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Receptor and cellular mechanisms of antipsychotic drugs

University of British Columbia

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.

Thesis/Dissertation

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2009-03-16

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http://hdl.handle.net/2429/6098

Neuroscience

University of British Columbia

UBCV

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