Tonic GABAergic inhibition as a new way to regulate mesolimbic dopamine system

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Title: Tonic GABAergic inhibition as a new way to regulate mesolimbic dopamine system
Author: Vashchinkina, Elena
Contributor: University of Helsinki, Faculty of Medicine, Institute of Biomedicine, Pharmacology
Publisher: Helsingin yliopisto
Date: 2013-12-13
Language: en
Thesis level: Doctoral dissertation (article-based)
Abstract: Dopamine (DA) neurons of the ventral tegmental area (VTA) are critical for decision-making and motivation and have also been implicated in the development of addictive behaviors. The activity of these neurons and the subsequent changes in DA concentrations in the target regions of the VTA are strictly regulated by both excitatory and inhibitory inputs. Among those inhibitory inputs, GABAergic transmission is mediated by phasic and tonic currents generated through different GABAA receptor subtypes. Although the phasic currents arising through the activation of synaptic GABAA receptors have been well described, much less is known about extrasynaptic GABAA receptors mediating tonic currents and modulating neuronal activity in the VTA. Here, pharmacologically selective receptor modulators, transgenic mouse models and brain slice electrophysiology were all exploited to probe the role of extrasynaptic GABAA receptors in mediating neuroplasticity in VTA DA neurons. Even though they possess distinct molecular sites of action, gaboxadol (THIP) and ganaxalone (GAN) enhanced tonic inhibition by selective targeting of the extrasynaptic δ subunit-containing GABAA receptors located on VTA GABA neurons. The tonic inhibition induced in these neurons appeared to be sufficient to disinhibit DA neurons and induce persistent neuroplasticity in the glutamate synapses on VTA DA neurons, which resulted from insertion of new GluA2 subunit-lacking AMPA receptors into the synapses. Screening of reward-related behaviors associated with VTA DA activity revealed that THIP failed to induce any reinforcement during self-administration either in mice or baboons. Moreover, both THIP and GAN produced conditioned place aversion in mice. The study performed in δ subunit-knockout mice further supported the proposal that tonic inhibition of the VTA GABA neurons contributes to conditioned aversive behavior and THIP- and GAN-induced neuroplasticity. The c-Fos mapping of brain regions, which could take part in THIP-induced aversive behavioral effects and/or neuroplasticity on VTA DA neurons, revealed the bed nucleus of stria terminalis (BNST), a part of the so-called extended amygdala circuitry, as a possible participant in mediating the aforementioned THIP-induced aversive effects. In summary, these studies demonstrate that tonic inhibition mediated by δ subunit-containing GABAA receptors appears to be a significant component of the inhibition in the VTA, and thus important for the control of motivated behavior.Ei saatavilla
Subject: pharmacology
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