Withdrawal from a single exposure to cocaine increases 5-HT2A receptor and G protein function.

We previously reported that withdrawal from chronic cocaine produces supersensitivity of serotonin 2A receptors. We report here the minimum cocaine exposure necessary to produce withdrawal-associated increases in serotonin 2A receptor signaling in the frontal cortex. Rats withdrawn from cocaine treatments of 1, 3 or 7 days exhibited increases in G protein-stimulated and serotonin 2A receptor-stimulated phospholipase C activity in the frontal cortex. A single cocaine injection produced withdrawal-induced changes comparable to that produced by repeated exposure. None of these cocaine treatment paradigms are associated with changes in the levels of serotonin 2A receptors, Galphaq or Galpha11 proteins. These data demonstrate that only a single exposure to cocaine can produce unique withdrawal-associated neuroadaptations in serotonin 2A receptor signaling in the frontal cortex, which may be clinically relevant with respect to drug relapse.