Abstract
Objectives: To elucidate the pharmacological profile of aripiprazole, we examined its ameliorating effect on the methamphetamine-induced disruption of latent inhibition (LI) in rats. Method: The effect was measured using a conditioned emotional response procedure. The conditioned stimulus was a tone (2.8 kHz, 90 dB), and the unconditioned stimulus was a mild foot shock delivered through a floor grid. The conditioning procedure was repeated five times. Results: Methamphetamine-induced (1.0 mg/kg, i.p.) disruption of LI was ameliorated by the administration of haloperidol (0.2 mg/kg, i.p.) and by a moderate dose of aripiprazole (0.3 mg/kg, i.p.) but not by a lower or higher dose (0.1 or 3.0 mg/kg, i.p.) of aripiprazole. However, immunohistochemical examination showed increased levels of c-Fos expression in the shell of the nucleus accumbens after the administration of haloperidol (0.2 mg/kg, i.p.) but not of aripiprazole (0.3 mg/kg, i.p.). Conclusions: It is suggested that aripiprazole has an ameliorating effect on methamphetamine-induced disruption of latent inhibition within only a marginal therapeutic window.
Highlights
The present study aimed to characterize the psychopharmacological profile of aripiprazole, 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydrocar-bostycil, by examining its ameliorating effect on methamphetamine-induced disruption of latent inhibition (LI) in rats, an animal model of the cognitive impairments seen in schizophrenia [1]
LI is disrupted by the injection of the dopamine releasers, amphetamine and methamphetamine, in humans and rodents, and such disruption is ameliorated by typical and atypical antipsychotic drugs (APDs) [3,4,5,6]
A post hoc Bonferroni test carried out for an AcbSh section revealed that the number of cells in the Hal 0.2 was significantly greater than that in the Ari 0.3 and saline i.p. injection (SAL) (p < 0.001 for both) (Table 1). These results showed that the disruption of LI induced by methamphetamine was significantly ameliorated by administration of haloperidol (0.2 mg/kg) and by a moderate dose of aripiprazole (0.3 mg/kg) but not by a relatively low or high dose of aripiprazole (0.1 or 3.0 mg/kg)
Summary
The present study aimed to characterize the psychopharmacological profile of aripiprazole, 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydrocar-bostycil, by examining its ameliorating effect on methamphetamine-induced disruption of latent inhibition (LI) in rats, an animal model of the cognitive impairments seen in schizophrenia [1]. If a conditioned stimulus is presented several times without an unconditioned stimulus before conditioning, the animal learns to ignore, or not to pay attention to, the stimulus, and, the strength of the subsequent conditioning is inhibited [2]. This phenomenon is thought to relate to “attentional filtering mechanism”, which enables us to distinguish significant stimuli from irrelevant stimuli, and is known to be disrupted in patients with schizophrenia [1].
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