Abstract

Antipsychotic drugs are monoamine receptor antagonists. However, the mechanisms by which these direct actions are translated into therapeutic effects are unknown. Candidate mechanisms include receptor-mediated regulation of gene expression in target neurons. Inducible transcription factors, including certain immediate early genes (IEGs), may mediate between receptor-activated second messenger systems and expression of genes involved in the differentiated functions of neurons. We examined the specificity of induction of the IEGs c-fos and zif268 after acute administration of several antipsychotic drugs and, for comparison, the stimulant amphetamine, which has pharmacologic effects relatively opposite to those of antipsychotics. Antipsychotic drugs with potent dopamine D2 receptor antagonist properties, such as haloperidol, induced both c-fos and zif268 mRNA in the caudate-putamen; however, the atypical antipsychotic drug clozapine induced zif268 but not c-fos mRNA in that region. Similarly, haloperidol, but not clozapine, induced c-Fos-like immunoreactivity in the caudate-putamen. In contrast, both drugs induced c-Fos-like immunoreactivity in the nucleus accumbens. Like haloperidol, amphetamine induced both c-fos and zif268 mRNA in the caudate-putamen, but the anatomic patterns of induction of c-Fos-like immunoreactivity by the two drugs were dramatically different. Haloperidol and amphetamine induced AP-1 binding activity in cell extracts from the caudate-putamen, indicating that drug-induced IEG expression results in protein products that may function in the regulation of target gene expression. Thus these data demonstrate that inductions of IEG expression by haloperidol, clozapine, and amphetamine are specific, may be biologically relevant, and suggest avenues for further investigation.