Antidepressant-like effects of the nociceptin/orphanin FQ receptor antagonist UP-101: new evidence from rats and mice

Receptor antagonist and knockout studies have demonstrated that blockade of signalling via nociceptin/ orphanin FQ (N/OFQ) and its receptor (NOP) has antidepressant-like effects in mice submitted to the forced swimming test (FST). The aim of the present study was to explore further the antidepressant-like properties of the NOP antagonist UFP-101 in different species (mouse and rat) and using different assays [FST and tail suspension test (TST)], and to investigate the mechanism(s) involved in its actions. UFP-101 (10nmol i.c.v.) reduced immobility time of Swiss mice in the TST (mean +/- SEM) from 179 +/- 11 to 111 +/- 10 s. N/OFQ (1 nmol i.c.v.) was without effect per se, but fully prevented the effect of UFP-101. The spontaneous immobility time of NOP-/- CD1-C57BL/6J-129 mice in the TST was much lower than that of wild-type (NOP+/+) littermates (75 +/- 11 vs. 144 +/- 17 s) or of Swiss mice. UFP-101 (10 nmol i.c.v.) decreased immobility time (-65%) and increased climbing time (71%) in rats submitted to the FST. In rat brain slices, N/OFQ (100 nM) triggered robust K+-dependent hyperpolarizing currents in locus coeruleus and dorsal raphe neurons. UFP-101 (3muM) fully prevented N/OFQ-induced currents, but was inactive per se. Flu-oxetine, desipramine (both 30mg/kg i.p.) and UFP-101 (10 nmol i.c.v.) reduced immobility time of mice in the FST. The serotonin synthesis inhibitor p-chlorophenylalanine methylester (PCPA, 4x100 mg/kg per day i.p.) prevented the antidepressant-like effects of fluoxetine and UFP-101 (but not desipramine), whereas N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, neurotoxic for noradrenergic neurons; 50 mg/kg i.p., 7 days beforehand), suppressed only the effect of desipramine. Neither pretreatment affected spontaneous immobility time per se. Thus, UFP-101 exhibits pronounced antidepressant-like effects in different species and animal models, possibly by preventing the inhibitory effects of endogenous N/OFQ on brain monoaminergic (in particular serotonergic) neurotransmission. Participation of the N/OFQ-NOP receptor system in mood modulation sets new potential targets for antidepressant drug development.