Abstract
The regulatory mechanisms underlying the response to addictive drugs are complex, and increasing evidence indicates that there is a role for appetite-regulating pathways in substance abuse. Leptin, an important adipose hormone that regulates energy balance and appetite, exerts its physiological functions via leptin receptors. However, the role of leptin signaling in regulating the response to cocaine remains unclear. Here we examined the potential role of leptin signaling in cocaine reward using a conditioned place preference (CPP) procedure. Our results showed that inhibition of leptin signaling by intracerebroventricular infusion of the leptin receptor (LepR) antagonist SMLA during cocaine conditioning increased the cocaine-CPP and upregulated the level of dopamine and its metabolites in the nucleus accumbens (NAc). We then selectively knocked down the LepR in the mesolimbic ventral tegmental area (VTA), NAc core and central amygdala (CeA) by injecting AAV-Cre into Leprflox/flox mice. LepR deletion in the VTA increased the dopamine levels in the NAc and enhanced the cocaine-conditioned reward. LepR deletion in the NAc core enhanced the cocaine-conditioned reward and impaired the effect of the D2-dopamine receptor on cocaine-CPP, whereas LepR deletion in the CeA had no effect on cocaine-CPP but increased the anxiety level of mice. In addition, prior exposure to saccharin increased LepR mRNA and STAT3 phosphorylation in the NAc and VTA and impaired cocaine-CPP. These results indicate that leptin signaling is critically involved in cocaine-conditioned reward and the regulation of drug reward by a natural reward and that these effects are dependent on mesolimbic LepR.
Highlights
The hormones of the neuroendocrine system modulate and command perception, cognition and the emotional process.1 They regulate multiple physiological and pathological states, such as eating and digestion, exploration and survival, and addiction and anxiety.2 Hormones influence motivation and reward through changing the release of different neurotransmitters in substance abuse and eating disorders.3 Increasing evidence shows that appetite-regulating hormones such as glucagon-like peptide, ghrelin and leptin are involved in the development processes of substance abuse.4,5 Consumption of palatable food and addictive drugs can promote continuous overfeeding or drug-seeking behaviors through eliciting similar hormone-mediated neuroadaptive changes within brain reward circuitry and stress systems,6 indicating that there might be shared neuronal circuits or molecular mechanisms in food and addictive rewards
The function of leptin signaling in the D1R- or D2R-positive neurons in the nucleus accumbens (NAc) will be assessed in the future using Cre-expressing mice and might help elucidate the Leptin has been shown to be involved in energy homeostasis and stress;30 emerging evidence has shown that structural and functional changes in the mesolimbic reward system are associated with reward-related behaviors, which involve hormonal regulators such as leptin, ghrelin and insulin
We found that downregulation of leptin signaling in the ventral tegmental area (VTA) and NAc enhanced the acquisition of cocaine-conditioned place preference (CPP), while upregulation of leptin signaling induced the opposite effect
Summary
The hormones of the neuroendocrine system modulate and command perception, cognition and the emotional process. They regulate multiple physiological and pathological states, such as eating and digestion, exploration and survival, and addiction and anxiety. Hormones influence motivation and reward through changing the release of different neurotransmitters in substance abuse and eating disorders. Increasing evidence shows that appetite-regulating hormones such as glucagon-like peptide, ghrelin and leptin are involved in the development processes of substance abuse. Consumption of palatable food and addictive drugs can promote continuous overfeeding or drug-seeking behaviors through eliciting similar hormone-mediated neuroadaptive changes within brain reward circuitry and stress systems, indicating that there might be shared neuronal circuits or molecular mechanisms in food and addictive rewards. The hormones of the neuroendocrine system modulate and command perception, cognition and the emotional process.1 They regulate multiple physiological and pathological states, such as eating and digestion, exploration and survival, and addiction and anxiety.. The functional role of leptin signaling within mesolimbic brain regions in regulating the response to addictive drugs still needs to be thoroughly elucidated. We inhibited LepR-mediated signaling in several regions in the mesolimbic system by infusion of the LepR antagonist superactive mouse leptin antagonist (SMLA) or injection of AAV-Cre into the VTA, nucleus accumbens (NAc) or central amygdala (CeA) to selectively deplete LepRs in Leprflox/flox mice. The role of mesolimbic LepR signaling on the effect of a natural reward on cocaine-CPP was assessed
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