Molecular mechanisms of amphetamine-induced behavioral sensitization

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Repeated administration of psychostimulants like amphetamine or cocaine results in an increased behavioral response to the drugs at subsequent exposure, a phenomenon called sensitization. Behavioral sensitization is suggested to be associated with drug addiction as well as some psychotic symptoms of schizophrenia.  The enduring nature of sensitization suggests long-term adaptations in the property of neurons associated with central dopamine systems; however, the molecular mechanisms underlying these changes are poorly understood. We have previously reported changes in the levels of a protein called syntaxin-1 in the nucleus accumbens of amphetamine sensitized rats.  As syntaxin-1 is involved in mediating neurotransmitter release as well as in regulating synaptic plasticity, our work suggests that alterations in this protein may be a key mechanism mediating neuronal changes in sensitized animals. In the proposed research, our aim is to further understand the mechanisms by which syntaxin affects amphetamine sensitization.  For example, we want to know which neurons within nucleus accumbens of amphetamine-sensitized animals show changes in syntaxin-1 and whether manipulations of the protein will affect sensitized behaviour.   Further we want to explore if the effects of amphetamine are generalizable to other psychostimulants such as cocaine.  A better understanding of neuronal changes following chronic drug use may help in developing novel pharmacological agents to prevent the harmful effects of these drugs on behavior.