In animal studies, when you give a drug that binds both presynaptic and postsynaptic receptors (e.g. alpha agonist), how to determine whether the drug binds to pre or postsynaptic receptor in a particular brain region?
One can use in-vivo microdialysis (with local drug infusion), to detect the presence of inhibitory presynaptic receptors, for example alpha-2 autoreceptors. This would be evident from the relatively diminished presence of neurotransmitter in the dialysate, compared with a control run without the drug and would suggest that the drug is acting to block the release of norepinephrine via a presynaptic mechanism. See the paper below for an example using an alpha-2 agonist.
https://www.jneurosci.org/content/25/25/5998
I'm of the opinion that true pre- vs post-synaptic selectivity is typically exaggerated (and not convincingly demonstrated) in the pharma literature (for example D2 antagonist sulpiride, 5-HT1A preferential post-synatpic agonists) and am inherently skeptical of such claims, since receptor isoforms would have to be so different as to make the idea these are the same proteins paradoxical. That's why pre and post synaptic alpha-2 receptors are neuroanatomically distinct in their location (there may be exceptions).
Hope that helped. Please tell me what you think!
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