Ethanol Blocks Long-Term Potentiation of GABAergic Synapses in the Ventral Tegmental Area Involving μ-Opioid Receptors

Abstract

It is well documented that ethanol exposure alters GABA (γ-aminobutyric acid)-releasing synapses, and ethanol addiction is associated with endogenous opioid system. Emerging evidence indicates that opioids block long-term potentiation in the fast inhibitory GABAA receptor synapses (LTPGABA) onto dopamine-containing neurons in the ventral tegmental area (VTA), a brain region essential for reward-seeking behavior. However, how ethanol affects LTPGABA is not known. We report here that in acute midbrain slices from rats, clinically relevant concentrations of ethanol applied both in vitro and in vivo prevents LTPGABA, which is reversed respectively by in vitro and in vivo administration of naloxone, a μ opioid receptor (MOR) antagonist. Furthermore, the blockade of LTPGABA induced by a brief in vitro ethanol treatment is mimicked by DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin), a MOR agonist. Pared-pulse ratios are similar in slices 24 hours after in vivo injection with either saline or ethanol. Sp-cAMPS, a stable cAMP analog, and pCPT-cGMP, a cGMP analogue potentiates GABAA-mediated IPSCs in slices from ethanol treated rats, indicating that a single in vivo ethanol exposure does not maximally increase GABA release; instead, ethanol produces a long-lasting inability to generate LTPGABA. These neuroadaptations to ethanol might contribute to early stage of addiction.

Psychotic symptoms in young adults exposed to childhood trauma—A 20year follow-up study

“…There has been considerable interest in the effects of cannabis on brain function (Müller-Vahl and Emrich, 2008) but alcohol has received much less attention. Alcohol interacts with the GABA and endocannabinoid receptor systems (Guan, 2010), both of which are implicated in psychosis (Thompson et al, 2009;Müller-Vahl and Emrich, 2008), and can precipitate alcohol-induced psychotic disorder (Soyka, 2008;Joordan et al, 2009). It is possible that cannabis and alcohol abuse are a reaction to earlier trauma, and certainly high rates of comorbid substance abuse are found in people with PTSD (Leeies et al, in press).…”

Glycine blocks long-term potentiation of GABAergic synapses in the ventral tegmental area

“…The midbrain slices were prepared as described previously (Guan and Ye, 2010). Briefly, Sprague–Dawley rats (21–35 d old) were anesthetized using ketamine/xylazine and then sacrificed.…”

“…As previously described (Guan and Ye, 2010), LTP GABA was induced by stimulating afferents at 100 Hz for 1 s, and the train was repeated twice, 20 s apart (high-frequency stimulation; HFS). After recording the baseline currents, during the drug application and washout, synaptic stimulation was stopped and the recorded neuron was taken from voltage-clamp into bridge mode.…”

“…Changes in synaptic strength are important for persistent pathologies such as drug addiction. In particular, accumulating evidence indicates that long-term potentiation of GABAergic synapses (LTP GABA ) in VTA dopamine neurons increases or decreases in response to the actions of drugs of abuse, including ethanol (Nugent et al, 2007, Nugent et al, 2009, Guan and Ye, 2010). …”

Morphine-induced modulation of LTD at GABAergic synapses in the ventral tegmental area

“…Opiate-induced blockade of LTP GABA could emerge as early as 2 h after morphine exposure and could last up to 5 days. Intriguingly, LTP GABA is also found to be a major target for other addictive drugs (nicotine, cocaine and ethanol) and even stress suggesting that GABAergic plasticity in the VTA may in fact be a common synaptic target for all addictive drugs (Guan and Ye, 2010;Niehaus et al, 2010). It is worthwhile to be mentioned that the common method for identification of DA neurons in the VTA slices is the measurement of a hyperpolarization-activated current (I h ) including the present study.…”