Confused about psychoactive effects related to pharmocological profile (example)

[purplehaze147]

I'm totally confused right now. Ok so cocaine and tricyclic anti-depressants (amitriptyline, doxipin, etc.) both are dopamine, serotonin, and norepinephrine inhibitors but have completely different psychoactive effects. Why is this and also why is cocaine euphoric and tricyclic anti-depressants not? My guess is cocaine has a greater effect on dopamine and norepinephrine(?) which makes it a stimulant and tricylics have more of an effect on serotonin which makes them a depressant. Does dopamine have more influence on euphoria than serotonin? If a drug is an inhibitor than it binds to and blocks the respective monoamine transporter, right?

 

[purplehaze147]

oh I forgot, trycylics are also powerful anti-histamines which also probably account for the drowsiness associated with them. I think I answered my own question but I'd still appreciate any feedback

 

[QUARE]

I think the biggest reason is the half-life (time that take a molecule to lose half of its effect). Cocaine have a half-life of 1 hour and Doxepin 17 hours. Doxepin also antagonise some subtype of those receptor which makes it less enjoyable and the effect it have of Acetylcholine is definitly unpleasant.

 

[atara]

Tricyclic antidepressants:

* generally antagonize a number of monoamine receptors, incl. alpha1, alpha-2, 5-ht2a, 5-ht2b, 5-ht2c, 5-ht6, 5-ht7
* generally inhibit serotonin and norepinephrine transporters but not dopamine transporter
* generally antagonize additionally H1 (drowsiness) and certain mAChR subtypes, leading to sedation
* have long half-lives and long duration of onset

Cocaine:

* strongly inhibits serotonin, norepinephrine, and dopamine transporters
* inhibits action potentials by affecting sodium efflux, commonly referred to as voltage-gated sodium channel inhibition, i.e. local anaesthetic activity
* has a short duration of action and very fast onset

So receptor inhibition is half the story, lack of dopamine activity on the part of tricyclics is half the story, and the timeline of activity is probably also half the story. That's 3/2 of a story, which is a long story. (bold indicates a receptor or neurotransmitter commonly associated with euphoria)

 

[Privateer]

Also a note, certain research suggests that SERT inhibition actually decreases the reinforcing properties of cocaine. So any triple reuptake inhibitor that has a relatively greater SERT: DAT affinity could actually be less euphoric/rewarding than cocaine (edit: despite acting at the same sites.)