout CNS.

GABA receptors allow a influx of chloride ions across post-synaptic membrane, hyperpolarises the neuron.

what are arguments for dopamine hypothesis of schizophrenia?

• Antipsychotics block postsynaptic dopamine receptors and drugs that increase.
  dopamine cause psychosis –amphetamine, cocaine, L-dopa

• Reserpine depletes Dopamine transmission and has an antipsychotic effect (stops MOAs getting into vesicles).

• PET and SPECT scans show increased brain Dopamine activity when people have Schizophrenia.

what are arguments against dopamine hypothesis of schizophrenia?

• Neurotransmitter effects are immediate but antipsychotics take 2+ weeks to work on symptoms.

• Critical potential role for environmental factors during brain development.

• Other neurotransmittes involved in psychosis, e.g glutamate.

what are the “positive” symptoms seen during episodes of schizophrenia?

• Hallucinations

• Delusions

• Thought disorder

Aim of treatment is to decrease dopamine transmission via mesolimbic pathway

what are the “negative” symptoms seen during episodes of schizophrenia?

• Lack of motivation

• Reduced speech/emotion

• Social withdrawal

Aim of treatment is to increase dopamine transmission via mesocorticol pathway

what do antipsychotics typically target?

antagonise D2 receptors in mesolimbic system

what conditions are antipsychotics used for?

schizophrenia (delusions, hallucinations, thought disorder…).

mania, delirium, depression w/ hallucinations.

what are first generation antipsychotics?

typical – Haloperidol – target both D2 and D1.

what are second generation antipsychotics?

atypical – Risperidone – target D2, less on D1. also 5TH-2A antagonists.

what are side effects of antipsychotics on nigrostriatal system?

extrapyramidal side effects:

• Parkinsonism

• Akathisia

• Acute Dystonias

• Tardive Dyskinesia

what are side effects of antipsychotics on Tuberoinfundibular system?

excess prolactin:

• Galactorrhoea (milk production when not pregnant/breastfeeding)

• Amenorrhoea (absence of menstruation)

• Infertility

what are general side effects of antipsychotics?

• Weight gain, Diabetes, Raised Cholesterol – particularly second generation.

• People with Schizophrenia may lose 15-20 years of life due to cardiovascular risk.

• Arrhythmias.

what is the mechanism of action of aripoprazole? (antipsychotic)

partial agonist - similar to an antagonist in high dopamine pathways (mesolimbic), acts as agonist in low dopamine pathways (mesocorticol).

what is “neuroleptic malignant syndrome”?

a rare but potentially fatal reaction to antipsychotic drugs:

high fever, confusion, muscle rigidity, sweating, fast HR, variable BP...

what is the monoamine theory of depression?

result of a deficiency in brain monoamine neurotransmitters –Noradrenaline, Serotonin, Dopamine.

what are arguments for the monoamine theory of depression?

• Antidepressants increase the availability of monoamines at synapses

• Reserpine which depletes monoamine transmission causes depression (stops monoamines getting into vesicles).

• People with depression can have lower levels of monoamine precursors/metabolites in their CSF or blood.

what are arguments against the monoamine theory of depression?

• Neurotransmitter effects of antidepressants are immediate but they take 2+ weeks to work on symptoms.

• Cocaine and amphetamine mimic NA and 5-HT but do not act as antidepressants.

• Agomelatine is a new melatonin-based antidepressant that does not directly affect the serotonergic systems.

what are different classes of antidepressants?

tricyclic antidepressants.

selective serotonin reuptake inhibitors (SSRIs).

monoamine oxidase inhibitors (MAOIs).

Serotonin Noradrenaline reuptake inhibitors (SNRIs).

Agomelatine (melatonin receptor agonist).

what is Agomelatine?

melatonin receptor agonist

how do tricyclic antidepressants work?

inhibits membrane pump mechanism responsible for the re-uptake of transmitter amines, (e.g norepinephrine and serotonin).

thereby increasing their concentration at the synaptic clefts of the brain.

what are examples of tricyclic antidepressants?

amitriptyline, imipramine

what are side effects of tricyclic antidepressants?

• Antagonises Histamine (H1) receptors → sedation.

• Antagonises muscarinic receptors → dry mouth, blurred vision, constipation, urinary retention.

• Antagonises alpha adrenoceptors → postural hypotension.

• Can cause drug interactions as rely on hepatic metabolism via cytochrome (CYP)450.

• Potentiates the effect of alcohol and anaesthetics.

• Toxic in overdose.

what are side effects of SSRIs antidepressants?

• Nausea and vomiting.

• Sexual dysfunction.

• Can inhibit metabolism of other drugs – interaction risk.

• Withdrawal reaction.

• Safer in overdose.

what are examples of SSRIs?

Fluoxetine, Citalopram

why do antidepressants typically take 2 weeks to work?

• initially the increased 5HT in synapses is cancelled out by presynaptic auto-receptors reducing 5HT release and more reuptake of the extra 5HT in the synapses.

• after a couple of weeks, the auto-receptors desensitise and the blocked reuptake transporters get internalised - eventually increases.

why can MAOIs trigger a hypertensive crisis?

if people eat foods rich in Tyramine e.g. mature cheese, red wine, Bovri.

(MAOIs block enzyme that can break down tryamine).

what drug class is typically prescribed for anxiety?

benzodiazapines

what are side effects of benzodiazepines?

• Drowsiness.

• Confusion.

• Forgetfulness.

• Impaired motor control.

• Tolerance and Dependence.

• Respiratory depression –especially with alcohol.

what are examples of benzodiazepines?

diazepam, lorazepam, temazepam.

how do benzodiazepines work?

Bind to the GABA receptor (allosteric site).
Potentiates the effects of GABA. increases Cl- flux and more inhibition.