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Nociceptin/orphanin FQ presynaptically decreases GABAergic transmission and blocks the ethanol-induced increase of GABA release in central amygdala - PubMed

  • ️Sun Jan 01 2006

Nociceptin/orphanin FQ presynaptically decreases GABAergic transmission and blocks the ethanol-induced increase of GABA release in central amygdala

Marisa Roberto et al. Proc Natl Acad Sci U S A. 2006.

Free PMC article

Abstract

Behavioral studies show that the GABAergic system in the central amygdala (CeA) nucleus has a complex role in the reinforcing effects effects of ethanol and the anxiogenic response to ethanol withdrawal. Opioid peptides and nociceptin/orphanin FQ (nociceptin) within the CeA are implicated also in regulating voluntary ethanol consumption and ethanol relapse. Recently, we reported that basal GABAergic transmission was increased in ethanol-dependent rats, and that acute ethanol increases GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs) in CeA neurons from both naïve and ethanol-dependent rats to the same extent, suggesting lack of tolerance for the acute effect of ethanol. Here, we investigated the effect of nociceptin on IPSCs in CeA neurons and its interaction with ethanol effects on these GABA synapses. We found that nociceptin moderately decreased IPSC amplitudes, acting mostly presynaptically as it increased paired-pulse facilitation ratio of IPSCs and decreased miniature IPSC frequencies (but not amplitudes). Nociceptin also prevented the ethanol-induced augmentation of IPSCs in CeA of naïve rats. Interestingly, in CeA of ethanol-dependent rats, the nociceptin-induced inhibition of IPSCs was increased, indicating an enhanced sensitivity to nociceptin. Nociceptin also blocked the ethanol-induced augmentation of IPSCs in ethanol-dependent rats. Our data suggest that nociceptin has a role in regulating the GABAergic system and opposing the effect elicited by ethanol. Thus, nociceptin may represent a therapeutic target for alleviating alcohol dependence.

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Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.

Nociceptin decreases basal GABAergic transmission in CeA. (A) Nociceptin (Noc) decreases the amplitude of evoked IPSCs in CeA neurons. (Upper) Current records of evoked IPSCs in a CeA neuron from a naïve rat. (Lower) In CeA neurons, nociceptin significantly (P < 0.05; n = 8) decreases the mean amplitudes of evoked IPSCs by 15% over all of the used stimulus strengths, with recovery on washout. (B) Application of nociceptin increases the PPF ratio of IPSCs in CeA neurons. (Upper) Current records of IPSCs in response to two stimuli 50 ms apart in a CeA neuron. (Lower) Pooled data of PPF ratios expressed as the second IPSC amplitude over the first. Nociceptin significantly (∗, P < 0.05) increases the mean PPF ratio by 56%, suggesting a presynaptic effect of nociceptin.

Fig. 2.
Fig. 2.

Nociceptin decreases the frequency but not the amplitude of mIPSCs in CeA neurons. (A) Current traces from a representative CeA neuron from a naïve rat. Nociceptin decreases the frequency of the mIPSCs. (B) Cumulative frequency histogram for the neuron of A showing a shift to the right (lower frequencies) during the application of nociceptin. Data are means from a 2-min recording. (C) Mean (±SEM) frequency of mIPSCs (∗, P < 0.05; n = 7). Nociceptin significantly decreases the mean frequency of mIPSCs. (D) The same group of neurons shows that nociceptin does not alter the mean amplitude of mIPSCs. (E) Cumulative amplitude histogram from the neuron of A showing no changes in the distribution of mIPSC amplitudes.

Fig. 3.
Fig. 3.

Pretreatment with nociceptin prevents the ethanol-induced enhancement of GABAergic transmission in CeA neurons. (A) (Upper) Representative recordings of evoked IPSCs in a CeA neuron. (Lower) Superfusion of nociceptin alone significantly (P < 0.05, n = 6) decreases the mean IPSC amplitudes to 88% of control (as in Fig. 1A) and prevents the enhancement of IPSCs induced by subsequent ethanol (compare with Fig. 4 and ref. 35) in CeA neurons. (B) Nociceptin also significantly (∗, P < 0.05; n = 6) increases the PPF ratio of IPSCs (as in Fig. 1B) and blocks the usual ethanol-induced decrease of PPF ratio (see Fig. 4B and ref. 35). (C) Nociceptin decreases the frequency of mIPSCs. Subsequent addition of ethanol does not increase the mIPSC frequency as normally seen in controls. (D) Mean (± SEM) frequency of mIPSCs for CeA neurons from naïve rats (∗, P < 0.05; n = 3). As in Fig. 2, nociceptin alone significantly decreased the mean mIPSC frequency to 75 ± 10% of control. The subsequent coapplication of ethanol with nociceptin did not alter the frequency of mIPSCs (77 ± 4% of control).

Fig. 4.
Fig. 4.

Pretreatment with acute ethanol increases GABAergic transmission in CeA neurons, and subsequent nociceptin blocks this effect. (A) (Upper) Representative evoked IPSCs in a CeA neuron from a naïve rat. (Lower) Ethanol significantly (P < 0.05; n = 7) increases (to 150% of control) the mean IPSC amplitudes in CeA neurons. Nociceptin in the presence of ethanol abolishes the ethanol-induced facilitation of evoked IPSC amplitude. (B) (Upper) Current traces of paired IPSCs in a CeA neuron from a naïve rat. (Lower) Ethanol significantly (∗, P < 0.05) reduces by 30% the mean PPF ratio of IPSCs. Nociceptin completely blocks this ethanol effect on PPF. (C) Superfusion of ethanol significantly (∗, P < 0.05) increases mean mIPSC frequencies. Nociceptin that was added during the superfusion of ethanol totally blocks this ethanol effect.

Fig. 5.
Fig. 5.

NOPs mediate nociceptin effects on CeA GABA synapses. (Upper) Representative evoked IPSCs recorded at different (a–f) treatment times, as shown in the time-course chart below. (Lower) Time-course of the mean effects of the sequential application of NOP antagonist together with nociceptin and then with ethanol (n = 5; stimulus intensity equal to half-maximal IPSC amplitude). The NOP antagonist blocks the nociceptin-induced inhibition of IPSC amplitudes but does not prevent the ethanol-induced enhancement of IPSCs. Lowercase letters match the time to recordings shown in Upper.

Fig. 6.
Fig. 6.

The nociceptin-induced decrease of evoked and spontaneous GABAergic transmission in CeA is larger in ethanol-dependent compared with naïve rats. (A) (Upper) Representative evoked IPSCs in a CeA neuron from an ethanol-dependent rat. (Lower) Nociceptin markedly decreases the mean IPSC amplitudes, whereas subsequent ethanol has no effect (nociceptin and ethanol curves are superimposable; n = 7), with recovery on washout. (B) (Upper) Representative evoked IPSCs in a CeA neuron from an ethanol-dependent rat. (Lower) Ethanol increases (to 146% of control; n = 6) the mean IPSC amplitudes. Subsequent nociceptin blocks this ethanol effect and further depresses the mean amplitude of IPSCs to 70% of control. (C) Pooled data of PPF ratios of IPSCs in CeA of ethanol-dependent rats. Nociceptin significantly (∗, P < 0.001; n = 6) increases the mean PPF ratio. Ethanol added to nociceptin does not decrease the PPF ratio. (D) In CeA neurons from ethanol-dependent rats, ethanol significantly (∗, P < 0.05; n = 6) increases the mIPSC frequency. Nociceptin not only blocks this ethanol effect on mIPSCs but also significantly (#, P < 0.05, compared with ethanol effect) decreases (to 75% of preethanol condition) the mean mIPSC frequency. (E) The NOP antagonist [Nphe1]nociceptin(–13)NH2 does not significantly (P < 0.05; n = 5) alter the basal evoked IPSC amplitudes (stimulus intensity equal to half-maximal IPSC amplitude) in naïve rats, but significantly (P < 0.05; n = 7) increases their amplitudes in CeA neurons of ethanol-dependent rats. (E) In the same group of neurons as shown in D, nociceptin does not alter the mean amplitude of mIPSCs (n = 6).

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