Posted 25 May 2012 - 03:12 AM
It's very hard to pick which dopamine receptors you want to sensitize and which you want to remain suppressed.
Long term use of dopamine antagonists causes tardive dyskinesia, which results from hypersensitization of dopamine receptors in the movement circuitry of the brain. The result? Unwanted, uncontrollable movements of muscles. Usually the facial muscles are involved, which can be very socially awkward, which introduces a new stressor into the environment. This does not aid recovery from mood or psychotic disorders.
Does it do the same thing to positive emotion? Evidently not. Depression is a well-known side effect of chronic antipsychotic treatment, so apparently the hedonic system does not fully sensitize when treated with dopamine antagonists. All the antipsychotics that help depression do things other than antagonize dopamine -- all atypicals are 5HT2A antagonists, aripiprazole is a D2 partial agonist, amisulpride is an irreversible 5HT7 antagonist, clozapine does all kinds of things, some of which we don't even know about yet...
On the contrary, reinforcement-related dopamine neurons do in fact sensitize when exposed to agonists like methamphetamine and cocaine. Obviously, drug addicts aren't the happiest people -- they're commonly depressed as well. This is because behavioral reinforcement conditioning and positive hedonic tone are not the same processes in the brain. Reinforcement mostly happens in secondary motor cortices and basal ganglia, whereas mood is a more complex phenomenon including processes across the cortex and also limbic and midbrain areas.
The result? People on antipsychotics stop caring about things, and people taking enough pro-dopaminergic drugs to affect emotion develop stereotyped behaviors (punding, tweaking...) and poorly controlled impulses to use the dopaminergic drug.
Really, I'm not criticizing the basic idea of inducing sensitization to a "good" receptor, I just don't think that antagonist treatment is the best way to do it. Complete tolerance to a drug, equal in all receptor subtypes and having equal effects in all relevant systems, is just plain rare. Way more common is the above-mentioned mess where some receptors are sensitized, some haven't changed so they're still under the influence of the drug, and sometimes you'll even encounter receptors that down-regulate in response to antagonists! (I believe 5HT2A does this. But only for inverse agonists, not ordinary antagonists.)
I might know of an exception, though. Ibogaine puts people in a miserable mood for the entire multi-day duration of the trip, but sometimes an extended period of mood elevation follows. It can last weeks to months. Here's the big question: Is mood elevation a direct chemical effect of ibogaine (de)sensitizing receptors? Or is it explained better by psychological phenomena of cognitive and behavioral changes? As an analogy, people commonly take LSD or mushrooms and then they don't feel any different afterwards. But sometimes people take hallucinogens and they see parts of themselves and their lives from new perspectives, and they retain those new perspectives long after the drug has left their systems and the tolerance has ended. Maybe ibogaine does that. Or maybe not.
