We are using the fruit fly, Drosophila melanogaster, as a genetic model system to study responsiveness and sensitization to aerosolized free base cocaine. We show that sensitization can be blocked by ectopic in vivo expression of stimulatory or inhibitory G proteins in the dopamine and serotonin neurons of the CNS. This shows the involvement of these transmitter systems, and implicates altered G protein signaling as an important component of sensitization. The degree of responsiveness to cocaine is correlated with the responsiveness of nerve cord receptor preparations to a D2-like dopamine agonist that is expected to interact directly with postsynaptic receptors.
We show the involvement of the octopamine precusor tyramine in sensitization; the mutant inactive (iav), is deficient in tyramine and the tyramine biosynthetic enzyme tyrosine decarboxylase (TDC). Octopamine is not required for sensitization since a null mutant in tyramine beta-hydroxylase, sensitizes normally. Active involvement of tyramine in sensitization is suggested since TDC is induced by cocaine exposure with a time course matching the time course for development of sensitization.
We also show the involvement of a subset of circadian genes in sensitization. Four of the five known circadian genes affect cocaine sensitization; only the gene timeless sensitizes normally. These genes function upstream of TDC since the induction of TDC that normally occurs following cocaine exposure is absent in these mutants. Mechanisms for cocaine sensitization will be discussed.
This work was supported by NIH/NIDA predoctoral grants 1F31DA05897-01 and 1F31DA05942-01, and NIH grant GM/DA 27318.