14-methoxymetopon, a highly potent [mu] opioid agonist, biphasically affects ethanol intake in Sardinian alcohol-preferring rats

Psychopharmacology (2007) 192:537546 DOI 10.1007/s00213-007-0746-7

ORIGINAL INVESTIGATION

14-methoxymetopon, a highly potent opioid agonist, biphasically affects ethanol intake in Sardinian alcohol-preferring rats

Valentina Sabino & Pietro Cottone & Luca Steardo &

Helmut Schmidhammer & Eric P. Zorrilla

Received: 12 September 2006 / Accepted: 10 February 2007 / Published online: 8 March 2007 # Springer-Verlag 2007

Abstract Rationale Increased opioidergic activity is thought to increase the propensity to consume ethanol. However, the dose monotonicity and receptor subtype for this effect remain uncertain. 14-methoxymetopon is a centrally acting, selective opioid receptor agonist with greater systemic antinociceptive potency than morphine and a putatively improved therapeutic index.Objective To determine whether 14-methoxymetopon influenced voluntary ethanol intake in Sardinian alcohol-preferring (sP) rats.Methods Male sP rats with continuous 2-bottle choice access to ethanol (10% v/v) or water were subjects. The

Valentina Sabino and Pietro Cottone contributed equally to this work.

V. Sabino (*) : P. Cottone : E. P. Zorrilla (*)

Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute,10550 N. Torrey Pines Road, SP30-2400,La Jolla, CA 92037, USAe-mail: [email protected]

V. Sabino : P. Cottone : E. P. ZorrillaHarold L. Dorris Neurological Research Institute, The Scripps Research Institute,La Jolla, CA 92037, USA

P. Cottone : L. Steardo Human Physiology and Pharmacology Department, University of Rome La Sapienza,00185 Rome, Italy

H. Schmidhammer Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck,Innrain 52a, A-6020,Innsbruck, Austria

e-mail: [email protected]

effects of systemic 14-methoxymetopon administration (2, 5, 12.25, 30 g/kg, s.c.) on 4-h ethanol intake were determined. The ability of naltrexone (50 g/kg, s.c.), an opioid antagonist, to block actions of 14-methoxymetopon(12.25, 30 g/kg, s.c.) was examined as were the effects of 14-methoxymetopon (12.25 g/kg, s.c.) on self-administered blood alcohol levels (BALs) and clearance of a passive ethanol bolus (1 g/kg). Finally, the effects of central 14-methoxymetopon administration (0.0003100 ng, i.c.v.) on 4-h ethanol intake were evaluated. Results Systemic 14-methoxymetopon very potently and dose-dependently suppressed ethanol and food intake for 30 min, followed by a greater, longer-lasting, and behaviorally specific increase in ethanol intake. The increased ethanol intake led to threefold higher BALs, was naltrexone-reversible, and not due to altered ethanol clearance. Intracerebroventricular 14-methoxymetopon administration rapidly altered ethanol intake per an inverted U-shaped dose-response function, increasing it at a...