Ventral Tegmental Area GABA Neurons Are Resistant to GABA(A) Receptor-Mediated Inhibition During Ethanol Withdrawal.

The neural mechanisms underlying alcohol dependence are not well-understood. GABAergic neurons in the ventral tegmental area (VTA) are a relevant target for ethanol. They are inhibited by ethanol at physiologically-relevant levels in vivo and display marked hyperexcitability during withdrawal. In the present study, we examined the effects of the GABA(A) receptor agonist muscimol on VTA neurons ex vivo following withdrawal from acute and chronic ethanol exposure. We used standard cell-attached mode electrophysiology in the slice preparation to evaluate the effects of muscimol on VTA GABA neuron firing rate following exposure to acute and chronic ethanol in male CD-1 GAD-67 GFP mice. In the acute condition, the effect of muscimol on VTA neurons was evaluated 24 h and 7 days after a single in vivo dose of saline or ethanol. In the chronic condition, the effect of muscimol on VTA neurons was evaluated 24 h and 7 days after either 2 weeks of twice-daily IP ethanol or saline or following exposure to chronic intermittent ethanol (CIE) vapor or air for 3 weeks. VTA GABA neuron firing rate was more sensitive to muscimol than DA neuron firing rate. VTA GABA neurons, but not DA neurons, were resistant to the inhibitory effects of muscimol recorded 24 h after a single ethanol injection or chronic ethanol exposure. Administration of the NMDA receptor antagonist MK-801 before ethanol injection restored the sensitivity of VTA GABA neurons to muscimol inhibition. Seven days after ethanol exposure, VTA GABA neuron firing rate was again susceptible to muscimol's inhibitory effects in the acute condition, but the resistance persisted in the chronic condition. These findings suggest that VTA GABA neurons exclusively undergo a shift in GABA(A) receptor function following acute and chronic exposure. There appears to be transient GABA(A) receptor-mediated plasticity after a single exposure to ethanol that is mediated by NMDA glutamate receptors. In addition, the resistance to muscimol inhibition in VTA GABA neurons persists in the dependent condition, which may contribute to the the hyperexcitability of VTA GABA neurons and inhibition of VTA DA neurons during withdrawal as well as the motivation to seek alcohol.

A meta-analysis of the relationship between symptom severity of Posttraumatic Stress Disorder and executive function.

INTRODUCTION: Some studies of Posttraumatic Stress Disorder (PTSD) find executive dysfunction, whereas others do not. We meta-analytically examined the association between executive function and PTSD and used meta-regression to examine the potential moderating effect of PTSD severity on executive function. METHODS: We conducted a meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We identified published peer-reviewed articles containing measures of executive function and PTSD symptom severity in subjects with PTSD compared to trauma-unexposed controls or trauma-exposed controls without PTSD, or both. We calculated an effect size for each study containing at least one measure of executive function and PTSD symptom severity. RESULTS: PTSD subjects for whom the Clinician-Administered PTSD Scale (CAPS) score was available had worse executive function compared to both trauma-unexposed controls (g = 0.464, p < .001) and to trauma-exposed controls without PTSD (g = 0.414, p = .001), as did PTSD subjects for whom the Mississippi Scale for Combat-Related PTSD (M-PTSD) score was available (g = 0.390, p < .001). Neither CAPS nor M-PTSD scores significantly moderated the effect size of executive function. CONCLUSIONS: PTSD is associated with executive dysfunction, but this association was not moderated by PTSD symptom severity, suggesting that once PTSD occurs, executive dysfunction may occur regardless of PTSD severity.

Ventral tegmental area GABA neurons and opiate motivation.

RATIONALE: Past research has demonstrated that when an animal changes from a previously drug-naive to an opiate-dependent and withdrawn state, morphine's motivational effects are switched from a tegmental pedunculopontine nucleus (TPP)-dependent to a dopamine-dependent pathway. Interestingly, a corresponding change is observed in ventral tegmental area (VTA) GABAA receptors, which change from mediating hyperpolarization of VTA GABA neurons to mediating depolarization. OBJECTIVES: The present study investigated whether pharmacological manipulation of VTA GABAA receptor activity could directly influence the mechanisms underlying opiate motivation. RESULTS: Using an unbiased place conditioning procedure, we demonstrated that in Wistar rats, intra-VTA administration of furosemide, a Cl(-) cotransporter inhibitor, was able to promote a switch in the mechanisms underlying morphine's motivational properties, one which is normally observed only after chronic opiate exposure. This behavioral switch was prevented by intra-VTA administration of acetazolamide, an inhibitor of the bicarbonate ion-producing carbonic anhydrase enzyme. Electrophysiological recordings of mouse VTA showed that furosemide reduced the sensitivity of VTA GABA neurons to inhibition by the GABAA receptor agonist muscimol, instead increasing the firing rate of a significant subset of these GABA neurons. CONCLUSIONS: Our results suggest that the carbonic anhydrase enzyme may constitute part of a common VTA GABA neuron-based biological pathway responsible for controlling the mechanisms underlying opiate motivation, supporting the hypothesis that VTA GABAA receptor hyperpolarization or depolarization is responsible for selecting TPP- or dopamine-dependent motivational outputs, respectively.