Elsevier

Neuroscience

Volume 153, Issue 1, 22 April 2008, Pages 240-248
Neuroscience

Neuropharmacology
Ethanol dually modulates GABAergic synaptic transmission onto dopaminergic neurons in ventral tegmental area: Role of μ-opioid receptors

https://doi.org/10.1016/j.neuroscience.2008.01.040Get rights and content

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 GABAA 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 GABAB receptor antagonist, did not change ethanol inhibition of IPSCs. Tyr-d-Ala-Gly-N-Me-Phe-Gly-ol enkephalin (DAMGO), a μ-opioid receptor agonist, conversely, silenced VTA GABAergic neurons and inhibited IPSCs. Of note, in the presence of a saturating concentration of DAMGO (3 μM), 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 μ-opioid receptors. This dual modulation of GABAergic transmission by ethanol may be an important mechanism underlying alcohol addiction.

Section snippets

Experimental procedures

All experiments were performed in accordance with the guidelines of the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of the University of Medicine and Dentistry of New Jersey. All efforts were made to minimize animal suffering and to reduce the number of animal used. The experiments were performed on Sprague–Dawley rats aged 14–28 postnatal (P) days.

Ethanol depresses GABAA-receptor-mediated IPSCs of VTA DA neurons

Monosynaptic eIPSCs were evoked in the presence of APV (50 μM) and DNQX (20 μM) at a holding potential of 0 mV; their suppression by BIC (10 μM; Fig. 1A) confirmed that they were mediated by GABAA receptors. As illustrated in Fig. 1A and C, ethanol (40 mM) significantly and reversibly diminished the peak amplitude of eIPSCs (by 23±3%, n=6, P<0.001). To determine whether ethanol inhibits GABAergic synaptic transmission via a pre- or a post-synaptic mechanism, we recorded eIPSCs in response to a

Discussion

Ethanol, at clinically relevant concentrations (10–40 mM) strongly suppressed action potential–dependent GABAergic synaptic transmission onto VTA DA neurons in acute midbrain slices of rats. DAMGO, a MOR agonist mimicked ethanol-induced inhibition of GABAergic transmission. Due to the fact that MORs are mostly expressed on the soma and dendritic area of GABAergic neurons in VTA, this result suggests that ethanol inhibition probably results from suppression of GABAergic neurons in VTA. In

Conclusion

In conclusion, our findings support growing evidence that VTA GABAergic transmission is a crucial target of ethanol.

Acknowledgments

This work was supported by grant AA015925 and AA016964 from the National Institute of Alcohol Abuse and Alcoholism (NIAAA) of the NIH.

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