| >> | >>135051
Well, to begin with, you've got the upregulation and downregulation backwards, but that's pretty understandable considering I used to confuse them for a bit when I first started looking into pharmacology and neurobiology out of personal interest years ago. Antipsychotics usually act as antagonists or inverse agonists of a massive array of dopamine, serotonin, histamine, adrenergic, and to a lesser extent, acetylcholine receptor subtypes. Antagonists and inverse agonists typically result in upregulation of the receptor subtypes it binds to, because the brain responds to consistently lower activity by increasing the number of receptors of the subtypes in
question--the idea being that the greater number of receptors are expressed on the synaptic terminal, the more sensitive it is to the monoamine/catecholamine/neuropeptide/whatever that acts as the endogenous ligand for that type of receptor. The endogenous ligand for all dopamine receptor subtypes is dopamine, for instance (although often times there are potentially many endogenous ligands capable of binding to and stimulating a neural receptor--usually with a significantly lower binding affinity and/or it is less effective at stimulating the cell).
The brain is too insanely complicated to be able to reduce things to certain neurons upregulating or downregulating such that simply using a drug that causes the opposite response to try and counteract the effects isn't a really a viable solution, at least directly.
The brain will adjust over time on its own, provided you don't just stop taking the antipsychotic cold turkey. That can lead to very serious withdrawal effects and can cause permanent disorders like tardive dyskinesia and shit. Amphetamine would indeed cause downregulation over time, same with most psychedelics regarding the 5-HT2A and 2C receptor subtypes in particular, but if you tried to quit taking an antipsychotic after using it for over 1-3 months, especially if you've been on it for over a year, simply quitting is dangerous already. If you combined quitting cold turkey with taking a 5-HT2A agonist psychedelic like LSD, shrooms, DMT, mescaline, etc., and/or amphetamines, you wouldn't be accelerating your recovery... you'd likely be accelerating withdrawal effects and the likelihood of developing something like tardive dyskinesia.
In the case of amphetamines, you'd be overstimulating dopamine receptors in the prefrontal cortex and as well as the reward center (where dopamine receptors are most widely distributed). I'm almost positive this would result in excessive neurotoxicity--damaging or killing dopamine neurons disproportionate to what is typically observed or expected from amphetamine (ab)use. The same could be said of taking a 5-HT2A agonist psychedelic, only neurotoxicity would be harder to gauge because amphetamines simply result in reverse transport of stored dopamine, serotonin, and norepinephrine (the proportions depend on the amphetamine in question really) by potently binding to TAAR1 receptors, and to a lesser extent, VMAT2 and acts as a mild MAOI too. The psychedelics bind to
5-HT2A and 2C receptors directly and stimulate them... but to make things even more complicated, sometimes a molecule that binds to a receptor on a neuron can exhibit functional selectivity, meaning they don't produce the same response as the endogenous ligand (or even other exogenous/foreign substances, necessarily). The ramifications this functional selectivity that all classical psychedelics possess has regarding neurotoxicity is something I haven't ever looked into. Maybe I'll read up on it and get back to you on that.
Anyway, ignoring these other uncertainties, what makes it all so complex is the fact that specific types of neurons and receptor subtypes are expressed in different amounts throughout the various brain structures. Dopamine neurons show up and are distributed most in a particular area of the brain, and same goes with serotonin, norepinephrine, and indeed all neuronal subtypes. Not only that, but the neurons don't exhibit a universal consistency in behavior and the effects they have on surrounding neural activity. Dopamine in the prefrontal cortex plays more of a role in executive function (planning for the future, behaving in a socially acceptable manner that benefits you, emotional regulation, controlling impulses, etc.), whereas dopamine in the nucleus accumbens (the reward pathway) mediates the reward effect (which doesn't actually produce feelings of euphoria or pleasure, shit's a fuckin enigma honestly lol), which guides your behavior through the anticipation of reward or punishment/pain, informs your motivation, and by reinforcing behaviors that you anticipate reward for (like eating, accomplishing a task, sex, drugs, etc.). Dopamine in the prefrontal cortex also mediates motor activity in several ways. People with Parkinson's, through dopamine neurotoxicity, lose the ability to filter gross motor function (large movements) and fine motor function (small, more precise movements), so normally a bunch of internal noise you brain is always producing naturally winds up causing tremors and symptoms like "ratcheting", where somebody with Parkinson's tries to move their arm by rotating at the elbow to wave, for instance, and instead of it being a nice fluid motion, it staggers and jumps between to intermediate positions throughout the motion.
That in particular is why using amphetamine or some kind of dopamine agonist to try and accelerate recovery is a really, really dangerous and bad idea. Not only would you potentially be subjecting yourself to a significantly higher change of amphetamine/stimulant psychosis form the excessive dopamine activity, but that overstimulation will not only cause a shit ton of oxidative stress (dopamine's primarily metabolite is a free radical and it contributes signific… Comment too long. Click here to view the full text. |
