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

Elena Vashchinkina,Teemu Aitta-Aho,Esa R Korpi,Anne Panhelainen

doi:10.3389/fphar.2014.00256

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.

Highlights

GABAA receptor agonists generally depress brain activity
BZs and general anesthetics are able to impair neurogenesis in both young and adult animals (Wu and Castren, 2009; Erasso et al, 2013; Thal et al, 2014). All these facts suggest that GABAA receptor agonists have little potential for neuroplasticity outside the critical periods of brain development, when the role of GABAergic interneurons is obligatory (Hensch and Stryker, 2004)
GABAergic neurons in the lateral part of the central nucleus of amygdala are excited by low acute doses of BZs through disinhibition and this is associated with anxiolytic effects (Beck and Fibiger, 1995; Salminen et al, 1996; Panhelainen and Korpi, 2012)

Summary

INTRODUCTION

GABAA receptor agonists generally depress brain activity. Benzodiazepines (BZs) and other GABAmimetic drugs depress gene expression in the brain, including the neuroplasticity-related genes such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and Fos-genes (Zafra et al, 1991; Huopaniemi et al, 2004). Tan et al (2010) examined a mutant mouse with BZinsensitive α1 subunits, and found that in these mice midazolam was not able to inhibit the firing of VTA GABAergic interneurons, to disinhibit the DA neurons, to induce plasticity at glutamatergic synapses or to support drug-reinforcement behavior. It is possible that BZs are positively reinforcing due to mainly activating and modifying the DA neurons detecting reward whereas the drugs activating the extrasynaptic GABAA receptors lead to conditioned aversion because they activate and induce LTP in the DA neurons involved in negative motivation This hypothesis remains to be carefully tested, the post-study examination of the recording sites for DA neuron plasticity by THIP failed to indicate any anatomical localization within the VTA (Vashchinkina et al, 2012). The glutamatergic receptors appear to be regulated differently depending on the specific phase of the drug effect

CONCLUSION

Method Electrophysiology