Research reportThe effects of chronic administration of quetiapine on the methamphetamine-induced recognition memory impairment and dopaminergic terminal deficit in rats
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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2018, Behavioural Brain ResearchCitation Excerpt :For example, it has been reported that QUE transiently disrupts avoidance behavior in a conditioned avoidance response task because it only transiently blocks D2 receptors [44]. It has also been reported that QUE decreases object recognition deficits in a rat model of malformations of cortical development [26], stress-induced spatial working memory impairment [45], and reverses methamphetamine-induced cognitive deficits [46]. The benefits attributed to QUE could be due, in part to, to increased levels of DA in the frontal cortex.
Object Novelty Recognition Memory
2018, Handbook of Behavioral NeuroscienceCitation Excerpt :These crossings have been considered as indicative of general locomotor activity during the test; hence they appear to represent a direct measure of this activity. A number of studies did measure crossings in the open field in a pretest habituation session (Bianchi et al., 2009; González et al., 2014; Hopkins and Bucci 2010; Hopkins et al., 2011; Schrijver et al., 2002) and/or during the recognition memory test (He et al., 2006; Grayson et al., 2007; O'Shea et al., 2004; Bertaina-Anglade et al., 2011; Ryabinin et al., 2002; Sargolini et al., 2003). This measure of crossings has been used to distinguish the changes in locomotor activity from the changes in object exploration.