ΔFosB induction in orbitofrontal cortex potentiates locomotor sensitization despite attenuating the cognitive dysfunction caused by cocaine
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- 作者：Catharine A. Winstanley ; Thomas A. Green ; David E.H. Theobald ; William Renthal ; Quincey LaPlant ; Ralph J. DiLeone ; Sumana Chakravarty ; Eric J. Nestler
- 关键词：Addiction ; Impulsivity ; Frontal cortex ; Nucleus accumbens ; Real-time PCR ; Viral-mediated gene transfer
- 刊名：Pharmacology Biochemistry and Behavior
- 出版年：2009
- 出版时间：September 2009
- 年：2009
- 卷：93
- 期：3
- 页码：278-284
- 全文大小：562 K
文摘
The effects of addictive drugs change with repeated use: many individuals become tolerant of their pleasurable effects but also more sensitive to negative sequelae (e.g., anxiety, paranoia, and drug craving). Understanding the mechanisms underlying such tolerance and sensitization may provide valuable insight into the basis of drug dependency and addiction. We have recently shown that chronic cocaine administration reduces the ability of an acute injection of cocaine to affect impulsivity in rats. However, animals become more impulsive during withdrawal from cocaine self-administration. We have also shown that chronic administration of cocaine increases expression of the transcription factor ΔFosB in the orbitofrontal cortex (OFC). Mimicking this drug-induced elevation in OFC ΔFosB through viral-mediated gene transfer mimics these behavioural changes: ΔFosB over-expression in OFC induces tolerance to the effects of an acute cocaine challenge but sensitizes rats to the cognitive sequelae of withdrawal. Here we report novel data demonstrating that increasing ΔFosB in the OFC also sensitizes animals to the locomotor-stimulant properties of cocaine. Analysis of nucleus accumbens tissue taken from rats over-expressing ΔFosB in the OFC and treated chronically with saline or cocaine does not provide support for the hypothesis that increasing OFC ΔFosB potentiates sensitization via the nucleus accumbens. These data suggest that both tolerance and sensitization to cocaine's many effects, although seemingly opposing processes, can be induced in parallel via the same biological mechanism within the same brain region, and that drug-induced changes in gene expression within the OFC play an important role in multiple aspects of addiction.