T-type calcium channel antagonism produces antipsychotic-like effects and reduces stimulant-induced glutamate release in the nucleus accumbens of rats

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• 作者：Jason M. Uslaner¹ ; ^{jason_uslaner@merck.com} ; Sean M. Smith¹ ; Sarah L. Huszar ; Rashida Pachmerhiwala ; Richard M. Hinchliffe ; Joshua D. Vardigan ; Shannon J. Nguyen ; Nathan O. Surles ; Lihang Yao ; James C. Barrow ; Victor N. Uebele ; John J. Renger ; Janet Clark ; Pete H. Hutson
• 关键词：Psychosis ; Amphetamine ; MK-801 ; Conditioned avoidance responding ; Dopamine ; c-fos
• 刊名：Neuropharmacology
• 出版年：2012
• 出版时间：March 2012
• 年：2012
• 卷：62
• 期：3
• 页码：1413-1421
• 全文大小：474 K

文摘

T-type calcium channels are important in burst firing and expressed in brain regions implicated in schizophrenia. Therefore, we examined the effects of novel selective T-type calcium channel antagonists in preclinical assays predictive of antipsychotic-like activity. TTA-A2 blocked the psychostimulant effects of amphetamine and MK-801 and decreased conditioned avoidance responding. These effects appeared mechanism based, rather than compound specific, as two structurally dissimilar T-type antagonists also reduced amphetamine-induced psychomotor activity. Importantly, the ability to reduce amphetamine¡¯s effects was maintained following 20 days pre-treatment with TTA-A2. To explore the neural substrates mediating the observed behavioral effects, we examined the influence of TTA-A2 on amphetamine-induced c-m>fosm> expression as well as basal and stimulant-evoked dopamine and glutamate release in?the?nucleus accumbens. TTA-A2 decreased amphetamine-induced c-m>fosm> expression as well as MK-801-induced, but not basal, glutamate levels in the nucleus accumbens. Basal, amphetamine- and MK-801-induced dopamine efflux was altered. These findings suggest that T-type calcium channel antagonism could represent a novel mechanism for treating schizophrenia.

This article is part of a Special Issue entitled ¡®Schizophrenia?