Muscarinic, adenosine A(2) and histamine H(3) receptor modulation of haloperidol-induced c-fos expression in the...

It is generally believed that haloperidol exerts its motor side effects and therapeutic effects mainly by antagonizing dopamine D(2) receptors in the striatum and the nucleus accumbens, respectively. Several neurotransmitters/modulators, including glutamate, acetylcholine, adenosine and histamine, affect dopaminergic activity in these centers. We have recently shown that N-methyl-D-aspartate receptor-mediated modulation of haloperidol-induced c-fos expression differs in functionally specific regions of the striatum and the nucleus accumbens. In the present study, the entire striatum and the nucleus accumbens were comprehensively examined for the pattern of modulation of haloperidol-induced c-fos expression by adenosine A(2), histamine H(3) and muscarinic receptor antagonists. Blockade of muscarinic and H(3) receptors resulted in a profound suppression of haloperidol-induced c-fos expression in the dorsolateral part of the striatum. In addition, the H(3) receptor antagonist suppressed the effects of haloperidol in the ventrolateral aspect of the striatum and the rostral parts of the medial striatum. Muscarinic receptor antagonists suppressed haloperidol-induced c-fos expression throughout the shell and in the mid-level of the core of the nucleus accumbens while A(2) and H(3) receptor antagonists did not.We found that the muscarinic and H(3) receptor antagonists suppress the induction of c-fos by haloperidol in the dorsolateral aspect of the striatum, an area implicated in the development of extrapyramidal motor symptoms following chronic haloperidol treatment. By contrast, haloperidol-induced c-fos expression in the nucleus accumbens, an area implicated in the therapeutic effects of haloperidol, was suppressed by the muscarinic receptor antagonist, but not by the H(3) receptor antagonist. Therefore we conclude that H(3) receptor modulation may provide a useful therapeutic target in future efforts to minimize neuroleptic-induced motor side effects.