S-(+)-Gamma vinyl-GABA (S-GVG) blocks methamphetamine-induced increases in brain dopamine and 18FDG uptake in adolescent animals as well as the metabolic response to methamphetamine as adults

Abstract

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Objectives: Over the past decade, we demonstrated that racemic GVG dose-dependently blocked the biochemical and behavioral effects of cocaine, methamphetamine (METH), amphetamine, heroin, morphine, alcohol, nicotine and their combinations in adult female baboons (papio anubis) and male Sprague-Dawley rats (for review see Schiffer, et al., 2004). As a result, we recently completed two small open-label clinical trials using racemic GVG in cocaine and METH abusers (Brodie, et al., 2003; 2005). These studies suggested clinical efficacy and demonstrated visual safety (Fechtner, et al., In Press). In an ongoing effort to develop S-GVG (the active enantiomer) for the treatment of adolescent METH addiction, we used small animal imaging in combination with 11C-raclopride (11C-rac) and 18FDG to examine the effects of S-GVG on METH-induced increases in brain dopamine and metabolism, respectively.

Methods: Briefly, adolescent animals (30 days old) received baseline microPET scans (CTI Microsystems, R4) using 11C-rac and 18FDG. Following completion of these scans, animals received a METH challenge (1.0 mg/kg, iv) followed by another set of 11C-rac and 18FDG scans. In the same animals, we then examined the effects of S-GVG on the expression of METH-induced conditioned place preference (CPP) and METH-triggered reinstatement of this expression following its extinction. 60 days later, we challenged these animals with a single dose of METH during 18FDG uptake.

Results: METH significantly reduced striatal 11C-rac binding (consistent with an increase in dopamine) by approximately 22% and increased 18FDG uptake cortically, subcortically, and in the cerebellum. There were no effects of METH on occipital 18FDG uptake. However, an acute dose of S-GVG (150 mg/kg) completely abolished these increases just as it blocked the expression of METH-induced conditioned place preference (CPP). S-GVG (150 mg/kg/day) treatment for 5 days blocked METH-triggered reinstatement of this expression following its extinction. As adults (> 90 days old), these animals received another METH challenge during 18FDG uptake. Adolescent exposure to S-GVG blocked METH-induced increases in 18FDG uptake in these adult animals suggesting that adolescent S-GVG exposure may be neuroprotective.

Conclusions: Taken with our previous clinical and preclinical work, these studies suggest that early S-GVG intervention may effectively block the biochemical and behavioral consequences of adolescent and adult METH abuse.

Research Support (if any): USDOE/OBER DE-AC02-98CH10886; NIH DA015041