In light of the knowledge accumulated during the past couple of decades, it is apparent that schizophrenia is a complex and heterogeneous disease (Lieberman and Koreen 1993). Even though, classical neuroleptics are clearly useful in the treatment of positive aspect of the disease, they have a limited efficacy on negative symptoms and cognitive deterioration (Meltzer 1991). Conversely, clozapine and the novel antipsychotics have been termed 'atypicals' because they have a lower incidence of extrapyramidal side effects and can be effective in the treatment of negative symptoms (Deutch et al. 1991;Kinon and Lieberman 1996).The molecular basis of these differences has not been clearly established, but could be related to receptor profiles, regional specificity within the CNS and the possibility to produce adaptive changes in specific neurotransmitter systems whose function is altered in schizophrenia (Ellenbroek 1993). Among the others, dopamine, glutamate, and their reciprocal interactions within discrete neuronal circuitry, can be viewed as major players in schizophrenia imbalance (Weinberger 1987;Carlsson and Carlsson 1990;DiChiara et al. 1994). Hyperdopaminergic activity is thought to be relevant for positive symptoms of the disease, whereas alterations in glutamatergic system could explain several features of the disorder including negative symptoms and cognitive dysfunctions (Olney and Farber 1995;Weinberger and Lipska 1995). Hence, on the basis of its functional interaction with dopamine, glutamate and Received September 15, 1998; revised February 15, 1999; accepted February 25, 1999. Recently, a number of different laboratories, including our own, have examined the regulation of glutamate receptors in response to treatment with haloperidol and clozapine (Fitzgerald et al. 1995;Riva et al. 1997;Healy and Meador-Woodruff 1997;Brené et al. 1998). In the present study, we investigated the modulation of the mRNA encoding for NMDA and AMPA glutamate receptor subunits in response to the atypical antipsychotic drug "Seroquel (quetiapine fumarate, quetiapine)" (Goldstein 1996).In order to gain insight in the possible relationships between the changes in glutamate receptor expression and the clinical properties of the drug, we have compared the effects elicited by quetiapine to those observed with haloperidol and clozapine, the prototypes for classical and atypical antipsychotics.
MATERIALS AND METHODMale Sprague Dawley rats (Charles River, Calco, Italy) weighing 250-350 g were used throughout the experiments. The animals were maintained under a 12 hr light/12 hr dark cycle with food and water available ad libitum. Animals received daily subcutaneous injections with saline, haloperidol (1 mg/kg), clozapine (30 mg/ kg), or quetiapine (25 mg/kg) for 21 days. Rats were sacrificed by decapitation 6 hr after the last injection. The brain regions were rapidly dissected, frozen in liquid nitrogen, and stored at Ϫ 70 Њ C for further analysis. All animal manipulations have been carried out in accordance with the Guide for...
