Abstract
Cocaine addiction is characterized by dysfunction in reward-related brain circuits, leading to maladaptive motivation to seek and take the drug. There are currently no clinically available pharmacotherapies to treat cocaine addiction. Through a broad screen of innate immune mediators, we identify granulocyte-colony stimulating factor (G-CSF) as a potent mediator of cocaine-induced adaptations. Here we report that G-CSF potentiates cocaine-induced increases in neural activity in the nucleus accumbens (NAc) and prefrontal cortex. In addition, G-CSF injections potentiate cocaine place preference and enhance motivation to self-administer cocaine, while not affecting responses to natural rewards. Infusion of G-CSF neutralizing antibody into NAc blocks the ability of G-CSF to modulate cocaine’s behavioral effects, providing a direct link between central G-CSF action in NAc and cocaine reward. These results demonstrate that manipulating G-CSF is sufficient to alter the motivation for cocaine, but not natural rewards, providing a pharmacotherapeutic avenue to manipulate addictive behaviors without abuse potential.
Highlights
We found no difference between the two treatment groups (Supplementary Fig. 3a; two-tailed Student’s t-test: t(7) = 0.348, p = 0.74). These results suggest that granulocyte-colony stimulating factor (G-CSF) enhances associative learning for drug rewards, but is not inherently rewarding or aversive, and does not affect preference for a natural reward
By using in vivo manipulations of G-CSF function, we identify its role in promoting neural responses to cocaine, as measured by upregulation of c-Fos, and find that G-CSF is a potent enhancer of behavioral responses to cocaine, but not natural rewards, in multiple behavioral tasks
Our data suggest that the locus of effect for G-CSF in both neural and behavioral responses to cocaine is the nucleus accumbens (NAc), a limbic structure well characterized for its role in addictive behaviors
Summary
We aimed to define the complex interaction between cocaine use and cytokine signaling and how these factors alter reward, motivation, and economic decision making to drive cocaine addiction. Because we found that serum G-CSF levels were highly correlated with the extent of cocaine experience, we aimed to define where in the brain it might influence cocaine responses. While there were clear increases in G-CSF expression in NAc following cocaine exposure, we aimed to elucidate the underlying mechanisms. We aimed to determine if increases in the activity of specific projection pathways in brain were capable of increasing central or peripheral G-CSF levels using designer receptors exclusively activated by designer drugs (DREADDs)
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