MDMA (Ecstasy) and alpha-ethyltryptamine (AET) are drugs of abuse that elicit powerful alterations in emotions and empathy apparently as a result of their serotonin (5-HT) releasing properties. The exact nature of the receptors that are activated as a consequence of MDMA-induced 5-HT release is unknown because the available pharmacological tools do not allow to discriminate between the 13 known 5-HT receptors. Previous studies, however, have suggested an involvement of 5-HT1B receptors in the motor- stimulating effects of MDMA. An alternative way to study the influences of MDMA and AET on 5-HT receptors is the gene knock-out strategy that enables the selective ablation of one receptor subtype. Using recently generated mice that lack the 5-HT1B receptor this project will test the hypothesis that psychoactive drugs of abuse such as MDMA and AET act as indirect agonists at 5-HT1B receptors in rodents. The project has three main objectives: 1. The first objective is to compare the acute effects of MDMA and related drugs on wild-type mice and mice lacking the 5-HT1B receptor in order to evaluate the contribution of 5-HT1B receptors to the effects of MDMA. This objective includes three specific aims addressing three distinct behavioral domains that are modulated by MDMA and 5-HT agonists: unconditioned motor activity; aggressive behavior; and startle plasticity. 2. The second objective is to analyze the regional levels of 5-HT and dopamine receptors in mice lacking 5-HT1B receptors and contrast these levels with those characteristic of wild-type mice. This study should determine whether compensatory mechanisms have taken place in the mutant mouse and will help elucidate the non-5-HT1B-mediated responses that 5-HT releasers might elicit in the mutant mice. 3.The third main objective is to further develop the gene knock-out approach to the study of 5-HT receptor function. Specifically, mutant mice will be generated with inducible and tissue specific knock-out of the 5- HT1B receptor. In these mutants, expression of the 5-HT1B receptor will be turned off specifically in the adult striatum which should therefore circumvent the """"""""compensation issue"""""""" raised by the classic knock-out strategy. Such mice will be used to test the hypothesis that specific behavioral effects of MDMA are mediated by striato-nigral 5-HT1B receptors. This work should further our understanding of the basic neural mechanisms mediating the behavioral effects of serotonergic drugs of abuse and facilitate the development of antagonists for their effects.
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