| Summary: | The mechanisms contributing to the atypical clinical profile of clozapine remain
uncertain. To address this question, Fos-immunostaining in combination with drug
manipulation, brain lesions and in situ hybridization histochemistry were used to examine
neurotransmitter systems involved in the effects of antipsychotic drugs. This research
program employed these techniques (1) to determine receptor mechanisms mediating
clozapine-induced c-fos expression in the forebrain and (2) to characterize the phenotypes of
neurons targeted by clozapine and the typical antipsychotic haloperidol.
In the first experiment, scopolamine, a muscarinic receptor antagonist, attenuated
haloperidol-induced Fos immunoreactivity in the striatum. This suggests that haloperidolinduced
Fos induction in the striatum is modulated by muscarinic cholinergic mechanisms,
and that the antimuscarinic action of clozapine may contribute to its failure to increase Fos
induction in the striatum.
5,7-dihydroxytryptamine lesions of the medial forebrain bundle or 6-
hydroxydopamine lesions of the dorsal noradrenergic bundle produced extensive serotonin
and noradrenaline depletions in the forebrain, respectively. However, neither type of lesion
affected clozapine-induced c-fos expression in the rat forebrain, suggesting that neither
serotonergic nor noradrenergic mechanisms are involved in this action of clozapine.
7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OHDPAT), a D3 receptor-preferring
agonist, attenuated clozapine-induced c-fos expression in the nucleus accumbens (NAc),
lateral septum (LSN) and the major island of Calleja (ICjM), without affecting the medial
prefrontal cortex (mPFC). Quinpirole, which has similar affinities for D3 and D4 receptors,
produced a small but significant attenuation of clozapine's effects in the mPFC and blocked clozapine's actions in the ICjM, NAC and LSN. Given the different affinities of quinpirole
and 7-OHDPAT for D2, D3 and D4 receptors, these data suggest that clozapine-induced c-fos
expression in the ICjM, NAc and LSN is due to its antagonist actions at D3 receptors, while
antagonist actions at D4 receptors may contribute, in part, to the Fos induction in the mPFC.
In situ hybridization for D3 receptor mRNA confirmed that most of the clozapineinduced
Fos positive neurons in the ICjM, and the majority in the NAc and LSN express D3
receptor mRNA. In contrast, haloperidol-induced Fos positive neurons rarely expressed D3
mRNA in any brain region. Further studies demonstrated that clozapine increased c-fos
expression in both enkephalin (Enk) and dynorphin (Dyn) containing neurons in the NAc and
LSN. Haloperidol also increased c-fos expression in Enk and Dyn neurons, albeit in a
different pattern. This suggests that while some Enk and/or Dyn neurons targeted by
clozapine express D3 receptors, others do not.
|
|---|
