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 gene c-fos and the neuropeptide gene neurotensin/neuromedin N (NT/N) are significantly increased by haloperidol. An acute behavioral response to haloperidol is catalepsy, considered to be a rodent correlate of some of the immediate extrapyramidal motor side effects seen in humans. Several lines of evidence suggest a link between neurotensin induction in the dorsolateral striatum and catalepsy. We hypothesize that both striatal gene induction and catalepsy elicited by haloperidol arise from the combined effect of excitatory adenosinergic and glutamatergic inputs acting at adenosine A(2A) and N-methyl-D-aspartate (NMDA) receptors, respectively. In agreement with our previous reports, adenosine antagonists reduced haloperidol-induced c-fos and neurotensin gene expression as well as catalepsy. In agreement with other reports, 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 show here that blocking both A(2A) and NMDA receptors simultaneously in conjunction with haloperidol resulted in a combined effect on gene expression and behavior that was greater than that for block of either receptor alone. Both c-fos and NT/N mRNA levels were reduced, and catalepsy was completely abolished. 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 NMDA receptors.
Chartoff
E H
EH
Program in Neurobiology and Behavior, University of Washington, Seattle, Washington, USA. echartof@u.washington.edu
Ward
R P
RP
Dorsa
D M
DM
D000818:Animals; D001345:Autoradiography; D002375:Catalepsy / Q000235:genetics* / Q000517:prevention & control; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004347:Drug Interactions; D016762:Genes, fos / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology*; D017403:In Situ Hybridization; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D009496:Neurotensin / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018004:Receptors, Bombesin / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D018028:Receptors, Neurotensin / Q000187:drug effects; D018047:Receptors, Purinergic P1 / Q000502:physiology*
D018492:Dopamine Antagonists; D018696:Neuroprotective Agents; D018004:Receptors, Bombesin; D016194:Receptors, N-Methyl-D-Aspartate; D018028:Receptors, Neurotensin; D018047:Receptors, Purinergic P1; D009496:Neurotensin; D016291:Dizocilpine Maleate; D006220:Haloperidol