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The physiological mechanism through which food restriction (FR) enhances the biobehavioral actions of psychostimulants is unknown but may involve the gut peptide ghrelin. Plasma levels of ghrelin are increased by FR and reduced by eating. Moreover, systemically administered ghrelin crosses into the brain and is known to augment the locomotor-stimulating effects of cocaine [COC: Wellman et al, 2004]. This study sought to determine whether pretreatment with ghrelin (5 nmol) would enhance the rewarding properties of COC (0.0, 0.312, 0.625, or 1.25 mg/kg i.p.) as measured by conditioned place preference (CPP). Adult male Sprague-Dawley rats were given free access to both sides of a CPP chamber to determine initial side preference. The rats were then confined for 30 min to either their preferred side or non-preferred side on 8 consecutive days. When rats were confined to the least preferred side, each was injected with 0.5 ml (i.p.) of either ghrelin (5 nmol) or saline 1 h before the conditioning trial and then injected (i.p.) with one of the COC doses immediately prior to the conditioning trial. On alternate days, rats were injected with vehicle one hour before and again immediately before the conditioning trial. Place preference scores were computed as the differences in time (min) spent on the least preferred side of the chamber for the pre-test and the post conditioning test, covaried by the initial degree of preference (% time spent on the black side during the pre-test). These analyses indicated a significant interaction between ghrelin pretreatment and COC dose on changes in preference scores. Significantly higher place preference scores were noted for rats treated with either 0.312 or 0.625 mg/kg COC doses, but only when these COC doses were preceded by administration of 5 nmol ghrelin. In contrast, saline pretreated rats exhibited significant CPP at the 1.25 mg/kg COC dose, but the ghrelin pretreated group did not. These results provide partial support for the contention that ghrelin pretreatment can augment the rewarding effects of subthreshold doses of COC in a CPP procedure. Moreover, these findings are consistent with the view that ghrelin may play a role in the capacity of FR to augment psychostimulant action.

Rationale: Variation in dietary constituents such as carbohydrate are known to alter psychostimulant function in brain. Relatively few studies have examined the reinforcing effects of psychostimulants in subjects maintained on high-fat diets. The present experiment compared the rate of acquisition of an operant response for intravenous (i.v.) cocaine infusions (0.2 mg/kg) in rats fed either a chow-pellet diet or a 35.9% (by weight) high-fat diet for 45 days prior to cocaine selfadministration testing.Results: Rats maintained on a high-fat diet for 45 days exhibited diminished acquisition of cocaine self-administration, and this effect was not a function of dietary-induced obesity. Conclusions:The results suggest that prolonged exposure to a high-fat diet diminishes the efficacy of cocaine reinforcement.

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