Chronic exposure to psychomotor stimulants produces long-term changes in behavior including addiction and sensitized responses to further drug exposure. There is a great need to understand the changes in the central nervous system that occur with repeated drug exposure. A large body of evidence has implicated the striatum (caudoputamen and nucleus accumbens) in these brain effects, together with the midbrain dopamine systems that innervate the striatum. An interesting recent series of studies has demonstrated that exposure to psychomotor stimulants can produce striking effects on the expression of a series of immediate early genes (IEGs) that code for transcription factors. These experimental data are interesting because changes in transcription factor expression could have long-term effects on neuronal function. We propose a series of interrelated experiments to study these changes in expression. We propose to test specific hypotheses under three Aims.
In Aim 1, we propose to test the hypothesis that chronic intermittent exposure to cocaine and amphetamine leads to long-term changes in the inducibility of IEGs in the striatum and that these involve down-regulation of IEG expression in the matrix relative to the striosome (patch) compartment. This hypothesis is based directly on preliminary experiments showing increased patchiness in striatal IEG expression following chronic intermittent exposure. To test for long-term effects, IEG expression after prolonged withdrawal periods will also be examined.
In Aim 2, we will test the hypothesis that changes in dopamine receptor sensitivity occur with chronic exposure, that glutamate receptor function also is important for changes in IEG expression, and that IEG expression after cocaine and amphetamine treatment will show cross-sensitization. Finally, in Aim 3 we will test the hypothesis that drug-selective IEG expression patterns induced in the striatum by acute cocaine and amphetamine will be present in the squirrel monkey striatum, with amphetamine inducing a striosome-predominant pattern relative to cocaine. Taken together, these experiments will provide critical new data on the systems-level molecular change occurring in the striatum in response to chronic psychomotor stimulant exposure, on the duration of these changes, and on the receptor systems involved in producing these changes. In addition, these experiments will provide new and much-needed data on molecular responses to these drugs in acutely treated non human primates, a critical bridge toward understanding their effects in humans.
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