I just want to add that, the reason why the effects of meth are so prolonged is because of the overwhelming power of Dopamine and Norepinephrine reuptake inhibition that keeps the brain flooded in those neurotransmitters for very long periods of time.
Things that are D2 antagonists and especially adrenergic receptor antagonism will help a lot! Stuff like Hydroxyzine which in combination will shut down histamine receptors, will have pronounced effect with the addition of blocking the dopamine and adrenal activity keeping you wired. Even a Clonidine and a few benedryl would do the trick. just countering the adrenaline activity with sleep deprivation / reason-to-be-tired, will have synergistic sedation, then add an antihistamine on top and you should knock yourself out for sure.
But honestly, it all comes down to blocking the D2 and α2A activity, that is the source of the prolonged energy you get from meth. That's why a seroquel can abort effects of drugs so dramatically. you can just start tweakin hard as fuk, pop a seroquel, and add sleep deprivation and you will just pass out HARD!
You do know that the dopamine type 2 receptor (D2) exists presynaptically as well, as a feedback regulating autoreceptor. When activated by excess dopamine that's released, it tells the cell not to release more. A
D2 agonist would do this. The D2 receptor is inhibitory - binding of dopamine postsynaptically activates a GIRK channel it shares with the GABA B receptor causing hyperporizations. That's why D2 agonists such as pramipexole, ropiniorle, apomorphine are
sedating and can cause sudden
sleep attack The D2 receptor is not excitatory so blocking it will not have the effect you're thinking of.
A D2 antagonist would do the opposite. It would block the presynaptic receptors, increasing dopamine release from the neuron. D2 antagonists cause seizures because they block the D2 inward rectifing potassium current.
And an alpha 1 antagonist would work better than an alpha 2 agonist like clonidine. You mentioned seroquel? That's a dual alpha1/alpha2 antagonist. So basically it's latter action on the alpha 2 autoreceptor (which controls the release of norepinephrine and serotonin in some parts of the brain) would release
more norepinephrine. Seroquel works because of it's powerful alpha 1 blocking activity, 5-ht1a partial agonism (which is also autoreceptor for serotonin, so it would decrease release and subsequent serotonergic EPSPs) and 5-ht2a antagonism, and its antihistaminergic effect, which also relies on potassium for its effects.
Seroquel has unique properties at the D2 receptor as well. It doesn't bind tightly to them and doesn't have high intrinsic activity. Were it not for the alpha adrenergic antagonism, serotonergic effects, and histaminergic, at the right dose it would potentiate the recreational effects of drugs. Similarly how buspirone does in low doses...it's a D2 antagonist and in low doses it's only able to hit the autoreceptors, so dopamine release would be enhanced, not antagonized. Low doses of any D2 antagonist that's releatively pure would only enhance the effects. And blocking the D2 postsynaptic receptors inhibits the IPSP, disallowing them to cause hyperpolarizations upon activation.
This is why hydroxyzine goes so well with opioids (Not counting its histaminergic effects.) It has very weak D2 antagonistic effects, that, at the dose used, mostly just affect the autoreceptors, increasing synaptic dopamine levels. I always found hydroxyzine to be stimulating on its own at 100mg, and it definitely increases the stimulant effect of bupropion, I've noticed.
"From biochemical and physiological studies on D2-like receptors, it was shown that these coupled, via G-proteins, to the inhibition of adenyly cylcase, the stimulation of potassium channels, and the inhibition of calcium channels." - from my dopamine receptor book. There are a lot of reports of "sleep attacks" on pramipexole (a dopamine receptor agonist) as well as ropinirole which is similar. They pretty much make people nod out out of nowhere. I read a story where it happened to this woman while she was driving. The GiRK channel the D2 receptor shares with the GABA B receptor is very inhibitory by itself. Notwithstanding the other effects of D2 activation, such as reduced dopamine release, and the above mentioned effects.
It's mostly the D1 receptor responsible for the positive effects of stimulants. Most of what the D2 receptor does is cause reward seeking and cravings. This is evidenced by modafinil, which is a selective dopamine reuptake inhibitor - it lacks the prolonged energy and hypervigilance induced by norepinephrine. Modafinil is not stimulating like amphetamines, and were it not for it's pro-histaminergic and orexin effects in the brain, it wouldn't be classified as a wakefulness promoting agent. The DRI effect is not responsible for "stimulating" properties, but for it's focus, concentration, and motivation it provides.
The adrenergic activity is what you want to block. And there are safer things than the atypical antipsychotics, such as prazosin, clonidine, guanfacine, trazodone. All which strongly inhibit adrenergic activity. Seroquel has too many side effects, ranging from metabolic problems, hormonal problem (it can cause men to grow boobs), blood sugar problem, akathisia and tardive dyskinesia, as well as seizures by blocking all the inhibiting qualities of the D2 receptor. The full-antagonist antipsychotics are best to be avoided unless you absolutely need them.
Now if you're having racing thoughts and whatnot and having other distressing psychological symptoms (paranoia, delusions, hallucinations, etc.), a D2 receptor antagonist would work well. For psychological purposes. But physiologically? The D2 receptor does not cause sedation by being antagonized. The GIRK channel it's coupled to is linked to t type calcium channels just like the GABA B receptor...and it can elicit burst openings of the calcium channel which can cause manic symptoms, just like baclofen can, but antagonizing eradicates it's inhibitory postsynaptic potentials, which makes the brain more excitable.