GABAergic attenuation of cocaine‐induced dopamine release and locomotor activity

Abstract

GABA modulates dopamine concentrations in the nucleus accumbens and corpus striatum. Using in vivo microdialysis techniques we examined this modulatory role and the extent to which three different GABAergic drugs can attenuate cocaine's ability to increase extracellular dopamine concentrations and gross locomotor activity. Ethanol, lorazepam (Ativan), and gamma-vinyl GABA (GVG) significantly and dose-dependently attenuated cocaine-induced dopamine release in the corpus striatum of freely moving animals. Unlike ethanol or lorazepam, however, GVG is not a sedative hypnotic in the doses used, and hence the strategy of selectively increasing GABAergic activity by suicide inhibition of the catabolic enzyme, GABA-transaminase, offers the unique advantage of attenuating cocaine-induced dopamine release without the apparent side effects typically associated with sedative hypnotics.

A pharmacologic strategy for the treatment of nicotine addiction

“…1B). Consistent with our previous findings (Dewey et al, 1997), GVG did not alter gross locomotor activity during the 2.5-hour pretreatment interval. However, nicotine increased gross locomotor activity in all animals regardless of the dose of GVG they received.…”

“…Based upon the doseresponse curve obtained from the microdialysis data, GVG at a dose of 18.75 mg/kg would not be expected to have any effect on nicotine-induced increases in NAc DA. Furthermore, we observed a similar effect using cocaine where a dose of 300 mg/kg of GVG reduced cocaine-induced increases in NAc DA levels by 25 % while a dose of 150 mg/kg completely abolished the expression and acquisition phase of cocaine-induced CPP (Dewey et al, 1997. Together, these data suggest at least two plausible and perhaps combined explanations.…”

“…Therefore, our analysis included the corpus striatum bilaterally and the cerebellum. Marshall et al (1995) have demonstrated that nicotine increased DA equally in both the NAc and the corpus striatum, while our own microdialysis data demonstrates that GVG decreases DA concentrations equally in both regions as well (Dewey et al, 1997). These primate data further support the use of this imaging technique to evaluate the functional consequences of pharmacologic challenges in the living brain.…”

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

“…First, the present ineffectiveness of GVG on NAc DA is unlikely to have been due to the doses being too low, because such doses (25-300 mg/kg) dose-dependently inhibited cocaine-or sucrose-triggered reinstatement (present study) and increase extracellular glutamate levels (Xi et al, unpublished data); and these are the effective doses used in other experiments with drug self-administration, conditioned place preference, locomotor sensitization and intracranial brain stimulation reward (Kushner et al, 1997(Kushner et al, , 1999Dewey et al, 1997Dewey et al, , 1998Barrett et al, 2005;Gardner et al, 2002). Second, the present ineffectiveness is also unlikely to have been due to inappropriate GVG pretreatment time, because GVG, when administered either 1, 3 or 6 h prior to cocaine priming, still failed to alter either basal or cocaine-enhanced NAc DA (the present study), but inhibited cocaine self-administration, cocaine-induced place preference and brain stimulation reward (Kushner et al, 1997(Kushner et al, , 1999Dewey et al, 1997Dewey et al, , 1998Barrett et al, 2005). Third, the present ineffectiveness would appear to be unrelated to animals' cocaine experience, because the same ineffectiveness was observed in both cocaine-treated rats and drug naïve rats.…”

Evaluation of the cardiovascular and subjective effects of rivastigmine in combination with methamphetamine in methamphetamine-dependent human volunteers

“…Of particular interest, nicotinic ACh receptors modulate activity of GABA-interneurons in the VTA (Erhardt et al 2002;Mansvelder et al 2002), a brain region known to play a critical role in modulating reward learning. Activation of GABA interneurons inhibits DA outflow to the nucleus accumbens and may consequently reduce drug-seeking behavior and craving (Dewey et al 1997). The direct and indirect effects of AChE inhibitors, like rivastigmine, on DA system functioning are predicted to be the mechanism of action for attenuating cardiovascular and subjective effects observed in this report.…”