¹Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA, USA

Correspondence: Dr SA Chen, Laboratory of Clinical and Translational Studies, NIH/NIAAA, Section for the Study of Primate Models of Psychopathology, NIH Animal Center, PO Box 529, Bldg 112, Poolesville, MD 20837, USA. Tel: +1 301 443 0821; Fax: +1 301 496 0630; E-mail: scott.chen@mail.nih.gov

Received 21 June 2005; Revised 8 November 2005; Accepted 9 November 2005; Published online 25 January 2006.

Abstract

The goal of the present study was to develop and validate an animal model of unlimited access to intravenous heroin self-administration combined with responding for food and water to characterize the transition to drug dependence. Male Wistar rats were allowed to lever press for heroin (60 g/kg/0.1 ml infusion/s; fixed ratio 1; 20-s time out) and nosepoke for food and water in consecutive, daily 23-h sessions. Daily heroin intake increased over days, reaching significance by Day 14. Drug-taking increased across the circadian cycle, reflected as increases in both the nocturnal peak and diurnal nadir of heroin intake. Changes in the circadian pattern of food intake and meal patterning preceded and paralleled the changes in heroin intake. By Day 7, the circadian amplitude of feeding was blunted. Nocturnal intake decreased because rats consumed smaller and briefer meals. Diurnal intake increased due to increased meal frequency, whereas total daily food intake decreased. To control for time or experience in the self-administration boxes as a possible confound, rats with saline (no drug) tethers were tested and did not display significant changes in food intake pattern. Body weight gain slowed slightly in heroin rats relative to saline controls. Separate groups of rats revealed that significant physical dependence as measured by physical signs of opiate withdrawal following a naloxone injection (1.0 mg/kg, subcutaneous (s.c.)) was reached by Day 14. Significant increases in heroin intake could be produced using low doses of naloxone (0.003–0.03 mg/kg, s.c.) on days 28–31 of heroin access. After 6 weeks of heroin self-administration, rats injected with buprenorphine (0, 0.01, 0.04, and 0.2 mg/kg, s.c.) showed a dose-dependent reduction in heroin intake. Changes in the pattern of drug and food intake in the present unlimited heroin access model may serve as independent motivational markers for the transition to a drug-dependent state.