GABABeta Regulation of METH-Induced Associative Learning

描述（由申请人提供）：GABABR受体（GABABR）激动剂减少渴望和药物寻求行为；然而，它们有很大的副作用，这限制了它们的临床应用。GABABR阳性变构调节剂（PAMs）也能减少药物自我给药，但没有严重的运动损伤。pam本身没有直接影响；它们的效用与内源性GABA激活GABABR的水平直接相关。GABA的强直性释放是动态的，并且根据药物暴露的剂量和持续时间以及停药时间的长短而发生不同的变化。以下目的将用于验证在甲基苯丙胺（METH）致敏方案后给予GABABR配体将抑制条件位置偏好（CPP）和运动致敏（MS）的表达以及发生在神经元水平上的相关（分子和功能）变化的假设。目的一：确定GABABR配体是否降低大鼠甲基苯丙胺诱导的CPP的表达。目的II：确定丘脑内侧背侧GABAB受体的激活是否对抑制甲基甲醚诱导的CPP表达至关重要。目的III：确定甲基甲醚诱导CPP的大鼠GABABR功能是否发生变化，以及GABABR配体治疗是否逆转这种变化。

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.