Abstract
Cocaine affects food intake, metabolism and bodyweight. It has been hypothesized that feeding hormones like leptin play a role in this process. Preclinical studies have shown a mutually inhibitory relationship between leptin and cocaine, with leptin also decreasing the rewarding effects of cocaine intake. But prior studies have used relatively small sample sizes and did not investigate individual differences in genetically heterogeneous populations. Here, we examined whether the role of individual differences in bodyweight and blood leptin level are associated with high or low vulnerability to addiction-like behaviors using data from 306 heterogeneous stock rats given extended access to intravenous self-administration of cocaine and 120 blood samples from 60 of these animals, that were stored in the Cocaine Biobank. Finally, we tested a separate cohort to evaluate the causal effect of exogenous leptin administration on cocaine seeking. Bodyweight was reduced due to cocaine self-administration in males during withdrawal and abstinence, but was increased in females during abstinence. However, bodyweight was not correlated with addiction-like behavior vulnerability. Blood leptin levels after ∼6 weeks of cocaine self-administration did not correlate with addiction-like behaviors, however, baseline blood leptin levels before any access to cocaine negatively predicted addiction-like behaviors 6 weeks later. Finally, leptin administration in a separate cohort of 59 animals reduced cocaine seeking in acute withdrawal and after 7 weeks of protracted abstinence. These results demonstrate that high blood leptin level before access to cocaine may be a protective factor against the development of cocaine addiction-like behavior and that exogenous leptin reduces the motivation to take and seek cocaine. On the other hand, these results also show that blood leptin level and bodyweight changes in current users are not relevant biomarkers for addiction-like behaviors.
Highlights
Cocaine is used primarily for its pleasurable effects by young adults
When looking at the bodyweight differences split further between naive like behaviors (LA) and high addictionlike behaviors (HA) groups, the sex difference obviously remains during acute withdrawal [Figure 1E, two-way ANOVA with sex and group as between variables: Group × Sex F(2,118) = 4.69 with p = 0.011; N: F = 9 naive + 20 LA + 33 HA, M = 11 naive + 23 LA + 28 HA; 1F + 3M cocaine were removed as outliers] and protracted abstinence [Figure 1F, two-way ANOVA with sex and group as between variables: Group × Sex F(2,167) = 5.35 with p = 0.0056; N: F = 15 naive + 35 LA + 40 HA, M = 15 naive + 34 LA + 34 HA; 1M naive, 1F + 3M cocaine were removed as outliers]
These results indicate that a history of cocaine self-administration differently affects bodyweight in male vs. female but that these effects do not depend on the severity of addiction-like behaviors (HA vs. LA)
Summary
Cocaine is used primarily for its pleasurable effects by young adults. Overall, 5.5 million Americans reported using cocaine in 2019, which includes 1 million with cocaine use disorders (Samhsa, 2020). While most research on cocaine focuses on its rewarding effect, cocaine has effects on food intake (Mitchell and Roseberry, 2019) and metabolism (Billing and Ersche, 2015). These results suggest that cocaine use affects bodyweight control and feeding hormones, such as the satiety hormone leptin (Schwartz et al, 1996; Friedman, 2014). This is of therapeutic interest, as increased weight gain during cocaine abstinence can hinder recovery (Cochrane et al, 1998; Billing and Ersche, 2015; Bruening et al, 2018) and feeding hormones can affect rewarding effects of drugs in addition to food. The exact role of cocaine self-administration on bodyweight and leptin level, and the effect of leptin on cocaine-seeking is unclear, partly due to the lack of longitudinal studies and experiments with low sample size or identical inbred animals
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