The use of the reinstatement model to study relapse to palatable food seeking during dieting

Abstract

Excessive consumption of unhealthy foods is a major public health problem. While many people attempt to control their food intake through dieting, many relapse to unhealthy eating habits within a few months. We have begun to study this clinical condition in rats by adapting the reinstatement model, which has been used extensively to study relapse to drug seeking. In our adaptation of the relapse model, reinstatement of palatable food seeking by exposure to food-pellet priming, food-associated cues, or stress is assessed in food-restricted (to mimic dieting) rats after operant food-pellet self-administration training and subsequent extinction of the food-reinforced responding. In this review, we first outline the clinical problem and discuss a recent study in which we assessed the predictive validity of the reinstatement model for studying relapse to food seeking during dieting by using the anorexigenic drug fenfluramine. Next, we summarize results from our initial studies on the role of several stress- and feeding-related peptides (corticotropin-releasing factor, hypocretin, melanin-concentrating hormone, peptide YY3-36) in reinstatement of palatable food seeking. We then present results from our studies on the role of dopamine and medial prefrontal cortex in stress-induced reinstatement of food seeking. We conclude by discussing potential clinical implications. We offer two main conclusions: (1) the food reinstatement model is a simple, reliable, and valid model to study mechanisms of relapse to palatable food seeking during dieting, and to identify medications to prevent this relapse; (2) mechanisms of relapse to food seeking are often dissociable from mechanisms of ongoing food intake. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Keywords: Dieting; Food; Priming; Reinstatement; Relapse; Self-administration; Stress; cue.

Figure 1. The adaptation of the drug reinstatement model to study relapse to palatable food seeking during dieting

(A) Training phase. Rats are trained to lever press for palatable food pellets every other day under a fixed-ratio-1 (FR-1) 20 sec timeout reinforcement schedule for 9–10 sessions; pellet delivery is paired with the presentation of a discrete tone-light cues. Data are mean±sem number of pellets earned, timeout lever presses, and inactive lever presses during the training sessions. (B) Extinction phase. Lever presses are extinguished in the presence of tone–light cues (for pellet- and yohimbine-induced reinstatement) or without tone-light cues (for cue-induced reinstatement) until rats reach an extinction criterion. Data are mean±sem number of presses on the previously active lever or the inactive lever. (C) Reinstatement testing. Tests are conducted under extinction conditions. During tests for pellet-priming-induced reinstatement rats are given several (typically 4) non-contingent food pellets at the beginning of the test session. During tests for discrete cue-induced reinstatement, lever responding leads to contingent presentation of the tone-light cues. During tests for yohimbine-induced reinstatement, rats are injected with yohimbine (2 mg/kg, i.p.) 30–45 min prior to the start of the test sessions. Data are mean±sem number of presses on the previously active lever in the presence or absence of the reinstating stimuli. Data are based on results from Ghitza (2007). Note: the food reinstatement model has also been successfully used to study mechanisms of context-induced reinstatement of food seeking (Bossert et al., 2006; Hamlin et al., 2006).

Figure 2. Demonstration of the predictive validity of the reinstatement model: effect of fenfluramine on yohimbine- and pellet-priming-induced reinstatement of food seeking in female and male rats

Data are mean±sem number of active lever presses during the reinstatement tests after (A) yohimbine injections or (B) pellet priming; rats were pretreated with vehicle and fenfluramine before the reinstatement tests. Dashed arrows: represent baseline extinction responding in the fenfluramine vehicle condition in the absence of the reinstating stimuli. * Different from the fenfluramine vehicle condition, p<0.05. Data are based results from Pickens et al. (2012).

Figure 3. Effect of a CRF1 receptor antagonist and an alpha-1 adrenoceptor antagonist on yohimbine-induced reinstatement of food seeking

Data are mean±sem number of active lever presses during the tests for vehicle- or yohimbine-induced reinstatement tests after pretreatment with (A) antalarmin and (B) prazosin. * Different from the vehicle condition, p <0.05. Data are based results from Ghitza et al. (2006) and Le et al. (2011).

Figure 4. Dorsal mPFC dopamine D1-family receptors mediate yohimbine-induced reinstatement of food seeking

(A) Systemic SCH23390 (0.01 mg/kg) injections block yohimbine-induced reinstatement; data are mean±sem number of active lever presses during the reinstatement tests. (B) Systemic SCH23390 (0.01 mg/kg) injections block yohimbine-induced Fos expression in dorsal mPFC; data are mean±sem Fos immunoreactive neurons per mm². (C) Dorsal mPFC SCH23390 injections (0.5 or 1.0 μg/side) decrease yohimbine-induced reinstatement; data are mean±sem number of active lever presses during the reinstatement tests. * Different from the SCH 23390 vehicle condition, p <0.05. Data are based on results from Nair et al. (2011).

Figure 5. Yohimbine-induced reinstatement is associated with glutamatergic plasticity in activated (GFP positive) neurons in dorsal mPFC

(A) Yohimbine (2 mg/kg)-induced reinstatement of food seeking; data are mean±sem number of active lever presses during the reinstatement tests. * Different from baseline extinction condition, p<0.05. (B) Reduced AMPA/NMDA current ratios in GFP-positive but not GFP-negative neurons after yohimbine-induced reinstatement. Mean±sem of AMPAR/NMDAR current ratios were determined using an NMDA receptor antagonist (D-APV) application procedure. Example traces show AMPAR (black) and NMDAR-mediated EPSCs (gray) in GFP+ and GFP- dorsal mPFC neurons. * Different from the GFP-negative condition, p<0.05. Data are based on results from Cifani et al. (2012).

Figure 6. Optogenetic inhibition of dorsal mPFC decreases yohimbine-induced neuronal activation and reinstatement of food seeking

(A) Yellow light stimulation inhibits yohimbine (2 mg/kg)-induced Fos activation in the dorsal mPFC hemisphere injected with the halorhodopsin construct (eNpHR3.0). The light stimulation had no effect on yohimbine-induced Fos activation in the other hemisphere injected with the control viral construct (eYFP); data are mean±sem Fos immunoreactive neurons per mm². (B) Yellow light stimulation inhibits yohimbine-induced reinstatement, but not pellet-priming-induced reinstatement; data are mean±sem number of active lever presses during the reinstatement tests. * Different from the eYFP condition, p<0.05. Data are based on results from Calu et al. (2013).