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γ-Aminobutyric acid (GABA) administration improves action selection processes: a randomised controlled trial.

ABSTRACT: In order to accomplish a task goal, real-life environments require us to develop different action control strategies in order to rapidly react to fast-moving visual and auditory stimuli. When engaging in complex scenarios, it is essential to prioritise and cascade different actions. Recent studies have pointed to an important role of the gamma-aminobutyric acid (GABA)-ergic system in the neuromodulation of action cascading. In this study we assessed the specific causal role of the GABA-ergic system in modulating the efficiency of action cascading by administering 800 mg of synthetic GABA or 800 mg oral of microcrystalline cellulose (placebo). In a double-blind, randomised, between-group design, 30 healthy adults performed a stop-change paradigm. Results showed that the administration of GABA, compared to placebo, increased action selection when an interruption (stop) and a change towards an alternative response were required simultaneously, and when such a change had to occur after the completion of the stop process. These findings, involving the systemic administration of synthetic GABA, provide the first evidence for a possible causal role of the GABA-ergic system in modulating performance in action cascading.

SUBMITTER: Steenbergen L

PROVIDER: S-EPMC4521208 | biostudies-other | 2015 Jul

REPOSITORIES: biostudies-other

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Project description:Male rats escalate intravenous self-administration of entactogen psychostimulants, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxymethamphetamine (MDMA) under extended access conditions, as with typical psychostimulants. Here, we investigated whether female rats escalate self-administration of methylone, 3,4-methylenedioxypentedrone (pentylone), and MDMA and then studied consequences of MDMA and pentylone self-administration on GABAA receptor and kappa opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA), a brain area critically dysregulated by extended access self-administration of alcohol or cocaine. Adult female Wistar rats were trained to self-administer methylone, pentylone, MDMA (0.5 mg/kg/infusion), or saline-vehicle using a fixed-ratio 1 response contingency in 6-h sessions (long-access: LgA) followed by progressive ratio (PR) dose-response testing. The effects of pentylone-LgA, MDMA-LgA and saline on basal GABAergic transmission (miniature post-synaptic inhibitory currents, mIPSCs) and the modulatory role of KOR at CeA GABAergic synapses were determined in acute brain slices using whole-cell patch-clamp. Methylone-LgA and pentylone-LgA rats similarly escalated their drug intake (both obtained more infusions compared to MDMA-LgA rats), however, pentylone-LgA rats reached higher breakpoints in PR tests. At the cellular level, baseline CeA GABA transmission was markedly elevated in pentylone-LgA and MDMA-LgA rats compared to saline-vehicle. Specifically, pentylone-LgA was associated with increased CeA mIPSC frequency (GABA release) and amplitude (post-synaptic GABAA receptor function), while mIPSC amplitudes (but not frequency) was larger in MDMA-LgA rats compared to saline rats. In addition, pentylone-LgA and MDMA-LgA profoundly disrupted CeA KOR signaling such as both KOR agonism (1 mM U50488) and KOR antagonism (200 nM nor-binaltorphimine) decreased mIPSC frequency suggesting recruitment of non-canonical KOR signaling pathways. This study confirms escalated self-administration of entactogen psychostimulants under LgA conditions in female rats which is accompanied by increased CeA GABAergic inhibition and altered KOR signaling. Collectively, our study suggests that CeA GABA and KOR mechanisms play a critical role in entactogen self-administration like those observed with escalation of alcohol or cocaine self-administration.

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γ-Aminobutyric acid (GABA) administration improves action selection processes: a randomised controlled trial.

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