The addictive properties of psychostimulants such as cocaine and amphetamine depend in part upon their ability to modulate the dopamine neurotransmitter system. Following dopamine receptor stimulation, the cAMP signal transduction cascade is activated. This in turn leads to an altered activity of downstream substrates that control neuronal activity. Chronic intermittent exposure to cocaine or amphetamine results in neurochemical adaptations in the cAMP pathway, particularly in the nucleus accumbens, a brain region that is strongly implicated in the actions of these drugs. The molecular basis for these adaptations and the implications for nucleus accumbens function are not fully understood. We propose to examine the role played by two newly identified proteins in the responses to psychostimulants. These proteins, """"""""spinophilin"""""""" and """"""""neurabin"""""""" control the activity of a signaling enzyme, """"""""protein phosphatase-1,"""""""" and are important regulatory elements at excitatory synapses in the nucleus accumbens; they serve to facilitate the control of both ion channel activities and alterations in synaptic structure. Most significantly, we have found that the regulatory functions of spinophilin and neurabin are themselves controlled by the cAMP pathway. These findings, plus the fact that psychostimulant drugs require activity at excitatory synapses to elicit neuroadaptive responses, and that these responses include a remodeling of synaptic architecture, together make spinophilin and neurabin highly attractive candidate targets for psychostimulant drugs. We propose to test these ideas by examining alterations in the regulatory functions of these proteins following psychostimulant drug administration in viva. In addition we propose to examine their functional roles in drug responses by exploiting the availability of animals in which the genes for these proteins have been deleted. These experiments will involve an analysis of the biochemical, anatomical, electrophysiological and behavioral responses to administration of psychostimulants in mutant and wild type animals. Protein phosphatase-1 is also controlled by the cAMP pathway and is implicated in responses to psychostimulants. We further propose to examine the contribution of protein phosphatase-1 to drug responses using animals in which the genes for isoforms of this enzyme have been deleted in nucleus accumbens neurons in a temporally defined manner.
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