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.

Effects of tiagabine in combination with intravenous nicotine in overnight abstinent smokers

“…In a transcranial magnetic stimulation study with humans, changes in brain excitability, attributed to increased synaptic GABA levels, have been observed following acute tiagabine administration (Werhahn et al 1999), suggesting that tiagabine effects on the subjective response to nicotine may be mediated by increased synaptic GABA levels. This possibility is consistent with preclinical studies suggesting that medications enhancing the GABA levels in the brain reward areas attenuate the reinforcing effects of nicotine (Dewey et al 1999). Nicotinic receptors located presynaptically modulate both GABA and glutamate release.…”

“…The inhibitory effects of GABA on nicotine reinforcement have been supported by a number of animal studies. Vigabatrin, which increases brain GABA levels by inhibiting its breakdown, has been shown to attenuate nicotine-induced place preference, nicotine self-administration, and nicotine-induced dopamine release (Bevins et al 2001;Dewey et al 1999;Paterson and Markou 2002). Thus, enhancing GABA activity may be a strategy to decrease the reinforcing effects of nicotine.…”

Cannabinoid CB1 receptors are involved in motivational effects of nicotine in rats

“…This might be due to the actual difficulties to demonstrate reliable motivational effects of nicotine by place conditioning procedures. Indeed, in rats and mice, some studies indicated that nicotine does not support place conditioning (Clarke and Fibiger 1987;Parker 1992;Rogers et al 2004), whereas others reported either modest place preference (Fudala et al 1985;Fudala and Iwamoto 1986;Shoaib et al 1994;Horan et al 1997;Dewey et al 1999;Castañé et al 2002;Vastola et al 2002;Zarrindast et al 2003;Belluzzi et al 2004), place aversion (Jorenby et al 1990;Horan et al 1997) or biphasic effects (Risinger and Oakes 1995;Philibin et al 2005), depending on the experimental design (biased or unbiased), the doses, the strain and even the age of the animals.…”

The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice

“…Nicotine self-administration by rats is thought to reflect the rewarding effects of nicotine, and has been shown to be sensitive to modulation of dopaminergic (Corrigall and Coen 1991;Picciotto and Corrigall 2002), cholinergic (Watkins et al 1999;Corrigall et al 2002;Picciotto and Corrigall 2002) and gamma-amino-butyric acid (GABA)-ergic (Dewey et al 1999;Paterson and Markou 2002;Picciotto and Corrigall 2002) neurotransmission. Additional work has suggested a possible role for glutamate in mediating the rewarding effects of nicotine (McGehee et al 1995;Reid et al 2000;Schilstrom et al 2000).…”