Elsevier

Biological Psychiatry

Volume 71, Issue 8, 15 April 2012, Pages 666-676
Biological Psychiatry

Priority Communication
Nociceptin/Orphanin FQ Blockade of Corticotropin-Releasing Factor-Induced Gamma-Aminobutyric Acid Release in Central Amygdala Is Enhanced After Chronic Ethanol Exposure

https://doi.org/10.1016/j.biopsych.2011.10.032Get rights and content

Background

The central nucleus of the amygdala (CeA) mediates stress- and addiction-related processes. Corticotropin-releasing factor (CRF) and nociceptin/orphanin FQ (nociceptin) regulate ethanol intake and anxiety-like behavior. In the rat, CRF and ethanol significantly augment CeA gamma-aminobutyric acid (GABA) release, whereas nociceptin diminishes it.

Methods

Using electrophysiologic techniques in an in vitro slice preparation, we investigated the interaction of nociceptin and CRF on evoked and spontaneous GABAergic transmission in CeA slices of naive and ethanol-dependent rats and the mechanistic role of protein kinase A.

Results

In neurons from naive animals, nociceptin dose-dependently diminished basal-evoked GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs) by decreasing GABA release and prevented, as well as reversed, CRF-induced augmentation of IPSPs, actions that required PKA signaling. In neurons from ethanol-dependent animals, nociceptin decreased basal GABAergic transmission and blocked the CRF-induced increase in GABA release to a greater extent than in naive controls.

Conclusions

These data provide new evidence for an interaction between the nociceptin and CRF systems in the CeA. Nociceptin opposes CRF effects on CeA GABAergic transmission with sensitization of this effect in dependent animals. These properties of nociceptin may underlie its anti-alcohol and anxiolytic properties and identify the nociceptin receptor as a useful therapeutic target for alcoholism.

Section snippets

Slice Preparation

As previously described (18, 21), we prepared CeA slices from male Sprague-Dawley rats (150–300 g; 7–9 weeks old) that were anesthetized with halothane (3%) and decapitated.

Chronic Ethanol Treatment

We used the standard ethanol inhalation method of The Scripps Research Institute Alcohol Research Center to induce ethanol dependence (Supplement 1) (20, 27). On experiment days, the chronic ethanol-treated rats were maintained in the ethanol vapor chamber until preparation of slices (under ethanol-free conditions). We

Nociceptin Reverses CRF-Induced Enhancement of GABAergic Synaptic Transmission

We recorded intracellularly from 104 CeA neurons by stimulating locally within the CeA. The mean resting membrane potential of these CeA neurons was −76.7 ± 1.3 mV with input resistance of 131.5 ± 5.8 MΩ.

In CeA neurons of naive rats, nociceptin dose-dependently reduced the mean amplitude of evoked IPSPs (Figures 1A and 1B). The lowest concentration of nociceptin tested (100 nmol/mL) produced a slight decrease in evoked IPSPs that was not statistically significant (p > .05; df = 6; t = 2.22),

Discussion

To our knowledge, there are no previous electrophysiologic studies on the interaction between the nociceptin and CRF systems on GABAergic synapses in the CeA and the influence of alcohol dependence on this interaction. Here, we find that nociceptin pretreatment blocks CRF-stimulated GABA release. Additionally, when applied subsequent to CRF, nociceptin reverses the action of CRF. The ability of nociceptin to oppose the CRF effect was stronger in ethanol-dependent rats. Our data also indicate

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