The overall goal of this research is to elucidate how the opioid peptide gene families in the basal ganglia are regulated by endogenous neurotransmitters and intracellular messengers which mediate the effects of psychostimulant drugs. In characterizing the responses of medium spiny neurons of the dorsal and ventral striatum to psychostimulant administration, we have focused so far on transynaptic regulation by dopaminergic and glutamatergic systems. Investigations of these interactions has provided us with clues which have prompted us to investigate how striatal muscarinic and opioid receptors modulate the actions of psychostimulants. In this proposal, the following questions will be addressed using quantitative in situ hybridization histochemistry for the opioid peptides, preprodynorphin and preproenkephalin, and the tachykinin, substance P. (A) How do cholinergic interneurons in the striatum exert opposite effects on striatonigral preprodynorphin/substance P-containing neurons and striatopallidal preproenkephalin-containing neurons? (B) How does stimubtion of kappa, or blockade of delta, opioid receptors alter psychostimulant-induced increases in opioid peptide mRNA in the striatum? In addition to transynaptic actions, acute stimulant administration induces immediate early genes in the brain. However, less is known about the nuclear regulatory mechanisms which mediate long-term changes in gene expression underlying drug addition. Therefore, semi-quantitative immunocytochemistry will be used to investigate psychostimulant effects on 2 proteins which are induced by repeated stimulant administration, phosphorylated cyclase responsive element binding proteins (P-CREB) and fos-related antigens (FRAs), to answer the following questions. (C) Does repeated psychostimulant administration sustain P-CRFB and FRA immunoreactivity in striatonigral neurons beyond that obtained after acute stimulant administration or after repeated administration followed by a delayed challenge dose? (D) What neurotransmitter systems, besides doparnine, regulate the psychostimulant-induced elevation of these putative transcription factors? Answers to these questions will contribute to the understanding of the transynaptic and intracellular mechanisms of action of psychostimulants with the potential of targeting areas for medicinal development to treat the widespread abuse of cocaine and amphetamines.
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