Local GABA_A Receptor-Mediated Suppression of Dopamine Release within the Nucleus Accumbens

Abstract

Benzodiazepines make up a class of psychoactive drugs that act as allosteric co-activators of the inhibitory GABA A receptor. These drugs are useful for the treatment of several psychiatric disorders but also hold considerable abuse liability. Despite the common use and misuse of benzodiazepines, the mechanisms through which these drugs exert their reinforcing effects remain incompletely understood. Transient phasic increases in dopamine levels are believed to play an important role in defining the reinforcing properties of drugs of abuse, and we recently demonstrated that systemic administration of benzodiazepines increased the frequency of these events but concomitantly reduced their amplitude. This observation provides insight into the pharmacological effects of benzodiazepines on dopamine signaling, but the processes through which benzodiazepines drive changes in phasic dopamine signals remain unclear. In these studies, we investigated the mechanisms through which benzodiazepines may reduce the phasic dopamine transient amplitude. We tested the effect of the benzodiazepine diazepam and the GABA A agonist muscimol on evoked dopamine release from nucleus accumbens brain slices using fast scan cyclic voltammetry. We found that both diazepam and muscimol reduce dopamine release and that reductions in dopamine release following GABA A receptor activation can be blocked by co-application of a GABA B receptor antagonist. These results suggest that activation of GABA A receptors in the nucleus accumbens decreases dopamine release by disinhibition of local GABA signaling and subsequent activation of GABA B receptors. Overall, this work provides a putative mechanism through which benzodiazepines reduce the amplitude of phasic dopamine release in vivo.

Sex‐specific alterations in GABA receptor‐mediated responses in laterodorsal tegmentum are associated with prenatal exposure to nicotine

“…Similar to other GABAR-focused studies using brain slices (Brodnik, Batra, Oleson, & Espana, 2019;Galeffi, Sah, Pond, George, & Schwartz-Bloom, 2004;Schmidt, Boller, Ozen, & Hall, 2001;Vizuete et al, 2019;Wollman, Levine, & Fregosi, 2018), muscimol was used as the agonist to examine differences in GABA A R functionality associated with PNE. Muscimol is known to exhibit high affinity for synaptically located GABA A R receptors comprised of two α 1-6 , two β 1-4 and one subunit of γ 1-3 δ, ε, ϴ or π, however, it also acts as a partial agonist at the GABA Aρ R subtype (Connolly & Wafford, 2004;Kusama et al, 1993;Woodward, Polenzani, & Miledi, 1993).…”

A unique multi-synaptic mechanism regulates dopamine release in the nucleus accumbens during adolescence

“…Bath application of -Ctx increases dopamine release in adolescents, indicating that blocking 6 nAChRs leads to disinhibition of dopamine release in adolescents, but not adults. GABA has been shown to inhibit terminal dopamine release (Pitman et al, 2014;Melchior et al, 2015;Brodnik et al, 2019;Lopes et al, 2019) indicating that -Ctx could be reducing GABA tone in adolescents. In addition, some striatal GABA interneurons express nAChRs (see Tepper et al, 2018)( Figure 4C).…”

“…(C) We next hypothesized that the age-related differences in 6-containing nAChR-modulation of dopamine release may be mediated by -Ctx causing reduction of GABA signaling in adolescents. GABA receptors regulate dopamine release (Brodnik et al, 2019) and nAChRs are found on GABA interneurons (Tepper et al, 2018). A schematic shows potential localization of nAChRs and GABA receptors in the nucleus accumbens core.…”

Striatal low-threshold spiking interneurons locally gate dopamine during learning

“…Importantly, local microcircuitry gates dopamine at the terminals, regulating the magnitude, spread, timing, and duration of dopamine signals 7 . A range of local homosynaptic and heterosynaptic mechanisms directly regulate dopamine at striatal terminals 7 , including striatal GABA tone [8][9][10] . Given the dynamic activity of LTSIs during reward retrieval, we hypothesized that LTSIs might provide a novel GABAergic mechanism of local dopamine regulation in the striatum with significant implications for learning.…”

“…Growing evidence points to a clear role of tonic GABA signaling locally modulating dopamine release in the striatum via both GABA A and GABA B transmission [8][9][10] . As LTSIs are tonically active in striatal slices, they are a compelling candidate source for this modulatory GABAergic tone.…”