Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) modulate several functions in the central nervous system. UFP-101 is a selective and high affinity NOP receptor antagonist [1], that has been reported to elicit antidepressant-like effects in rodents. The present study investigated the effect of UFP-101 in the chronic mild stress (CMS) paradigm in male Wistar rats. Animals were exposed to CMS for at least seven weeks, to induce a condition of anhedonia (measured as reduced consumption of a sucrose solution). UFP-101 (10 nmol/rat, i.c.v. continuously infused by means of minipumps for 24 days) did not influence sucrose intake in non-stressed animals, but reinstated basal sucrose consumption in stressed animals (+ 40% vs non treated stressed rats), beginning from the second week of treatment. The reference drug fluoxetine (FL, 10 mg/kg, i.p.) produced identical effects. Similarly, in the forced swimming test (FST) performed 2, 9, 16 and 23 days after treatment, UFP-101 reverted the effects of stress in a dose- and time-dependent manner, reducing the time of immobility of stressed rats to the level of non-stressed controls (−78% vs non treated stressed rats); FL produced the same effect from day 9 onwards. Moreover, repeated co-administration of N/OFQ (5 nmol/rat i.c.v., from day 15 to 24) completely prevented the behavioural effects of UFP-101. In previous animal studies the stress/depression condition has been associated to plastic alterations of neuronal networks, including reduced hippocampal volume, neuronal atrophy, cell death and alterations in cell proliferation and cell survival of newly generated neurons in key limbic brain region implicated in depression [2], [3]. Neurotrophic factors (NTFs) such as BDNF and FGF-2 may be involved in the modulation of activitydependent plasticity associated with mood pathologies. Therefore, it was investigated whether the CMS procedure associated with continuous central infusion of UFP-101 can affect NTFs expression, as well as proliferation and survival of hippocampal newborn cells. After in vivo BrdU labelling, all rats were sacrificed on day 24 and their brains were collected for immunohistochemical analysis. Our preliminary data confirm that CMS reduces proliferation of neural stem cells in hippocampus. The 21-day UFP-101 treatment, which did not produce any primary effect on cell proliferation, also did not affect the reduced proliferation observed in stressed animals. Experiments are now in progress to evaluate the NTFs expression levels in discrete brain areas. These findings support the view that blockade of NOP receptor signaling in the brain produces antidepressantlike effects in the CMS protocol, and indicate that the behavioural efficacy of the NOP receptor antagonist UFP- 101 is comparable to that of classical antidepressants. However, this effect does not appear to be mediated by increased hippocampal stem cell proliferation. These findings support the hypothesis that NOP receptor may represent a candidate target for innovative antidepressant drugs.

Influence of UFP-101 central infusion on behavioural and cellular effects in a chronic stress model in the rat.

CIFANI, Carlo;
2010-01-01

Abstract

Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) modulate several functions in the central nervous system. UFP-101 is a selective and high affinity NOP receptor antagonist [1], that has been reported to elicit antidepressant-like effects in rodents. The present study investigated the effect of UFP-101 in the chronic mild stress (CMS) paradigm in male Wistar rats. Animals were exposed to CMS for at least seven weeks, to induce a condition of anhedonia (measured as reduced consumption of a sucrose solution). UFP-101 (10 nmol/rat, i.c.v. continuously infused by means of minipumps for 24 days) did not influence sucrose intake in non-stressed animals, but reinstated basal sucrose consumption in stressed animals (+ 40% vs non treated stressed rats), beginning from the second week of treatment. The reference drug fluoxetine (FL, 10 mg/kg, i.p.) produced identical effects. Similarly, in the forced swimming test (FST) performed 2, 9, 16 and 23 days after treatment, UFP-101 reverted the effects of stress in a dose- and time-dependent manner, reducing the time of immobility of stressed rats to the level of non-stressed controls (−78% vs non treated stressed rats); FL produced the same effect from day 9 onwards. Moreover, repeated co-administration of N/OFQ (5 nmol/rat i.c.v., from day 15 to 24) completely prevented the behavioural effects of UFP-101. In previous animal studies the stress/depression condition has been associated to plastic alterations of neuronal networks, including reduced hippocampal volume, neuronal atrophy, cell death and alterations in cell proliferation and cell survival of newly generated neurons in key limbic brain region implicated in depression [2], [3]. Neurotrophic factors (NTFs) such as BDNF and FGF-2 may be involved in the modulation of activitydependent plasticity associated with mood pathologies. Therefore, it was investigated whether the CMS procedure associated with continuous central infusion of UFP-101 can affect NTFs expression, as well as proliferation and survival of hippocampal newborn cells. After in vivo BrdU labelling, all rats were sacrificed on day 24 and their brains were collected for immunohistochemical analysis. Our preliminary data confirm that CMS reduces proliferation of neural stem cells in hippocampus. The 21-day UFP-101 treatment, which did not produce any primary effect on cell proliferation, also did not affect the reduced proliferation observed in stressed animals. Experiments are now in progress to evaluate the NTFs expression levels in discrete brain areas. These findings support the view that blockade of NOP receptor signaling in the brain produces antidepressantlike effects in the CMS protocol, and indicate that the behavioural efficacy of the NOP receptor antagonist UFP- 101 is comparable to that of classical antidepressants. However, this effect does not appear to be mediated by increased hippocampal stem cell proliferation. These findings support the hypothesis that NOP receptor may represent a candidate target for innovative antidepressant drugs.
2010
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/328382
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