This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Substance abuse is one of the most pressing medical and social issues today. We have previously demonstrated that a single dose of cocaine results in a long-term change in the synaptic sensitivity of the midbrain dopamine neurons. We have also shown that this effect happens following a single exposure to a forced cold water swim stress. We hypothesize that the congruence between the effects of exposure to addictive substances and stress may underlie stress induced relapse and enhanced drug seeking. We have now shown that all classes of addictive drugs have a similar effect despite diverse primary mechanisms of action. This proposal is to investigate the mechanisms underlying and the behavioral implications of this effect. Specifically we have been asking if the mechanisms are congruent with the general mechanisms of long-term potentiation described in the hippocampal literature. In particular, we asked if GluR1, which is believed to mediate LTP mechanisms, is important in this process. In fact GluR1 lacking mice lack the synaptic changes in the midbrain that follow stress and cocaine exposure. This implies that the midbrain dopamine neurons plasiticity in response to both stress and cocaine share mechanisms with classical models of LTP. We have also examined correlations with simple behavioral paradigms: cocaine behavioral sensitization, conditioned place preference, and a novel, priming paradigm. During much of this past year we have been setting up the lab at Emory to continue the project. At present we are focusing more extensively on the stress effect.
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