1. ¹Behavioral Neuroscience Branch, NIDA/IRP/NIH/DHHS, Baltimore, MD, USA
2. ²Clinical Pharmacology and Therapeutics Research Branch, NIDA/IRP/NIH/DHHS, Baltimore, MD, USA
3. ³Laboratory of Medicinal Chemistry, NIDDK/NIH/DHHS, Bethesda, MD, USA

Correspondence: Dr Y Shaham, Behavioral Neuroscience Branch, IRP/NIDA/NIH, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. Tel: +1 410 550 1746; Fax: +1 410 550 1612; E-mail: yshaham@intra.nida.nih.gov

Received 7 July 2005; Revised 14 September 2005; Accepted 12 October 2005; Published online 7 December 2005.

Abstract

The major problem in treating excessive eating is high rates of relapse to maladaptive eating habits during diet treatments; this relapse is often induced by stress or anxiety states. Preclinical studies have not explored this clinical problem. Here, we adapted a reinstatement model (commonly used to study relapse to abused drugs) to examine the role of stress and anxiety in relapse to palatable food seeking during dieting. Rats were placed on restricted diet (75–80% of daily standard food) and for 12 intermittent training days (9 h/day, every other day) lever-pressed for palatable food pellets (25% fat, 48% carbohydrate) under a fixed ratio 1 (20-s timeout) reinforcement schedule. Subsequently, the rats were given 10 daily extinction sessions during which lever presses were not reinforced, and were then injected with yohimbine (an -2 adrenoceptor antagonist that induces stress and anxiety in humans and non-humans) or given a single food pellet to assess reinstatement of food seeking. The rats rapidly learned to lever press for the palatable pellets and across the training days the ratio of timeout nonreinforced lever presses to reinforced lever presses progressively increased more than three-fold, suggesting the development of compulsive eating behavior. After extinction, yohimbine injections and pellet priming reliably reinstated food seeking. The corticotropin-releasing factor₁ (CRF₁) receptor antagonist antalarmin attenuated the reinstatement induced by yohimbine, but not pellet priming. Antalarmin also reversed yohimbine's anxiogenic effects in the social interaction test. These data suggest that CRF is involved in stress-induced relapse to palatable food seeking, and that CRF₁ antagonists should be considered for the treatment of maladaptive eating habits.