A novel strategy for the treatment of cocaine addiction

Abstract

Cocaine's addictive liability has been linked to its pharmacologic actions on mesotelencephalic dopamine (DA) reinforcement/reward pathways in the central nervous system (CNS). Dopaminergic transmission within these pathways is modulated by gamma-aminobutyric acid (GABA). With this knowledge, we examined the utility of gamma vinylGABA (GVG), a selective and irreversible inhibitor of GABA-transaminase (GABA-T) known to potentiate GABAergic inhibition, to alter cocaine's biochemical effects as well as its effects on behaviors associated with these biochemical changes. GVG significantly attenuated cocaine-induced increases in neostriatal synaptic DA in the non-human primate (baboon) brain as assessed by positron emission tomography (PET) and abolished both the expression and acquisition of cocaine-induced conditioned place preference (CPP). It had no effect on CPP for a food reward, the delivery of cocaine to the brain or locomotor activity. These findings suggest the possible therapeutic utility in cocaine addiction of a pharmacologic strategy targeted at the GABAergic neurotransmitter system, a system distinct from but functionally linked to the DA mesotelencephalic reward/reinforcement system. However, rather than targeting the GABA receptor complex with a direct GABA agonist, this novel approach with GVG takes advantage of the prolonged effects of an irreversible enzyme inhibitor that raises endogenous GABA levels without the addictive liability associated with GABA agonists acting directly at the receptor itself. Human trials with GVG are currently being developed to directly examine the utility of this novel strategy for the treatment of cocaine addiction.

Treating cocaine addiction: From preclinical to clinical trial experience with γ‐vinyl GABA

“…Further, we demonstrated that GVG blocked cocaine self-administration and cocaineinduced lowering of brain stimulation reward thresholds (Kushner et al, 1997). In addition, we demonstrated that GVG blocked the expression and acquisition of cocaine-seeking behavior (conditioned place preference, Dewey et al, 1998) as well as sensitization to cocaine (Gardner et al, 2002). We subsequently extended this work to include similar findings with heroin, nicotine, methamphetamine and amphetamine, and alcohol Paul et al, 2001a;Dewey et al, 1999).…”

Effects of gabapentin on cocaine self-administration, cocaine-triggered relapse and cocaine-enhanced nucleus accumbens dopamine in rats

“…Also, GABA B receptor agonists inhibit both cocaine self-administration (Roberts et al, 1996;Roberts, 2005) and cocaine-triggered reinstatement of drug-seeking behavior (Campbell et al, 1999;Di Ciano and Everitt, 2003). Second, elevation of extracellular GABA levels by inhibition of GABA degradation by γ-vinyl GABA (GVG) inhibits the rewarding effects of cocaine as assessed by intravenous self-administration, conditioned place preference and electrical brain stimulation reward (Kushner, 1997;Kushner et al, 1999;Dewey et al, 1998). GVG has also been reported to inhibit cocaine-enhanced NAc DA levels (Dewey et al, 1998;Schiffer et al, 2003).…”

“…Second, elevation of extracellular GABA levels by inhibition of GABA degradation by γ-vinyl GABA (GVG) inhibits the rewarding effects of cocaine as assessed by intravenous self-administration, conditioned place preference and electrical brain stimulation reward (Kushner, 1997;Kushner et al, 1999;Dewey et al, 1998). GVG has also been reported to inhibit cocaine-enhanced NAc DA levels (Dewey et al, 1998;Schiffer et al, 2003). Furthermore, clinical trials with the GABA A receptor modulator topiramate, the GABA B receptor agonist baclofen, or the GABA enhancers GVG or tiagabine (a GABA-uptake inhibitor) have shown significant decreases in self-reported cocaine craving and urine-confirmed cocaine use (Kampman et al, 2004;Shoptaw et al, 2003;Johnson, 2005;Brodie et al, 2003;González et al, 2003).…”

Neurotensin Receptor Antagonist Administered during Cocaine Withdrawal Decreases Locomotor Sensitization and Conditioned Place Preference

“…However, several other neurotransmitter/neuromodulator systems functionally linked to DA neurons within the motivational circuit may also contribute to the complex regulations underlying cocaine dependence (Dewey et al, 1998;de Vries et al, 2001;Sarnyai et al, 2001;Kreek et al, 2002;Beinfeld, 2003;Baptista et al, 2004). Therefore, new approaches investigating the potential of modulatory systems as alternative targets may be of fundamental importance.…”