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Control of glutamate and GABA release by nociceptin/orphanin FQ in the rat lateral amygdala - PubMed

  • ️Mon Jan 01 2001

Control of glutamate and GABA release by nociceptin/orphanin FQ in the rat lateral amygdala

S Meis et al. J Physiol. 2001.

Abstract

The actions of the heptadecapeptide termed nociceptin or orphanin FQ (N/OFQ) and the recently discovered putative precursor product nocistatin were examined on synaptic transmission in putative projection cells of the rat lateral amygdala using the whole-cell patch-clamp technique. N/OFQ decreased evoked non-NMDA receptor-mediated excitatory postsynaptic current (EPSC) amplitudes in a concentration-dependent manner, with a half-maximal inhibitory effect elicited by 21.8 +/- 7.5 nM and a Hill coefficient of 0.8 +/- 0.2 (n = 22). Responses were maximally suppressed to 70.3 +/- 1.7 % of the control value. The effect of N/OFQ was prevented by 1 microM [Phe1[psi](CH2-NH)Gly2]NC(1-13)NH2 (Phe[psi]N/OFQ), a substance known as an antagonist/partial agonist of the ORL receptor. GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs) elicited through intra-amygdaloid stimulation were reduced to 48.0 +/- 6.8 % by 1 microM N/OFQ (n = 5). Nocistatin had no measurable effect on evoked synaptic currents or membrane properties of recorded neurons. N/OFQ reduced the frequency of spontaneous miniature EPSCs and IPSCs to 74.0 +/- 2.6 % and 84.4 +/- 1.1 %, respectively, without affecting the amplitudes. The present findings indicate that N/OFQ, but not nocistatin, inhibits the release of glutamate and GABA in the lateral amygdala, presumably by acting on presynaptic release sites. These mechanisms may add to the role of N/OFQ in reducing stress vulnerability as recently proposed on the basis of behavioural and genetic approaches.

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Figures

Figure 5
Figure 5. Lack of effect of nocistatin in LA neurons

Normalized EPSCs (A) or IPSCs (b) before and after addition of nocistatin (10-100 μ

m

). C and D, typical responses of LA neurons to nocistatin and N/OFQ. Note that nocistatin did not affect the membrane current or modulate the N/OFQ-induced outward current.

Figure 1
Figure 1. Basic properties of EPSCs and IPSCs in LA projection neurons

Schematic representation of a coronal slice illustrating the location of the LA and the position of the stimulating electrodes above the external capsule (a) or the basolateral amygdaloid complex (BLA, b; modified from Paxinos & Watson, 1986). A, blockade of EPSCs (evoked by stimulation of the external capsule) with the non-NMDA receptor antagonist NBQX. B, blockade of IPSCs (elicited by intra-amygdaloid stimulation) with the GABAA antagonist bicuculline. Traces in A and B represent averages of 20 responses obtained immediately before application of the drugs and after a steady-state effect had been reached. Neurons were voltage clamped at a holding potential of -70 mV. Recordings in A were obtained in the presence of bicuculline (10 μ

m

), recordings in B in the presence of NBQX (10 μ

m

).

Figure 2
Figure 2. Suppression of evoked excitatory responses by N/OFQ

A, averaged EPSCs recorded before and after addition of N/OFQ at 10 n

m

, 100 n

m

and 1 μ

m

. Traces represent averages of 20 responses obtained immediately before application of the drugs and after a steady-state effect had been reached. B, time course of the depression of normalized EPSC amplitudes by N/OFQ at the respective concentrations. C, concentration-response relationship of the N/OFQ effect. Data are means from measurements in different numbers of cells, as indicated near the data points. The EC50 and Hill values obtained from the curve were 21.8 n

m

and 0.8, respectively, with a mean maximal inhibition to 70.3 % of the control value.

Figure 3
Figure 3. Antagonism of N/OFQ-induced EPSC suppression by PheψN/OFQ

A, lack of effect on EPSCs by 1 μ

m

PheψN/OFQ. B, prevention of N/OFQ action on EPSCs through pre-application of 1 μ

m

PheψN/OFQ.

Figure 4
Figure 4. Suppression of evoked inhibitory responses by N/OFQ

A, averaged IPSCs recorded before and after addition of N/OFQ at 1 and 10 μ

m

. Traces represent averages of 20 responses obtained immediately before application of the drug and after a steady-state effect had been reached. B, time course of the depression of normalized IPSC amplitudes by N/OFQ at the respective concentrations.

Figure 6
Figure 6. Effect of N/OFQ on mEPSCs

A, examples of mEPSCs recorded in the presence of 1 μ

m

TTX before (upper traces) and during action of N/OFQ (lower traces). Averaged mEPSCs are shown at an expanded time scale, as indicated. B and C, cumulative amplitude (b) and inter-event interval (C) frequency distributions obtained from the same neuron shown in A before addition of N/OFQ and after a steady-state effect had been reached. Note that N/OFQ did not affect the amplitude of mEPSCs, but shifted mEPSC inter-event intervals to larger values. D, time course of the N/OFQ effect. Only cells which were affected by N/OFQ are included. E and F, relative mEPSC amplitude (E) and frequency (F) pooled during control conditions and after addition of N/OFQ demonstrate a significant decrease in mEPSC frequency to 74.0 %, whereas the mean amplitude was left unchanged.

Figure 7
Figure 7. Effect of N/OFQ on mIPSCs

A, examples of mIPSCs recorded in the presence of 1 μ

m

TTX before (upper traces) and during action of N/OFQ (lower traces). Averaged mIPSCs are shown at an expanded time scale, as indicated. B and C, cumulative amplitude (b) and inter-event interval (C) frequency distributions obtained from the same neuron shown in A before addition of N/OFQ and after a steady-state effect had been reached. Note that N/OFQ did not affect the amplitude of mIPSCs, but shifted mIPSC inter-event intervals to larger values. D, time course of the N/OFQ effect. E and F, relative mIPSC amplitude (E) and frequency (F) pooled during control conditions and after addition of N/OFQ demonstrate a significant decrease in mIPSC frequency to 84.4 %, whereas the mean amplitude was left unchanged.

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