Gamma-vinyl GABA inhibits cocaine-triggered reinstatement of drug-seeking behavior in rats by a non-dopaminergic mechanism

Abstract

Relapse to drug use is a core feature of addiction. Previous studies demonstrate that gamma-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, attenuates the acute rewarding effects of cocaine and other addictive drugs. We here report that systemic administration of GVG (25-300 mg/kg) dose-dependently inhibits cocaine- or sucrose-induced reinstatement of reward-seeking behavior in rats. In vivo microdialysis data indicated that the same doses of GVG dose-dependently elevate extracellular GABA levels in the nucleus accumbens (NAc). However, GVG, when administered systemically or locally into the NAc, failed to inhibit either basal or cocaine-priming enhanced NAc dopamine in either naïve rats or cocaine extinction rats. These data suggest that: (1) GVG significantly inhibits cocaine- or sucrose-triggered reinstatement of reward-seeking behavior; and (2) a GABAergic-, but not dopaminergic-, dependent mechanism may underlie the antagonism by GVG of cocaine-triggered reinstatement of drug-seeking behavior, at least with respect to GVG's action on the NAc.

Fig. 1

General experimental protocol and effects of GVG on cocaine- or sucrose-triggered reinstatement of reward-seeking behavior. Panel A: general experiment protocol showing sequential experimental phases. Panel B: mean numbers of active lever presses during last session of cocaine self-administration, last session of extinction, and cocaine-primed reinstatement in presence of vehicle or various GVG doses. Panel C: mean numbers of active lever presses during last session of sucrose self-administration, last session of extinction, and sucrose-induced reinstatement in presence of vehicle or various GVG doses. *p < 0.05, **p < 0.01, ***p < 0.001, compared to vehicle treatment group.

Fig. 2

Effects of systemic administration of GVG on extracellular GABA, DA and cocaine-enhanced DA in the NAc in cocaine extinction rats during reinstatement testing. Panel A: effects of GVG (25–300 mg/kg, i.p.) on NAc extracellular GABA. Panel B: effects of GVG on NAc extracellular DA. Panel C: effects of GVG pretreatment (25–300 mg/kg, i.p., 1 h prior to cocaine priming) on cocaine-induced increases in NAc DA. *p < 0.05, **p < 0.01, ***p < 0.001, compared to baseline before GVG administration in each GVG dose group.

Fig. 3

Effects of systemic administration of GVG on extracellular GABA, DA and cocaine-enhanced DA in the NAc of drug naïve rats. Panel A: effects of GVG (25–300 mg/kg, i.p.) on NAc extracellular GABA. Panel B: effects of GVG on NAc extracellular DA. Panel C: effects of GVG pretreatment (300 mg/kg, i.p., 1, 3 or 6 h prior to cocaine priming) on cocaine-induced increases in NAc DA. *p < 0.05, **p < 0.01, ***p < 0.001, compared to baseline before GVG administration in each GVG dose group.

Fig. 4

Effects of local perfusion of GVG into the NAc on NAc extracellular GABA, DA and cocaine-enhanced DA in drug naïve rats. Panel A: effects of GVG (1–1000 μM) on extracellular GABA. Panel B: effects of the same concentrations of GVG on NAc extracellular DA. Panel C: effects of local perfusion of GVG (1000 μM) into the NAc on cocaine-induced increases in NAc DA. *p < 0.05, **p < 0.01, ***p < 0.001, compared to baseline before GVG administration in each group.

Fig. 5

Microdialysis probe placements within the NAc. The extent of each active semipermeable microdialysis membrane is depicted.