Gamma-vinyl GABA increases nonvesicular release of GABA and glutamate in the nucleus accumbens in rats via action on anion channels and GABA transporters

Abstract

Rationale: gamma-Amino butyric acid (GABA) is a well-characterized inhibitory neurotransmitter in the central nervous system, which may also stimulate nonvesicular release of other neurotransmitters under certain conditions. We have recently reported that gamma-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, elevates extracellular GABA but fails to alter dopamine release in the nucleus accumbens (NAc).

Objectives: Here, we investigated the mechanism(s) by which GVG elevates extracellular GABA levels and whether GVG also alters glutamate release in the NAc.

Materials and methods: In vivo microdialysis was used to simultaneously measure extracellular NAc GABA and glutamate before and after GVG administration in freely moving rats.

Results: Systemic administration of GVG or intra-NAc local perfusion of GVG significantly increased extracellular NAc GABA and glutamate. GVG-enhanced GABA was completely blocked by intra-NAc local perfusion of 5-nitro-2, 3-(phenylpropylamino)-benzoic acid (NPPB), a selective anion channel blocker and partially blocked by SKF89976A, a type 1 GABA transporter inhibitor. GVG-enhanced glutamate was completely blocked by NPPB or SKF89976A. Tetrodotoxin, a voltage-dependent Na(+)-channel blocker, failed to alter GVG-enhanced GABA and glutamate.

Conclusions: These data suggest that GVG-enhanced extracellular GABA and glutamate are mediated predominantly by the opening of anion channels and partially by the reversal of GABA transporters. Enhanced extracellular glutamate may functionally attenuate the pharmacological action of GABA and prevent enhanced GABA-induced excess inhibition.

Fig. 1

Effects of systemic administration of GVG (25, 100, and 300 mg/kg, i.p.) on extracellular GABA (a) and glutamate (b) in the NAc. *P<0.05, **P<0.01, ***P<0.001, compared to the vehicle control group at each time point

Fig. 2

The effects of intra-NAc local perfusion of GVG or GABA (1, 10, 100, and 1,000 μM) on extracellular GABA (a) and glutamate (b) in the NAc. *P<0.05, **P<0.01, ***P<0.001, compared to the vehicle group at each time point

Fig. 3

a Effects of intra-NAc local perfusion of SKF89976A (300 μM), TTX (1 μM), or NPPB (300 μM) alone on extracellular NAc GABA. b–d Effects of 300 mg/kg GVG on extracellular GABA in the absence or presence of intra-NAc local perfusion of SKF89976A (300 μM), TTX (1 μM), or NPPB (300 μM). b Percent (%) change in extracellular GABA over pre-intra-NAc drug perfusion baselines. c Renormalized data from b. d AUC data from c. *P<0.05, **P<0.01, ***P<0.001, compared with the vehicle (Veh) group (a), compared with the Veh + Veh group (c). #P<0.05, ##P<0.01, compared with the Veh + GVG group (c). ⁺P<0.05, ⁺⁺P<0.01, inter-group comparisons (d)

Fig. 4

a Effects of intra-NAc local perfusion of SKF89976A (300 μM), TTX (1 μM), or NPPB (300 μM) alone on extracellular NAc glutamate. b–d Effects of 100 mg/kg GVG on extracellular glutamate in the absence or presence of intra-NAc local perfusion of SKF89976A (300 μM), TTX (1 μM), or NPPB (300 μM). b Percent change (%) in extracellular glutamate over pre-intra-NAc drug perfusion baselines. c Renormalized data from b. d AUC data from c. *P<0.05, **P<0.01, ***P<0.001, compared with the Veh group (a) or compared with the Veh + Veh group (c). ⁺P<0.05, ⁺⁺P<0.01, inter-group comparisons (d)

Fig. 5

a Photomicrograph of a stained coronal brain section, demonstrating the position and extent of a representative guide cannula and representative microdialysis probe, including the non-membrane portion (~1 mm beyond the tip of the guide cannula) and the active membrane portion. b Schematic reconstructions of positions of active microdialysis membranes within the NAc. Dialysis membranes spanned the length of the core and shell compartments of the NAc