GABAA receptor drugs and neuronal plasticity in reward and aversion: focus on the ventral tegmental area

Abstract

GABAA receptors are the main fast inhibitory neurotransmitter receptors in the mammalian brain, and targets for many clinically important drugs widely used in the treatment of anxiety disorders, insomnia and in anesthesia. Nonetheless, there are significant risks associated with the long-term use of these drugs particularly related to development of tolerance and addiction. Addictive mechanisms of GABAA receptor drugs are poorly known, but recent findings suggest that those drugs may induce aberrant neuroadaptations in the brain reward circuitry. Recently, benzodiazepines, acting on synaptic GABAA receptors, and modulators of extrasynaptic GABAA receptors (THIP and neurosteroids) have been found to induce plasticity in the ventral tegmental area (VTA) dopamine neurons and their main target projections. Furthermore, depending whether synaptic or extrasynaptic GABAA receptor populations are activated, the behavioral outcome of repeated administration seems to correlate with rewarding or aversive behavioral responses, respectively. The VTA dopamine neurons project to forebrain centers such as the nucleus accumbens and medial prefrontal cortex, and receive afferent projections from these brain regions and especially from the extended amygdala and lateral habenula, forming the major part of the reward and aversion circuitry. Both synaptic and extrasynaptic GABAA drugs inhibit the VTA GABAergic interneurons, thus activating the VTA DA neurons by disinhibition and this way inducing glutamatergic synaptic plasticity. However, the GABAA drugs failed to alter synaptic spine numbers as studied from Golgi-Cox-stained VTA dendrites. Since the GABAergic drugs are known to depress the brain metabolism and gene expression, their likely way of inducing neuroplasticity in mature neurons is by disinhibiting the principal neurons, which remains to be rigorously tested for a number of clinically important anxiolytics, sedatives and anesthetics in different parts of the circuitry.

Acute Nicotine Exposure Alters Ventral Tegmental Area Inhibitory Transmission and Promotes Diazepam Consumption

“…Plasticity of inhibitory transmission on VTA GABA neurons can modify the pharmacological action of addictive drugs that target GABA A R (Vashchinkina et al, 2014). In agreement with previous studies (O'Brien and White, 1987;Tan et al, 2010), our findings show that positive modulation of GABA A R signaling by diazepam attenuates VTA GABA neuron activity in drug naïve animals.…”

Addiction and the itch‐scratch cycle. What do they have in common?

“…In addition, preclinical work has shown that activation of µ‐opioid receptors is also required for the acute rewarding and reinforcing effects of drugs. Other neurotransmitter systems, including serotonin (5‐hydroxytryptamine, 5‐HT) and gamma‐aminobutyric acid (GABA), are believed to contribute to the binge/intoxication stage by modulating DA and opioid systems.…”

Hippocampal-Prefrontal Circuit and Disrupted Functional Connectivity in Psychiatric and Neurodegenerative Disorders

“…The NAc sends GABAergic inhibitory projections to dopaminergic neurons of the VTA [ 19 , 20 ]. VTA has reciprocal projections with many forebrain structures including the NAc, dorsal striatum, amygdala, and mPFC [ 21 ]. Two major subdivisions of the mPFC, IL and the PL, send direct projections to the VTA [ 22 ].…”