Ethanol dually modulates GABAergic synaptic transmission onto dopaminergic neurons in ventral tegmental area: role of mu-opioid receptors - PubMed (original) (raw)

Ethanol dually modulates GABAergic synaptic transmission onto dopaminergic neurons in ventral tegmental area: role of mu-opioid receptors

C Xiao et al. Neuroscience. 2008.

Abstract

The mesolimbic dopaminergic system, originating from the ventral tegmental area (VTA) is implicated in the rewarding properties of ethanol. VTA dopaminergic neurons are under the tonic control of GABAergic innervations. Application of GABAergic agents changes ethanol consumption. However, it is unclear how acute ethanol modulates GABAergic inputs to dopaminergic neurons in the VTA. This report describes ethanol at clinically relevant concentrations (10-40 mM) dually modulates inhibitory postsynaptic currents (IPSCs). IPSCs were mediated by GABA(A) receptors and were recorded from VTA dopaminergic neurons in acute midbrain slices of rats. Acute application of ethanol reduced the amplitude and increased the paired pulse ratio of evoked IPSCs. Ethanol lowered the frequency but not the amplitude of spontaneous IPSCs. Nevertheless, ethanol had no effect on miniature IPSCs recorded in the presence of tetrodotoxin. These data indicate that ethanol inhibits GABAergic synaptic transmission to dopaminergic neurons by presynaptic mechanisms, and that ethanol inhibition depends on the firing of GABAergic neurons. Application of CGP 52432, a GABA(B) receptor antagonist, did not change ethanol inhibition of IPSCs. Tyr-d-Ala-Gly-N-Me-Phe-Gly-ol enkephalin (DAMGO), a mu-opioid receptor agonist, conversely, silenced VTA GABAergic neurons and inhibited IPSCs. Of note, in the presence of a saturating concentration of DAMGO (3 microM), ethanol potentiated the remaining IPSCs. Thus, ethanol dually modulates GABAergic transmission to dopaminergic neurons in the VTA. Ethanol modulation depends on the activity of VTA GABAergic neurons, which were inhibited by the activation of mu-opioid receptors. This dual modulation of GABAergic transmission by ethanol may be an important mechanism underlying alcohol addiction.

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Figures

Fig. 1

Fig. 1

Ethanol depresses evoked monosynaptic IPSCs (eIPSCs) in putative DA neurons in midbrain slices. A, IPSCs evoked by stimulation within the VTA was reduced by 40 mM ethanol and virtually abolished by 10 µM bicuculline (BIC). Data are averages of 10 traces. B, 40 mM ethanol significantly reduced the first, but enhanced the second of a pair of IPSCs evoked by paired stimuli (at 50 ms interval), thus increasing the paired pulse ratio (PPR). C, Summary of the effects of ethanol on the amplitude and the PPR of eIPSCs. For all figures, numbers in brackets are numbers of recorded neurons. ** p < 0.01, paired t test for ethanol application vs. pre-ethanol control. All IPSCs were recorded from putative DA neurons at a VH of 0 mV with CsF- containing pipette solution, in the presence of APV (50 µM) and DNQX (20 µM).

Fig. 2

Fig. 2

Ethanol decreases the frequency of spontaneous IPSCs (sIPSCs) recorded in VTA DA neurons. A, sIPSCs were abolished by 10 µM bicuculline (BIC). B, 40 mM ethanol reduced the frequency of sIPSCs. C, time course of ethanol suppression of sIPSC frequency in one cell. D, cumulative probability plots confirm that ethanol sharply reduced sIPSC frequency (D1) but not the amplitude (D2). E1–2, Summary of the dose-response relationship of ethanol inhibition of sIPSC frequency (E1) and the effect of 40 mM ethanol on sIPSC frequency in the absence (Control) and presence (CGP) of 1 µM CGP 52432 (E2). * p < 0.05, ** p < 0.01, paired t test for ethanol application vs. pre-ethanol control.

Fig. 3

Fig. 3

Ethanol has no effect on mIPSCs in VTA DA neurons. mIPSCs were recorded in the presence of 1 µM tetrodotoxin (TTX). Typical traces (A) and time course (B) showed that ethanol had no effect on mIPSC frequency. Ethanol did not change the cumulative probability of inter-event intervals (C1) and amplitude (C2) for mIPSCs. Insets show mean % changes (± SEM, n = 9 neurons) induced by 40 mM ethanol.

Fig. 4

Fig. 4

DAMGO (µ-opioid receptor agonist) inhibits IPSCs in VTA DA neurons. A, 3 µM DAMGO hyperpolarized and silenced the spontaneous firings of a putative GABAergic neuron in the VTA in a midbrain slice. B, 3 µM DAMGO suppressed a large portion of eIPSCs, recorded from a putative DA neurons in the VTA. C, DAMGO (3 µM) prominently inhibits sIPSC frequency. D, DAMGO (3 µM) did not change mIPSC frequency. E1–2, Summary of the effect of DAMGO on the amplitude (E1) of eIPSCs, sIPSCs, and mIPSCs and the frequency (E2) of sIPSC and mIPSC. Histograms show mean % changes (± SEM). ** p < 0.01, paired t test for DAMGO application vs. pre-DAMGO control.

Fig. 5

Fig. 5

Ethanol facilitates IPSCs in the presence of DAMGO. All IPSCs were recorded from putative DA neurons in the VTA in slices in the presence of 3 µM DAMGO. A, 40 mM ethanol enhances eIPSC amplitude (upper traces), and decreases paired pulse ratio (PPR, lower traces). B, typical traces (B) and time course (C) showed that 40 mM ethanol increased the frequency of sIPSCs. D, Summary of aforementioned effects of ethanol on eIPSC (D1) and sIPSC (D2). ** p < 0.01, paired t test for ethanol application vs. pre-ethanol control.

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