Effect of novel nociceptin/orphanin FQ-NOP receptor ligands on ethanol drinking in alcohol-preferring msP rats

Abstract

Activation of the NOP receptor by the endogenous ligand nociceptin/orphanin FQ (N/OFQ) reduces alcohol consumption in genetically selected alcohol-preferring Marchigian Sardinian (msP) rats. The present study evaluated the effect of three newly synthesized peptidergic and one brain-penetrating heterocyclic NOP receptor agonists on alcohol drinking in the two bottle choice paradigm. MsP rats were intracerebroventricularly (ICV) injected with the NOP receptor agonists OS-462 (0.5 and 1.0 microg), UFP-102 (0.25 and 1.0 microg) or UFP-112 (0.01 and 0.05 microg), or with Ro 64-6198 (0.3 and 1.0 mg/kg) given intraperitoneally (i.p.) and tested for 10% alcohol consumption. Results showed decreased alcohol consumption after treatment with all three peptidergic NOP receptor agonists (OS-462, UFP-102 and UFP-112). OS-462 (at the 1.0 microg dose) and UFP-102 (at the 0.25 microg dose) induced a significant increase in food intake as well. Surprisingly, Ro 64-6198 was ineffective at the 0.3 mg/kg dose, whereas it increased ethanol and food consumption at the 1.0 mg/kg dose. Pre-treatment with the selective mu-receptor antagonist naloxone (0.5 mg/kg, i.p.) reduced these effects of 1.0 mg/kg of Ro 64-6198. These findings confirm that activation of brain NOP receptors reduces alcohol drinking in msP rats and demonstrate that OS-462, UFP-102 and UFP-112 act as potent NOP receptor agonists. On the other hand, Ro 64-6198 increased alcohol drinking, an effect probably induced by a residual agonist activity of this compound at mu-opioid receptors. Overall, the results indicate that OS-462, UFP-102 and UFP-112 may represent valuable pharmacological tools to investigate the functional role of the brain N/OFQ system.

Fig. 1

Voluntary 10% alcohol intake (g/kg) following subchronic (6 days) ICV treatment with: (A) OS-462 (0.0, 0.5 and 1.0 μg/rat), (B) UFP-102 (0.0, 0.25 and 1.0 μg/rat) and, (C) UFP-112 (0.0, 0.01 and 0.05 μg/rat) in msP rats. OS-462 and UFP-102 were given ICV 10 min before access to ethanol. UFP-112 was ICV injected 30 min before access to ethanol. Data represent the means ± S.E.M. *P < 0.05, **P < 0.01 vs. controls.

Fig. 2

Voluntary 10% alcohol intake (g/kg) following subchronic (7 days) treatment with Ro 64-6198, ((1S,3aS)-8-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5] decan-4-one) (0.0, 0.03 and 1.0 mg/kg, IP) in msP rats. The compound was given alone intraperitoneally 30 min before access to ethanol and data were recorded at A) 30 min and B) 60 min. Alternatively, rats were pretreated with 0.5 mg/kg of naloxone (Nlx) or its vehicle followed by 1.0 mg/kg of Ro 64-6198 (Ro) or its vehicle, respectively. Also in this case data were recorded at C) 30 min and D) 60 min. Data represent the means ± S.E.M. *P < 0.05, **P < 0.01 vs. controls.