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Drugs & Neurotransmitters. At a substrate level ~ Tryptophan increases serotonin substrate  potentiation of other serotonergic meds Nerve condution ~ Role ions; Ca ++ & ?Mg + to stabilise ? One site of Li action  subsequent reduced neurotransmitter release Presynoptic Autoreceptors

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drugs neurotransmitters
Drugs & Neurotransmitters
  • At a substrate level
    • ~ Tryptophan increases serotonin substrate

 potentiation of other serotonergic meds

  • Nerve condution
    • ~ Role ions; Ca++ & ?Mg+ to stabilise
    • ? One site of Li action
    •  subsequent reduced neurotransmitter release
  • Presynoptic Autoreceptors
    • more is less and less is more (SSRIs & neurolepts)
  • Neurotransmitter reuptake
    • Serotonin/SSRIs
    • N.A./Serotonin - SSRIs; TCAs
  • MAO
    • nonspecific irreverseible inhibition - MAOIs
    • specific reversible MAO A (5HT) - moclobemide

MAO B (NA, DA) seleziline

  • Neurotransmitter release
    • Amphetamine & DA; serotonin & ecstasy
  • Neurotransmitter breakdown in synapse
    • Tacrine inhibits those relevant cholinesterases
    • Note various classes; all have some common features
      • cross tolerance - compounds other than the usual neurotransmitters may act on them eg etoh, phenobarbitone bind to the same ion channel is GABA and diazepam to Agonise it. Penicillin and picrotoxin bind and turn it off. Chronically this will affect the receptor sensitivity
      • Up & Down Regulation -

Chronic exposure to high and low concentrations of neurotransmitters (or any substance acting as a receptor) will result in adaptation. Too much for a long time makes the receptors less sensitive and vice versa. The mechanism for this varies; receptor number, receptor shape, and second messenger systems all involved.

      • Autoreceptors

on the presynoptic neorone when stimulated provide negative feedback to reduce release of neurotransmitters

  • Agonism/Antagonism

If a compound binds to a receptor, it will have some effect.

“Full” agonist when bound to a receptor, will turn it on fully.

Partial agonist when bound will only partially stimulate the effects. Thus, no matter how much you give, maximal effect (as compared to full agonist) won’t happen.

Antagonist binds to a receptor and doesn’t turn it on. Because its occupying the site, no one else (even the usual neurotransmitter) can’t get on. Reduced effect.

Note that things that bind to receptors may bind as firmly and not be removable; or loosely and be ‘knocked’ off if enough competition is present.
  • Second messengers

Probably some agents work here. Lithium appears to reduce the second messenger response to catecholamines; it reduces the response to TSH & ADH. Thus, the receptors are there in normal numbers; but nothing happens. This system can also be increased eg. Theophylline phosphodiesterase inhibition 


  • Neurolepts
    • At least in typical neurolepts, potency correlates to D2 receptor blockade
    • Relevant Dopaminergic pathways
      • mesolimbic
        • ~ emotion, cognition ~ = effect
      • mesocortical
      • nigrostriatial = parkinsonian S/E
      • tube - hyothalamus - pituitary = Prolectin
    • Around 70% D2 receptor occupation/blockade ~ correlates to maximal antipsychotic effect
    • At 80% occupancy movement disorders occur in most
  • Mechanism
    • Recently focused as Autoreceptor blockade, thus reduced negative feedback & subsequent increased initial DA secretion; eventual adaptive response (“depolarisation blockade’) results in reduced dopominergic transmssion.
    • Recent experimental drugs which specifically stimulate autoreceptors appear to be antipsychotic (by increasing negative feedback - reduced DA transmission)
Clozapine and olanzapine, binding to D4 more than D2 imply that this receptor, with different pathwyas, may be more important in psychosis and possible role of serotonin, NMDA and other receptors
    • Tardive dyskinesia ~ at present thought to result from D2 receptor upregulation due to chronically reduced transmission. Thus they are supersensitive and react excessively to normal, or subnormal amounts of DA.
  • SSRI’s/TCAs
    • Block reuptake at serotonin/noradrenaline variosly. Not only do they vary in which neurotransmitter system they affect; they also vary in potency at different sites (much like partial vs full agonists). Thus a flat dose response curve may occur; each drug can only block reuptake so much; after that no further benefits, but potential side effects.

Mode of action

1. Inhibition of reuptake of neurotransmitter amines increases the amount in synaptic cleft, increasing transmission. Delay in onset of action due to part synaptic adaptation.

2. Presynoptic autoreceptors stimulated by excess serotonin. Initial reduction in serotonergic transmission, less serotonin in synoptic cleft and subsequent autoreceptor down regulation. Eventually neurone adapts to increase serotonergic transmission and not be inhibited by normal concentrations of serotonin.

Reverse of neurolepts : more is less and less is more.

  • Diazepines
    • At least we understand this mechanism. Diazepines, like many other drugs, bind at a specific site on the GABA receptor to increase chloride ion flux into the neurone, making it hyperpolarised and refractory to stimulation. Alcohol, barbiturates and some other sedatives also act on GABA, and their chronic use potentiates tolerance to diazepines.
Penicillin and pirotoxin bind to the receptor to reduce its effect - a mechanism of penicillin related seizures.
    • Cross tolerance is common here.
  • Lithium
    • multiple theories, not sure
    • appears to increase serotonin secretion in some models
    • reduces postsynoptic response to noradrenaline (inhibits AC)
    • ? Direct effect on nerve membrane