GABABeta Regulation of METH-Induced Associative Learning

描述(由申请人提供)：GABAB受体(GABABR)激动剂可以减少渴求和寻找药物的行为；但是，它们有很大的副作用，限制了它们的临床应用。GABABR阳性变构调节剂(PAM)也减少了药物的自我给药，但不会造成严重的运动损伤。PAM本身没有直接作用；它们的效用与内源性GABA激活GABABR的水平直接相关。GABA的紧张性释放是动态的，并根据药物暴露的剂量和持续时间以及药物停药的时间长短而不同地改变。以下目的将用于检验以下假设：在甲基苯丙胺(METH)致敏方案后给予GABABR配体将抑制条件性位置偏爱(CPP)和运动敏化(MS)的表达，以及在神经元水平上发生的相关(分子和功能)变化。目的：探讨GABABR配体是否能降低冰毒诱导的大鼠脑内CPP的表达。目的II：探讨丘脑内侧背侧GABAB受体激活是否在抑制冰毒诱导的CPP表达中起关键作用。目的III：确定冰毒诱导慢性阻塞性肺疾病大鼠的GABABR功能是否发生改变，以及GABABR配体的治疗是否能逆转这种改变。

DESCRIPTION (provided by applicant): GABAB receptor (GABABR) agonists reduce craving and drug-seeking behaviors; however, they have substantial side effects, which limit their clinical usefulness. GABABR positive allosteric modulators (PAMs) also reduce drug self-administration, but without major motor impairment. PAMs have no direct effect on their own; their utility is directly correlated with the level of GABABR activation by endogenous GABA. Tonic release of GABA is dynamic, and is differentially altered depending upon the dose & duration of drug exposure and the length of drug withdrawal. The following Aims will be used to test the hypothesis that GABABR ligands administered after a sensitizing regimen of methamphetamine (METH) will inhibit the expression of conditioned place preference (CPP) and motor sensitization (MS) and the associated (molecular and functional) changes that occur on the neuronal level. Aim I: To ascertain if GABABR ligands reduce the expression of METH-induced CPP in rats. Aim II: To ascertain if GABAB receptor activation in the medial dorsal thalamus is critical to inhibit the expression of METH-induced CPP. Aim III: Determine if there is a change in GABABR function in rats showing METH-induced CPP and if this is reversed by treatment with GABABR ligands.