Responses to drugs of abuse and non-drug rewards in leptin deficient ob/ob mice

Abstract

Rationale Although leptin receptors are found in hypothalamic nuclei classically associated with homeostatic feeding mechanisms, they are also present in brain regions known to regulate hedonic-based feeding, natural reward processing, and responses to drugs of abuse. The ob/ob mouse is deficient in leptin signaling, and previous work has found altered mesolimbic dopamine signaling and sensitivity to the locomotor activating effects of amphetamine in these mice. Objectives We directly assessed responses to three drugs of abuse and non-drug rewards in the leptin-deficient ob/ob mouse. Methods Ob/ob mice were tested in assays of sweet preference, novelty seeking, and drug reward/reinforcement. Results In assays of novelty seeking, novel open field activity and operant sensation seeking were reduced in ob/ob mice, although novel object interaction and novel environment preference were comparable to wild types. We also found that ob/ob mice had specific phenotypes in regard to cocaine: conditioned place preference for 2.5 mg/kg was increased, while the locomotor response to 10 mg/kg was reduced, and cocaine self-administration was the same as wild types. Ob/ob mice also acquired self-administration of the potent opioid remifentanil, but breakpoints for the drug were significantly reduced. Finally, we found significant differences in ethanol drinking in ob/ob mice that correlated negatively with body weight and positively with operant sensation seeking. Conclusions In conclusion, ob/ob mice displayed task-specific deficits in novelty seeking and dissociable differences in reward/reinforcement associated with cocaine, remifentanil, and ethanol.

Effects of methamphetamine on locomotor activity and thalamic gene expression in leptin-deficient obese mice

“…It should be noted that locomotor activity tends to be depressed in obese mice, probably due to abnormal neuroendocrine function [21]. Locomotor responses to systemic administration of 10 mg/kg cocaine was reduced in ob/ob mice, while conditioned place preference was increased by 2.5 mg/kg of cocaine [22]. These results contributed new important information about METH effects on females, extending our group’s previous report [14].…”

Comparison of cocaine reinforcement in lean and obese Zucker rats: Relative potency and reinstatement of extinguished operant responding

“…The fact that the lean and obese Zucker rats in the current report were comparable in cocaine self-administration, including acquisition, supports the conclusions of Wellman et al because both groups were fed the same standard diet. Similarly, a recent report found that ob/ob mice with deficient leptin-receptor signaling were no different than their lean, wild-type counterparts in self-administration of a dose of cocaine (0.5 mg/kg/inj) under fixed and progressive-ratio schedules of reinforcement (Muelbl et al, 2016), and these animals also had the same standard diet histories. In addition to changes in cocaine self-administration, exposure to a high-fat diet has been reported to enhance the locomotor-stimulating effects of cocaine in adolescent male (Baladi et al, 2012), but not adult male or female (Baladi et al, 2012; Serafine et al, 2014) rats.…”

Reward Capacity Predicts Leptin Dynamics During Laboratory‐Controlled Eating in Women as a Function of Body Mass Index

“…Recent pre-clinical reports provide emerging mechanistic evidence for the role of leptin in reward functioning beyond food-related hedonic capacity. Central or peripheral leptin administration significantly attenuates cocaine-mediated reward processing ( 13 ), while obese, leptin-deficient ob/ob mice exhibit abnormal responses to standard reward tasks and to drugs of abuse (cocaine, opioids, and ethanol) compared to wild-type mice ( 14 ), suggesting leptin’s blunting of reward capacity may extend to non-food substances and other primary rewards. The extent to which these functions systematically differ according to fat mass have not been well-explored in humans.…”