Modulation of cue value and the augmentation of heroin seeking in chronically food-restricted male rats under withdrawal.

Food restriction augments drug seeking in abstinent rats. The underlying motivational mechanisms, however, remain unclear. We hypothesized that caloric restriction enhances the incentive value attributed to drug-associated cues and, in turn, augments drug seeking. Male rats were trained to lever-press for heroin, and then moved to the animal colony for a forced-abstinence period. Rats were maintained on free access to food (Sated) or subjected to 14 days of food restriction (FDR). In a series of experiments, we assessed the effect of food-restriction on the incentive value of heroin-associated cues. Tests included performance under a progressive ratio (PR) schedule of reinforcement maintained by heroin-associated cues, acquisition of a novel operant response reinforced by drug-associated cues, effect of food-restriction on operant response reinforced by neutral cues, acquisition of a novel operant response reinforced by drug-associated or neutral cues, and the effect of food-restriction on operant response reinforced by drug-associated or neutral cues, under a discrete choice procedure. Food-restriction did not change breakpoints in PR maintained by heroin-associated cues. FDR rats acquired the novel response at a greater level compared to the Sated group. Food-restriction-induced increase in novel-response rate was observed for both heroin-paired and the neutral cue. Responding for a heroin-associated cue was greater than for the neutral cue in both Sated and FDR groups. Response rate for the neutral cue, however, was greater in the FDR versus Sated group. Our findings suggest that food restriction increases the conditioned motivational properties of environmental stimuli, including, but not exclusive to, heroin-paired cues.

A role for leptin and ghrelin in the augmentation of heroin seeking induced by chronic food restriction.

RATIONAL: Caloric restriction increases the risk of relapse in abstinent drug users. Hormones involved in the regulation of energy balance and food intake, such as leptin and ghrelin, are implicated in drug-related behaviors. OBJECTIVES: We investigated the role of leptin and ghrelin in the augmentation of heroin seeking induced by chronic food restriction. METHODS: Rats self-administered heroin (0.1 mg/kg/infusion) for 10 days followed by 14 days of drug withdrawal. During withdrawal, rats were food restricted to 90% of their original body weight or were given free access to food. In experiment 1, we measured the plasma concentrations of leptin and ghrelin following heroin self-administration and withdrawal. In experiment 2, leptin was administered centrally (2.0 or 4.0 µg; i.c.v.) prior to a heroin-seeking test under extinction conditions. High density of both leptin and ghrelin receptors was previously identified in the ventral tegmental area (VTA), suggesting a direct effect on reward and motivation. Hence, we administered leptin (experiment 3; 0.125 or 0.250 µg/side), or ghrelin receptor antagonist JMV 2959 (experiment 4; 2.0 or 10.0 µg/side) directly into the VTA prior to the heroin-seeking test. RESULTS: Chronic food restriction significantly decreased plasma levels of leptin and elevated plasma levels of ghrelin. Central administration of leptin had no statistically significant effect on heroin seeking. Intra-VTA administration of either leptin or JMV 2959 dose-dependently and selectively decreased heroin seeking in the food-restricted rats. CONCLUSIONS: Leptin and ghrelin transmission in the VTA can modulate the augmentation of heroin seeking induced by chronic food restriction.

Augmentation of Heroin Seeking Following Chronic Food Restriction in the Rat: Differential Role for Dopamine Transmission in the Nucleus Accumbens Shell and Core.

Caloric restriction during drug abstinence increases the risk for relapse in addicts. In rats, chronic food restriction during a period of withdrawal following heroin self-administration augments heroin seeking. The mechanisms underlying this effect are largely unknown. Here, we investigated the role of nucleus accumbens (NAc) shell and core dopamine (DA) in food restriction-induced augmentation of heroin seeking. Rats were trained to self-administer heroin (0.1 mg/kg/infusion) for 10 days. Next, rats were moved to the animal colony for a withdrawal period, during which rats were food restricted to 90% of their original body weight (FDR group) or given unrestricted access to food (sated group). On day 14 of food restriction, rats were returned to the operant conditioning chambers for a heroin-seeking test under extinction conditions. Extracellular DA levels were assessed using in vivo microdialysis. In separate experiments, the DA D1-like receptor antagonist SCH39166 (12.5, 25.0, or 50.0 ng/side) was administered into the NAc before the heroin-seeking test. In the NAc shell, pre-test exposure to the heroin-associated context increased DA only in FDR rats; but in the NAc core, DA increased regardless of feeding condition. Food restriction significantly augmented heroin seeking and increased DA in the NAc shell and core during the test. Intra-NAc shell administration of SCH39166 decreased heroin seeking in all rats. In contrast, in the NAc core, SCH39166 selectively decreased the augmentation of heroin-seeking induced by chronic food restriction. Taken together, these results suggest that activation of the DA D1-like receptor in the NAc core is important for food restriction-induced augmentation of heroin seeking.

Food restriction-induced augmentation of heroin seeking in female rats: manipulations of ovarian hormones.

RATIONALE: Food restriction augments heroin seeking in chronically food-restricted male rats under withdrawal, an effect not yet examined in female rats. Importantly, women and female rats possess an increased vulnerability to drugs of abuse, which may be mediated by fluctuations in ovarian hormones. OBJECTIVES: We investigated the role of estradiol and progesterone in augmented heroin seeking in chronically food-restricted female rats, under withdrawal. METHODS: Female rats self-administered heroin for 10-12 days and were then allowed unrestricted (sated) or restricted access to food (FDR; ∼10 % reduction in body weight) for 14 days. On day 14, rats underwent a heroin-seeking test. Exp. 1: Rats underwent ovariectomy or sham surgery and were treated with a low dose of estradiol (5.0 % in cholesterol; subcutaneous capsule). Exp. 2: Rats underwent ovariectomy and were administered with a high dose of estradiol (0.5 mg/kg; subcutaneous) for 8 days before testing. Exp. 3: Progesterone injections (2.0 mg/kg; subcutaneous) were administered 24 h and 2 h before testing. RESULTS: Food restriction resulted in augmented heroin seeking, compared to sated controls. While ovariectomy had no effect, estradiol replacement attenuated the food restriction effect. Injections of progesterone had no effect on heroin seeking in either the sated or FDR groups. CONCLUSIONS: The effect of food restriction on heroin seeking in female rats under withdrawal is as robust as previously found in males. Interestingly, estradiol replacement, but not progesterone, attenuates the food restriction effect in the ovariectomized rats, possibly due to its anorexic properties.

The effects of chronic food restriction on cue-induced heroin seeking in abstinent male rats.

RATIONALE AND OBJECTIVES: Previous research with an animal model of relapse has shown that acute food deprivation will reinstate extinguished drug seeking. Recent evidence with humans, however, suggests that chronic food restriction rather than acute food deprivation is related to increases in drug taking and relapse, emphasizing a need for an animal model to elucidate the neural mechanisms mediating the effects of chronic food restriction on drug seeking. Here we studied the effects of chronic food restriction during a period of abstinence on heroin seeking in rats. METHODS: Rats were trained to self-administer heroin over 10 days (0.1 mg/kg/infusion; i.v.). Rats were then removed from the operant conditioning chambers and exposed to a mild food restriction (resulting in 10-15 % decrease in body weight) or given unrestricted access to food for 14 days while abstinent. The abstinence period was followed by a drug-seeking test under extinction conditions. Subsequent experiments manipulated the length of restriction and test conditions. RESULTS: Rats that were food restricted throughout the abstinence period demonstrated a robust increase in cue-induced heroin seeking compared to sated rats. Re-feeding prior to testing or decreasing the length of the food restriction period prevented the augmentation of drug seeking. CONCLUSIONS: A combination of chronic food restriction and a concurrent state of hunger appears to be necessary for an increase in cue-induced heroin seeking following abstinence. The procedure presented here may serve as a useful model to study the increased risk for relapse following dietary manipulations in abstinent subjects.