Baclofen facilitates the extinction of methamphetamine-induced conditioned place preference in rats.

Methamphetamine (Meth) is a highly abused psychostimulant. Even after long periods of abstinence, cues associated with the rewarding properties of psychostimulants can elicit drug-craving and seeking (Ehrman et al., 1992; Hartz et al., 2001; O'Brien et al., 1992). Thus, relapse to drug use remains a major challenge for psychostimulant-addicted individuals. These responses are attributed at least in part to the robust associative learning that occurs between contextual cues (conditioned stimulus) and the rewarding effects of abused substances (unconditioned stimulus) as well as the enduring nature of the drug-context memory. This long-lasting association can be demonstrated in the laboratory with conditioned place preference (CPP) in humans and laboratory rodents (Childs and deWit H., 2009; O'Brien et al., 1998; Tzschentke, 1998; Tzschentke, 2007), where the preference for the drug-paired context are robust and can persist for long periods of time. Unwanted associative memories can be disrupted by employing extinction learning procedures. For example, extinction procedures can reduce cue-induced anxiety associated with post traumatic stress disorder in humans (Brunet et al., 2008; McCleery and Harvey, 2004). However, extinction of reward-related memories is not particularly efficacious in reducing relapse in abstinent drug-dependent humans (Conklin and Tiffany, 2002) or in rodent models of addiction (Crombag and Shaham, 2002; Di Ciano P. and Everitt, 2004) which may be the consequence of studies not achieving optimal extinction procedures (e.g., number of extinction sessions or the proper cues used); but there is evidence that combining extinction therapy with a pharmacotherapy (e.g., ligands which target the GABAB receptor) can reduce cue-elicited relapse in humans (O'Brien et al., 1990) and mice (Heinrichs et al., 2010). Currently there are no FDA-approved pharmacotherapies for Meth addiction; however, the GABAB receptor has received considerable attention as a potential therapeutic target (Brebner et al., 2002; Rose and Grant, 2008; Xi and Gardner, 2008). GABAB receptors negatively regulate neurotransmitter systems important for reward- mediated behaviors and mnemonic processes, including glutamate (Harte and O'Connor, 2005; Lei and McBain, 2003; Porter and Nieves, 2004; Yamada et al., 1999) and dopamine (Santiago et al., 1993a; Santiago et al., 1993b; Smolders et al., 1995; Westerink et al., 1996). Cues associated with drug reward activate limbic brain regions in drug-addicted humans (Childress et al., 1999; Childress et al., 2008) and rodents (Brown et al., 1992; Ciccocioppo et al., 2001; Franklin and Druhan, 2000; Rhodes et al., 2005; Zombeck et al., 2008). This activation is attributed to the hyper-responsiveness of glutamatergic (Bell et al., 2000; Hotsenpiller et al., 2001) and dopaminergic (Lin et al., 2007) systems in response to drug-associated cues. Imaging studies indicate that baclofen, a GABAB receptor agonist, blunts the limbic activation associated with visual drug cues in drug-addicted humans (Brebner et al., 2002). Baclofen also inhibits the expression of many psychostimulant-induced behaviors in rodents including CPP (Li et al., 2001), motor sensitization (Bartoletti et al., 2004; Frankowska et al., 2009; Hotsenpiller and Wolf, 2003; Lhuillier et al., 2007) and conditioned motor sensitization, and self-administration (Brebner et al., 2005; Campbell et al., 1999; Filip et al., 2007; Ranaldi and Poeggel, 2002; Roberts and Andrews, 1997; Smith et al., 2004; Weerts et al., 2007). It is clear that baclofen can alter learning and memory process. Particularly relevant to the current study is the recent demonstration that baclofen administered immediately after daily forced extinction training sessions facilitated the extinction of morphine-induced CPP (Heinrichs et al., 2010). As baclofen modulates neurotransmitter systems that are critical for the expression of psychostimulant-induced behaviors as well as the extinction of opiate-induced CPP, we sought to determine the efficacy of baclofen to facilitate the extinction of Meth-induced associative learning. This experimental endeavor also determined if the baclofen effect seen with morphine-induced CPP generalized to the psychostimulant Meth.