A pharmacologic strategy for the treatment of nicotine addiction

Abstract

Like many psychostimulant drugs, nicotine elevates extracellular and synaptic dopamine (DA) concentrations in the nucleus accumbens (NAc). This elevation has been linked to its reinforcing properties. Dopaminergic transmission within the NAc is modulated by gamma-aminobutyric acid (GABA). Therefore, we examined the utility of gamma vinyl-GABA (GVG, Vigabatrin) for inhibiting nicotine's biochemical effects on NAc DA as well as its effects on behaviors associated with these biochemical changes. Given 2.5 hours prior to nicotine, GVG (75 mg/kg) had no effect on nicotine-induced increases in extracellular NAc DA. However, at 90 mg/kg, GVG significantly inhibited nicotine-induced increases by approximately 50% while at 100 or 150 mg/kg, GVG completely abolished nicotine-induced increases in both naive and chronically nicotine-treated animals. When given 12 or 24 hours prior to nicotine administration at a dose of 100 mg/kg, GVG-induced inhibition was diminished or abolished, respectively. In addition, at a dose of 18.75 mg/kg GVG abolished the expression of nicotine-induced conditioned place preference (CPP) while a dose of 75 mg/kg abolished the acquisition phase of CPP. Finally, using positron emission tomography (PET) and 11C-raclopride in primates, GVG (100 mg/kg) abolished nicotine-induced increases in synaptic DA while having no effect on the rate of metabolism of the radiotracer or its regional distribution. Together, these data suggest that GVG may be useful for the treatment of nicotine addiction and further support the strategy of targeting the GABAergic system with a suicide inhibitor of GABA-transaminase for the treatment of drug addiction.

Nicotine-Induced Dopamine Release in Primates Measured with [11C]Raclopride PET

“…The observed magnitude of change in BP after nicotine administration is consistent with other literature: Dewey et al (1999) and Schiffer et al (2000) reported a 12% change in BP after nicotine in anesthetized nonhuman primates treated with approximately the same dose of nicotine used here. Other published abstracts report smaller [ 11 C]raclopride displacements after nicotine injections and required higher nicotine doses to achieve the effect.…”

“…The current study examines the effect size of [ 11 C]raclopride displacement after nicotine infusion (at doses compatible with administration in humans) in nonhuman primates under isoflurane anesthesia. Similar experiments were performed by Dewey et al (1999), but the effect size could not be deduced from that study. Other such studies have appeared in abstract form Cumming and Gjedde (2001).…”

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

“…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).…”

Neurobiology of nicotine dependence

“…As discussed previously and depicted in figure 1, complex interactions occur between the GABA, dopaminergic and glutamatergic systems in the VTA . Increased GABAergic transmission abolishes both the nicotine-induced dopamine increases in the nucleus accumbens and the reinforcing effects of nicotine (Dewey et al 1999;Brebner et al 2002). g-Vinyl GABA (GVG; also referred to as vigabatrin) is an irreversible inhibitor of GABA transaminase, the primary enzyme involved in GABA metabolism.…”