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. Moderate and high doses of amphetamine produce hypo-activity 20 hours after they are administered. This hypo-activity may indicate the presence of an acute withdrawal state and of a low-grade depression. The purpose of the research is to develop an animal model of acute withdrawal and to use it to investigate mechanisms and treatments. In the past year we have continued to develop procedures designed to provide converging evidence for the presence of acute withdrawal 20 hours after amphetamine treatment. At different times following amphetamine administration, we have employed progressive ratio and conditioned place procedures, in order to assess willingness to work for reward and to infer the nature of the internal state present. In order to identify the short dopaminergic changes that might be necessary to produce longer term amphetamine-induced hypo-activity, we began to look at the ability of pre-treatment with dopamine receptor antagonists to block amphetamine induced effects. In order to begin to identify the molecular changes that mediate the proximate expression of amphetamine-induced hypo-activity, we completed a ?small scale? micro array study: Twenty hours after treatment with either saline or amphetamine, gene expression in the nucleus accumbens was assessed. Amphetamine administration supported a conditioned place aversion 20 hours later, and an aversive internal state may have been present at that time. Amphetamine also compromised willingness to work for reward at different times during the first 24 hours following administration. The micro-array results identified a number of candidate genes that might be involved in the expression of acute withdrawal. Results are consistent with the presence of acute withdrawal 20 hours after amphetamine administration. Factors that may promote the occurrence of acute withdrawal have been identified. The research may yield an animal model with which acute withdrawal and low grade depression can be studied. issues in informatics.
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