Regulation of Ionotropic Glutamate Receptors in the Rat Brain in Response to the Atypical Antipsychotic Seroquel (Quetiapine Fumarate)

Abstract

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...

Regulation of Ionotropic Glutamate Receptor Subunits in Different Rat Brain Areas by a Preferential Sigma1 Receptor Ligand and Potential Atypical Antipsychotic

“…These results resemble the reported effect of the new atypical antipsychotic quetiapine at mRNA level (Tascedda et al 1999) and of haloperidol and clozapine (Healy and Meador-Woodruff 1997). Regulation of GluR2/3 subunit after chronic treatment with E-5842 also follows a characteristic pattern: levels of the subunit immunoreactivity are clearly increased in the medial prefrontal cortex, while a small decrease is observed in the frontoparietal cortex and no significant change is seen in the posterior cingulate cortex.…”

“…This is a puzzling result, but contradictory published results are found, with up-and down-regulation of mRNA for GluR2 and GluR3 in different cortical and subcortical brain regions, using both typical and atypical antipsychotics (Fitzgerald et al 1995;Healy and Meador-Woodruff 1997;Tascedda et al 1999). In any case, E-5842, repeatedly administered, is able to differentially regulate levels of immunoreactivity of GluR2/3 in brain areas that have been involved in the pathophysiology of schizophrenia (while levels of mRNA for GluR2 in the frontal cortex of treated rats were also increased).…”

“…Regulation of glutamate receptor gene expression has been shown by different laboratories using either typical or atypical antipsychotics such as haloperidol, clozapine and quetiapine (Fitzgerald et al 1995;McCoy et al 1996;Healy and Meador-Woodruff 1997;Tascedda et al 1999). Given that the binding profile of these antipsychotics differs substantially from each other, it is difficult to assign the capacity to regulate the expression of glutamate receptors to a single interaction with a given (or some) neurotransmitter receptor.…”

“…Recently, a number of laboratories have demonstrated regulation of several glutamate receptor subunits by typical and atypical antipsychotics, using different experimental approaches (Fitzgerald et al 1995;McCoy et al 1996;Healy and Meador-Woodruff 1997;Tascedda et al 1999). Post mortem investigation of glutamate receptor subunits in human brain, in treated or untreated schizophrenics, have not yielded consistent results (Akbarian et al 1996;Healy et al 1998;Grimwood et al 1999).…”

Expression of AMPA Receptor Flip and Flop mRNAs in the Nucleus Accumbens and Prefrontal Cortex after Neonatal Ventral Hippocampal Lesions

“…When tested in rats, NMDA receptor antagonists produce behavioral responses that model schizophrenic symptoms and are blocked by antipsychotic drugs, including clozapine (e.g., Hauber 1993). Chronic administration of antipsychotic drugs alters glutamate receptor expression in rat brain (Chen et al 1998; Eastwood et al 1994 Eastwood et al , 1996 Fitzgerald et al 1995;Healy and Meador-Woodruff 1997;Riva et al 1997;Tascedda et al 1999) and alters EAA levels as measured by microdialysis (Daly and Moghaddam 1993;See and Chapman 1994;See and Lynch 1996;Yamamoto and Cooperman 1994).The ␣ -amino-3-hydroxy-5-methylisoxazole-4-priopionate (AMPA) subtype of glutamate receptor mediates the majority of excitatory transmission in brain. Different combinations of four AMPA receptor subunits (GluR1-4) give rise to heteromeric receptors with distinct properties (Hollman and Heinemann, 1994).…”