Is the onset of psychoactive drug effects compatible with a protein-synthesis mechanism?

While many have suggested that protein synthesis may mediate the action of antipsychotic drugs, it is difficult to test. In this math modeling study it is found that the time course of action of the drugs are compatible with a protein-synthesis model and, furthermore, that the half-lives required by the model are indeed found in relevant proteins in the brain.

Slow onset of CNS drugs: can changes in protein concentration account for the delay?

A 'protein regulation hypothesis' might explain the delay in reaching a maximal clinical effect, exhibited by some antipsychotic and addicting drugs. It also suggests that crucial 'effector' proteins that mediate the actions of these drugs might have half-lives of days to weeks. In this article, the rate of onset of some antipsychotic and addicting drugs will be examined and a model will be used to test if a change in the concentration of a given protein(s) could cause the drug-induced effects. This hypothesis uses a model where protein concentrations are determined by a zero-order synthesis rate and a first-order degradation rate. The model in its simplest form produces an exponential increase (or decrease) in protein concentrations over time, but reasonable extensions of the model can account for more complex mechanisms that allow for delayed time-courses and contributions of multiple proteins to the clinical effect.

Dopamine D1 and D2 receptors influence dopamine transporter synthesis and degradation in the rat.

Neurotransmitter transporters play an important role in maintaining synaptic homeostasis and in the actions of many drugs. Utilizing a technique for measuring the kinetics (synthesis, degradation, and half-life) of the dopamine transporter (DAT) protein in the rat striatum and nucleus accumbens, we have investigated the effects of systemic administration of dopamine receptor agonists and antagonists upon DAT kinetics in these brain regions. In the striatum, the dopamine D1 receptor agonist SKF38393 and the dopamine D1 receptor antagonist SCH23390 were without effect. However, the dopamine D2 receptor agonists R-(-)-propylnorapomorphine hydrochloride (NPA) and quinpirole decreased the half-life of DAT. This effect was blocked by the dopamine D2 antagonist eticlopride, which, by itself, increased the half-life of DAT. In the nucleus accumbens, the agonist SKF38393 increased the DAT half-life, whereas the antagonist SCH23390 decreased the half-life. In contrast to the striatum, NPA and quinpirole increased the DAT half-life, which was blocked by eticlopride and by itself had no effect on DAT kinetics. Cocaine increased the half-life of DAT in both the striatum and the nucleus accumbens. The results of the present study suggest that, through dopamine receptors, dopamine indirectly influences DAT protein turnover in the striatum and in the nucleus accumbens, but in different ways.