The Anxiogenic Drug Yohimbine Reinstates Palatable Food Seeking in a Rat Relapse Model: a Role of CRF1 Receptors

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 a-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 factor 1 (CRF 1 ) 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 CRF 1 antagonists should be considered for the treatment of maladaptive eating habits.

Yohimbine impairs extinction of cocaine-conditioned place preference in an α2-adrenergic receptor independent process

“…It has been recently used in the study of reinstatement of positive valence behaviors (Shepard et al 2004;Ledgerwood et al 2005;Ghitza et al 2006Ghitza et al , 2007. Our data suggest that yohimbine may impair extinction of the learned behavior; thus, the mice may still have a preference for the CS+ (side or lever) when tested.…”

Modulation of food reward by adiposity signals

“…Finally, it will be important to continue simulating the conditions of Westernized society that are associated with increased or excessive consumption of high energy density, highly palatable foods. Although most citizens in Westernized societies currently face little stress in the form of predators or chronic adverse physical conditions, psychological stressors are common in U.S. and European society (54) and thus the addition of a chronic or semi-chronic psychological stress component to studies of food reward should provide valuable new insight into modulation of food reward and reinforcement (55). These studies may be more technically difficult but they will be critical for true translation from what is learned in the laboratory regarding 'food reward', into potentially relevant insights for therapeutic application to the feeding habits and patterns of societies confronted with an obesity epidemic.…”

Peptide YY3-36 Decreases Reinstatement of High-Fat Food Seeking during Dieting in a Rat Relapse Model

“…The yohimbine dose (2 mg/kg, i.p.) is based on our previous work (Shepard et al, 2004;Le et al, 2005;Ghitza et al, 2006). PYY3-36 was injected systemically either 30 min (pellet selfadministration, priming-and cue-induced reinstatement) or 60 min (yohimbine-induced reinstatement) before the test sessions.…”