Implication of the GABAb receptor in gamma vinyl-GABA's inhibition of cocaine-induced increases in nucleus accumbens dopamine

Abstract

Previously, we demonstrated that gamma vinyl-GABA (GVG, Vigabatrin) dose-dependently inhibits cocaine-induced increases in dopamine (DA) concentrations in both the rodent and primate brain. Furthermore, it abolishes cocaine self-administration and conditioned place preference, while having no effect on locomotor activity or drug delivery to the brain. In an effort to better understand the mechanisms underlying this inhibition, we examined the effect of the selective GABA(B) receptor antagonist SCH 50911 on the GVG-induced decrease in cocaine's elevation of extracellular DA concentrations in the nucleus accumbens (NACC). Cocaine administration alone (20 mg/kg i.p.) produced a 480% increase in extracellular NACC DA levels. GVG (300 mg/kg i.p.) significantly reduced this increase by 25% (P<0.01). In sharp contrast, extracellular DA levels increased to 550% after the sequential administration of SCH 50911 (3 mg/kg i.p.), GVG, and cocaine. This increase is significantly different than GVG and cocaine (P<0.05) but similar to cocaine alone. These results demonstrate that the GABA(B) antagonist SCH 50911 was able to completely abolish GVG's inhibition of cocaine-induced increases in DA in the NACC and implicates the GABA(B) receptor in the mechanism underlying this inhibition.

GABA, ?-hydroxybutyric acid, and neurological disease

“…Similar effects for baclofen have been reported for other addictive drugs such as alcohol, nicotine, and heroin 60–62. Furthermore, administration of vigabatrin, which elevates levels of endogenous GABA, reduces intake of heroin and cocaine in rats 63, 64…”

Effects of positive allosteric modulators of the GABA B receptor on cocaine self-administration in rats

“…GABA B receptors are one of the most abundant classes of receptors in the CNS (Bischoff et al 1999;Margeta-Mitrovic et al 1999), and thus it is difficult to identify a particular locus of action for their role in cocaine reinforcement. It has been postulated that GABA B agonists produce their effects on cocaine self-administration by attenuating cocaine-induced increases in nucleus accumbens dopamine (Ashby et al 1999). Dopamine release in the accumbens is under tonic inhibitory control by GABAergic interneurons that make synaptic contact with dopaminergic cell bodies in the ventral tegmental area, and we have previously reported that intra-VTA baclofen attenuates cocaine self-administration (Brebner et al 2000b).…”

Ventral pallidal extracellular fluid levels of dopamine, serotonin, gamma amino butyric acid, and glutamate during cocaine self-administration in rats

“…These researchers also found that baclofen administered directly into the NA or VTA also suppressed responding maintained under an FR5 schedule of cocaine infusion. Further, the indirect agonist gamma-vinyl GABA attenuated the increases in extracellular DA in the NA produced by IP injection of cocaine, and this effect was reversed by co-administration of SCH 50911, a GABA B antagonist (Ashby et al 1999). Taken together, these data suggest that the activity of GABAergic innervation of the NA and VTA functions to inhibit DA release in these areas, thereby possibly attenuating the reinforcing efficacy of cocaine.…”