NOP agonists prevent the antidepressant-like effects of nortriptyline and fluoxetine but not R-ketamine

Abstract

NOP receptor activation inhibits the acute antidepressant effects of nortriptyline and fluoxetine, but not R-ketamine. The present findings contribute to further understand the role played by the N/OFQ-NOP receptor system in regulating mood states.

Role of nociceptin/orphanin FQ and nociceptin opioid peptide receptor in depression and antidepressant effects of nociceptin opioid peptide receptor antagonists

“…The similar antidepressant-like effects are reproduced by systemic injection of non-peptide antagonists J-113397 and SB-612111 in mice as well [111112113]. Recent studies also demonstrate that LY2940094, a selective and orally bioavailable NOP receptor antagonist, significantly reduces immobility in the FST in mice [4112] and rats [5]. Interestingly, LY2940094 in mice reduces immobility in the FST in a dose-dependent manner and the maximal effect by LY2940094 is equivalent to that obtained by imipramine [4].…”

“…Prior icv injection of peptide NOP receptor antagonists, [Nphe 1 ]N/OFQ(1–13)-NH 2 and UFP-101, into mice and rats reduces immobility in forced swim test (FST) in a dose-dependent manner, respectively [50110111], an effect commonly observed after antidepressant treatment. The similar antidepressant-like effects are reproduced by systemic injection of non-peptide antagonists J-113397 and SB-612111 in mice as well [111112113]. Recent studies also demonstrate that LY2940094, a selective and orally bioavailable NOP receptor antagonist, significantly reduces immobility in the FST in mice [4112] and rats [5].…”

“…In addition to FST and TST, NOP receptor antagonists also relieve learned helplessness. For example, NOP receptor antagonists such as SB-612111 and UFP-101 not only reduce escape latencies but also increase the number of escapes robustly in the learned helpless models of mice [112114]. The antidepressant-like effects of NOP receptor antagonists are also found in other animal models of depression.…”

“…Unexpectedly, icv injection of N/OFQ in mice fails to augment the immobility in the FST per se [111], while N/OFQ reverses the decrease in immobility induced by NOP receptor antagonists when given as a combination [110113]. Although it is possible that the lack of N/OFQ effects for increasing immobility may be attributable to relatively high baseline immobility in one study [111], other lines of evidence demonstrate that N/OFQ, SR-8993 and RO 65-6570, NOP receptor agonists, show no significant effect on the baseline immobility in the FST [112120]. Moreover, N/OFQ and RO-6570 are found not to affect baseline immobility or helpless behavior such as escape latency and number of escapes in the in the TST and LH, respectively [110112].…”

“…Although it is possible that the lack of N/OFQ effects for increasing immobility may be attributable to relatively high baseline immobility in one study [111], other lines of evidence demonstrate that N/OFQ, SR-8993 and RO 65-6570, NOP receptor agonists, show no significant effect on the baseline immobility in the FST [112120]. Moreover, N/OFQ and RO-6570 are found not to affect baseline immobility or helpless behavior such as escape latency and number of escapes in the in the TST and LH, respectively [110112]. These results suggest that N/OFQ-NOP signaling may be fully activated during the FST, TST, and LH, and thus exogenous N/OFQ administration may not affect baseline behavior in the FST, TST or LH, indicating a ceiling effect.…”