Expression of the proneurotensin gene in the rat brain and its regulation by antipsychotic drugs.
In this chapter, we have presented evidence for several potential levels of interaction of NT/N gene products with dopaminergic systems of the brain. We have focused on one manifestation of this interaction related to the effects of antipsychotic drugs on expression of the NT/N gene in two anatomically discrete populations of neurons. It appears that certain antipsychotic drugs can dramatically increase expression of this gene in the dorsolateral striatum by blocking dopamine D2 receptors, perhaps by increasing expression of the gene encoding the transcriptional regulator fos. In addition, a second group of NT cells in the shell region of the nucleus accumbens also respond to these drugs by increasing NT/N gene expression. Several other peptides have been suggested to respond to treatment with antipsychotic drugs. However, there are some important differences with respect to their effects on the NT cells we have studied. The most important of these is the differential responsiveness of the DLSt and nucleus accumbens NT neurons to typical and atypical antipsychotics. We showed that all antipsychotic drugs tested increased NT/N mRNA gene expression in the accumbens, a region thought to be involved in dopaminergic disturbances underlying psychosis. However, only the typical neuroleptics that have a high propensity to induce acute extrapyramidal motor side effects influenced NT/N gene expression in the dorsolateral striatum, a structure importantly involved in regulation of motor functions. We hypothesize, therefore, that NT/N-expressing neuronal systems in the nucleus accumbens may mediate some or all of the antipsychotic effects, whereas those in the dorsolateral striatum may be involved in motor effects of neuroleptic drugs. Thus, examination of the effects of these drugs on these neuronal populations will not only clarify their mechanism of action, but in addition may provide a useful "screening" assay for new drugs with enhanced antipsychotic activity, but reduced propensity to induce the debilitating extrapyramidal side effects that are a major cause of patient noncompliance. Future studies will focus on the effects of antipsychotic drugs on NT neurons in clinically relevant models of chronic administration, and on the molecular events involved in their effects on expression of the NT/N gene in the brain.
Department of Pharmacology, University of Washington, Seattle 98195.
K M
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Merchant
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Dobie
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D000375:Aging / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D002421:Caudate Nucleus / Q000378:metabolism / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology; D009496:Neurotensin / Q000235:genetics* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000378:metabolism / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D011699:Putamen / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D014150:Antipsychotic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011954:Receptors, Dopamine; D009496:Neurotensin; D006220:Haloperidol