Elsevier

Behavioural Brain Research

Volume 172, Issue 1, 15 September 2006, Pages 39-45
Behavioural Brain Research

Research report
The effects of chronic administration of quetiapine on the methamphetamine-induced recognition memory impairment and dopaminergic terminal deficit in rats

https://doi.org/10.1016/j.bbr.2006.04.009Get rights and content

Abstract

Previous studies have suggested that quetiapine, a new atypical antipsychotic drug, may have beneficial effects on cognitive impairment and be a neuroprotectant in treating neurodegenerative diseases. In the present study, we investigated the therapeutic effects of chronic administration of quetiapine on methamphetamine (METH)-induced recognition memory impairment and dopaminergic terminal neurotoxicity in rats. Rats were pretreated with METH (5 mg/kg; s.c.) four times at 2-h intervals while their body temperature was monitored. Fifteen minutes after the last METH injection, rats were administered quetiapine (10 mg/kg/day; i.p.) for 28 days. One day after the last quetiapine injection, rats were trained and tested on an object recognition task on days 29 and 30. Finally, on day 31, rats were sacrificed for immunohistochemistry, 1 day after the object recognition task. METH induced hyperthermia, recognition memory impairment and a decrease of tyrosine hydroxylase immunoreactivity in the caudate putamen (CPu) of striatum. Quetiapine attenuated the METH-induced hyperthermia. Furthermore, chronic post-treatment of quetiapine reversed the METH-induced memory impairment and dopaminergic terminal deficit. These findings suggest that quetiapine may have therapeutic effects in the treatment of cognitive impairment and neurodegeneration induced by METH.

Introduction

Quetiapine, a new atypical antipsychotic drug, effectively alleviates positive and negative symptoms, as well as cognitive impairment, in schizophrenia patients [4], [35], [39]. In in vitro studies, the atypical antipsychotics (clozapine, olanzapine, quetiapine, and risperidone) are effective in reducing PC12 cell death induced by hydrogen peroxide [43], β-amyloid peptide [44], or N-methyl-4-phenylpyridinium ions (MPP+) [36]. In in vivo studies, quetiapine attenuates the immobilization stress-induced decrease of brain-derived neurotrophic factor (BDNF) in rat hippocampus [46], and counteracts the phencyclidine-induced reference memory impairment and decrease of Bcl-XL/Bax ratio in the posterior cingulate cortex in rats [20], while olanzapine effectively attenuates okadaic acid-induced spatial memory impairment and hippocampal cell death in rats [23]. It is hypothesized that quetiapine may have beneficial effects on cognitive impairment and be a neuroprotectant in treating neurodegenerative diseases.

The most widely studied class of drug-induced models of schizophrenia is based on the behavioural effects of psychostimulant drugs. Methamphetamine (METH) is a psychomotor stimulant that is abused worldwide. The administration of this agent can cause neuropsychiatric complications [28] and cognitive impairment [38] in clinical studies. Furthermore, METH impairs recognition memory in rats [8], [37], and produces hyperthermia and long-term neurotoxicity to dopaminergic and serotonergic nerve terminals [14], [32], [41].

A previous study demonstrated that olanzapine effectively attenuated METH-induced neurotoxicity by inhibiting hyperthermia and preventing a Bcl-2 decrease in rats [21]. In the present study, we examined the effects of chronic administration of quetiapine on the consequences of an acute METH regimen on recognition memory and dopaminergic terminals of the striatum in rats. To evaluate the early therapeutic effects of quetiapine, the first quetiapine injection was administered 15 min after the last METH injection. Recognition memory was assessed by an object recognition task [9], [16]. The integrity of dopaminergic terminals of the striatum was evaluated by striatal tyrosine hydroxylase (TH) immunoreactivity, a neuronal marker [1], [15].

Section snippets

Animals

All procedures with animals were performed in accordance with the guidelines established by the Canadian Council on Animal Care and were approved by the Animal Care Committee of the University of Saskatchewan. A total of 38 male Sprague-Dawley rats (Charles River, St. Constant, Que., Canada) weighing 250–275 g at the beginning of the experiments were used. The rats were housed four or five per cage with free access to food and water under controlled laboratory conditions (a 12:12 h light/dark

Quetiapine attenuated the METH-induced hyperthermia

As shown in Fig. 1A, two-way ANOVA showed that METH and time produced a significant change on body temperature [F(METH)(1,36) = 245.70, P < 0.0001; F(time)(12,432) = 29.12, P < 0.0001], and that there was an interaction between the two factors [F(METH × time)(12,432) = 39.14, P < 0.0001]. A post hoc analysis indicated that METH significantly increased body temperature in rats by 0.5 h after the start of METH (Fig. 1A).

As shown in Fig. 1B, three-way ANOVA showed that METH, quetiapine and time have effects on

Discussion

Previous studies have shown that METH can induce object recognition memory impairment in animals [7], [8], [26], [37]. In the present study, the administration of METH (5 mg/kg × 4 times, at 2-h intervals) impairs both short- and long-term (1 and 24 h) retention of an object recognition task that was measured 4 weeks after METH injections in rats. The lower dose of METH (5 mg/kg × 4 times, at 2-h intervals) was chosen in the present study because high mortality (64.3%) was observed in our previous

Acknowledgments

This work was supported by Canadian Psychiatric Research Foundation, Canadian Institutes of Health Research, NeuroScience Canada and Saskatchewan Health Research Foundation. The authors thank Dr. Augusto V. Juorio and Dr. Sergey Fedoroff for their helpful comments during the preparation of this manuscript, and are grateful to Gabriel Stegeman for her excellent technical assistance.

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