The acute effects of systemic administration of the antipsychotic drug, zotepine, on extracellular dopamine (DA) in the frontal cortex of freely-moving rats were studied using in vivo microdialysis and compared with the actions of clozapine, olanzapine and haloperidol. Treatment with zotepine (1.0 mg/kg, i.p.) resulted in a prolonged elevation of cortical DA levels for up to 180 min post-drug. A maximal rise of +333% was observed at 120 min post-zotepine treatment. Clozapine (10.0 mg/kg, i.p.) also evoked a rise in extracellular DA which was similar in duration (200 min) to that resulting from treatment with zotepine. A maximal rise of +223% was observed at 100 min post-clozapine treatment. Olanzapine (1.0 mg/kg, i.p.) resulted in an immediate increase in DA levels which was maximal 40 min post-treatment (+280%) with levels returning to pre-injection values by 100 min after dosing. In contrast, haloperidol (0.1 mg/kg, i.p.) had no measurable influence on cortical DA levels. Local perfusion with the NA uptake inhibitor, nisoxetine (10 microM), resulted in an increase in cortical DA levels which was maximal at 100 min post-onset of perfusion (+257% above baseline). Administration of zotepine (1.0 mg/kg, i.p.) during nisoxetine perfusion elevated DA levels to a maximum of +301% above baseline, 60 min post-zotepine. These results show that acute administration of each of three drugs with an atypical antipsychotic profile causes an elevation of cortical DA in freely-moving rats at doses relevant to those derived from animal models which predict antipsychotic activity. As a dysfunction in cortical DA is thought to be involved in both the negative symptoms of schizophrenia and cognitive deficits in schizophrenic patients, it is possible that zotepine's ability to elevate cortical DA levels may underlie its effectiveness in successfully treating these components of schizophrenia. Furthermore, the ability of zotepine to elevate cortical DA is more likely to derive from its inhibition of the NA transporter rather than DA receptor blockade in this region.
This study was designed to compare some behavioral and biochemical effects of chronic treatment with a range of antipsychotic drugs. Gene expression of enkephalinAntipsychotic drugs are sometimes referred to as "atypical" if they demonstrate the ability to produce an antipsychotic action in most patients but with significantly less extrapyramidal side effects than classical (typical) antipsychotics (Fleischhacker and Hummer 1997). Lately, this distinction between "typical" and "atypical" antipsychotics has become the focus for much research aimed at establishing the pharmacological characteristics that serve to distinguish atypical antipsychotic drugs from the typical ones (Arnt and Skarsfeldt 1998). For example, in animals, acute and chronic treatment with these compounds causes distinct behavioral changes and alterations in the expression of different genes.Alterations in the biosynthesis of synaptic proteins and their mRNAs can be used to investigate changes in neuronal activity following different neuronal stimuli (MacArthur and Eiden 1996). Haloperidol increases tissue levels of enkephalin and the expression of mRNA (Normand et al. 1987;Romano et al. 1987) in medium spiny striatal neurons which are associated with the dopamine 2 receptor (Le Moine et al. 1991) whereas clozapine, the prototypical "atypical" antipsychotic, does not induce catalepsy and does not lead to an increased enkephalin gene expression in the striatum (Mercugliano and Chesselet 1992). Consequently, antipsychotics which do not induce catalepsy appear unlikely to increase enkephalin biosynthesis (Augood et al. 1993;Mijnster et al. 1998). Therefore, both behavioral changes and a distinct pattern of gene expression may be used to predict an atypical profile for an antipsychotic compound.The prefrontal cortex is an important brain area in schizophrenia research (Knable and Weinberger 1997;O'Donnell and Grace 1998). In animals, antipsychotic treatment causes an induction of immediate early genes in various brain areas including the prefrontal cortex. In this region, acute application of haloperidol or clozapine induces a differential expression of immediate early genes (Nguyen et al. 1992;Robertson and Fibiger 1992;Deutch and Duman 1996). Therefore, a different mechanism of action was postulated for haloperidol or clozapine treatment. However, most of these experiments investigated the induction of early genes after acute treatment.Chromogranin A, chromogranin B, and secretogranin II belong to the chromogranin family which are large protein molecules found in large dense core vesicles. They are endoproteolytically processed to smaller peptides, and are released after neuronal stimulation (Huttner et al. 1991). The distribution of chromogranin B (Mahata et al. 1991;Kroesen et al. 1996), secretogranin II mRNA, and their immunoreactivity (Marksteiner et al. 1993a) have been studied in rat brains. The biosynthesis of chromogranins is regulated by different stimuli (Shen and Gundlach 1996). For example, ten days of treatment with clozapine or hal...
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