Methamphetamine abuse.

There is an urgent need to develop a reliable mouse model of relapse to address the genetic factors involved in susceptibility to relapse of drug-seeking behavior by using mutant mice. This paper presents a feasible way to reinstate extinguished methamphetamine (METH)-seeking behavior. Male C57BL/6J mice acquired stable nose-poking responses for taking METH after approximately 10 daily 3-h sessions of METH (0.1mg/kg/infusion) self-administration under a fixed ratio 1 or 2 (FR1/2) schedule. During the self-administration, cue- and hole-lamps indicated the availability of METH and were inactivated simultaneously with each infusion for 5s. The mice were exposed to extinction training in the absence of METH-paired stimuli (cue- and hole-lamps) and METH infusion, until they met the extinction criterion (less than 25 active responses or 30% of active responses in the stable self-administration phase on 2 consecutive days). METH-paired stimuli (cue- and hole-lamps) during METH self-administration reliably triggered a relapse of METH-seeking behavior in the absence of METH infusion. A combination of non-contingent intravenous (i.v.) priming and self-injected METH also increased the reinstatement of METH-seeking behavior in the absence of METH-paired stimuli (cue- and hole-lamps) and without METH infusion posterior to the self-injection. These results suggest that the mouse model of relapse in our study might provide a new stage for the exploration of genetic factors involved in relapse of drug dependence and of the underlying mechanisms of drugs of abuse.

Amphetamine-Related Disorders↗

PubMed2006

NrCAM in addiction vulnerability: positional cloning, drug-regulation, haplotype-specific expression, and altered drug reward in knockout mice.

Several lines of evidence support roles for the cell adhesion molecule NrCAM in addictions. Fine mapping within a chromosome 7 region that contains previously linked and associated genomic markers identifies NrCAM haplotypes that are associated with substance abuse vulnerabilities in four samples of abusers and controls. Differential display identifies NrCAM as a drug regulated gene. NrCAM is expressed in neurons linked to reward and memory. NrCAM displays haplotype-specific gene expression in human post-mortem brain samples. Knockout mice display reduced opiate- and stimulant-conditioned place preferences. These observations support NrCAM as a positionally cloned and drug-regulated gene whose variants are likely to change expression and alter substance abuse vulnerabilities in human addictions and animal models of drug reward.

Amphetamine-Related Disorders↗