Role of adenosine and N-methyl-D-aspartate receptors in mediating haloperidol-induced gene expression and catalepsy

Acute blockade of dopamine D-2 receptors by the typical antipsychotic drug haloperidol leads to alterations in neuronal gene expression and behavior. In the dorsolateral striatum, the levels of mRNA for the immediate-early ge ne c-fos and the neuropeptide gene neurotensin/neuromedin N (NT/N) are sign ificantly increased by haloperidol. An acute behavioral response to haloper idol is catalepsy, considered to be a rodent correlate of some of the immed iate extrapyramidal motor side effects seen in humans. Several lines of evi dence suggest a link between neurotensin induction in the dorsolateral stri atum and catalepsy. We hypothesize that both striatal gene induction and ca talepsy elicited by haloperidol arise from the combined effect of excitator y adenosinergic and glutamatergic inputs acting at adenosine A(2A) and N-me thyl-D-aspartate (NMDA) receptors, respectively. In agreement with our prev ious reports, adenosine antagonists reduced haloperidol-induced c-fos and n eurotensin gene expression as well as catalepsy. In agreement with other re ports, the noncompetitive NMDA receptor antagonist MK-801 also reduced gene expression and catalepsy in response to haloperidol. The competitive NMDA receptor antagonist LY235959 decreased haloperidol-induced catalepsy. We sh ow here that blocking both A(2A) and NMDA receptors simultaneously in conju nction with haloperidol resulted in a combined effect on gene expression an d behavior that was greater than that for block of either receptor alone. B oth c-fos and NT/N mRNA levels were reduced, and catalepsy was completely a bolished. These results indicate that the haloperidol-induced increases in c-fos and NT gene expression in the dorsolateral striatum and catalepsy are driven largely by adenosine and glutamatergic inputs acting at A(2A) and N MDA receptors.