Impact of sleep on incubation of cocaine craving and dopamine terminal adaptations following abstinence

Ilse Pamela Alonso

doi:10.17918/00000688

Finding effective and tolerable treatments for cocaine addiction has been extremely challenging due to the high rates of relapse. Clinical and animal studies have shown a progressive intensification of cocaine seeking and craving during abstinence, increasing the likelihood of relapse. In addition, sleep disruptions are commonly observed during recovery from chronic cocaine use and manifest as abnormal sleep architecture which is posited to promote incubation of cocaine craving. While the neural mechanisms underlying the association between sleep disruption and incubation of cocaine craving are unclear, accumulating evidence suggests that alterations in mesolimbic dopamine (DA) neurotransmission may contribute to these processes. In these studies, we employed cocaine self-administration followed by a period of imposed abstinence to engender sleep disruptions that drive incubation of cocaine craving. We examined whether restoring sleep during abstinence from cocaine attenuates intensification of cocaine craving and whether these effects involve alterations in DA signaling in the NAc core. We examined for the first time whether DA terminal neurotransmission in naïve rats fluctuates across sleep/wake activity. Results showed a robust association between sleep/wake state and DA terminal neurotransmission, with higher DA uptake rate, increased phosphorylated DAT at Thr53 site, and enhanced cocaine potency after periods of sleep. Then, we examined how changes in DA dynamics in the NAc after cocaine abstinence relate to incubation of cocaine craving using three different schedules of reinforcement. These studies allowed us to select Intermittent Access (IntA) to cocaine as a rat model of cocaine self-administration capable of promoting incubation of cocaine craving and DA sensitization after abstinence; two critical factors associated with high rates of relapse. Finally, we assessed how adaptations in DA neurotransmission influence incubation of cocaine craving after cocaine exposure and abstinence. IntA to cocaine followed by abstinence engendered a significant intensification of cocaine seeking, decreases in REM sleep, and increases in DA release and uptake compared to cocaine naïve rats. Thus, we then tested whether sleep restoration during abstinence attenuates DA changes associated with incubation of cocaine craving. Restoring sleep attenuated incubation of cocaine craving and reversed DA terminal adaptations. This work provides crucial insight into the value of a highly accessible and low-cost treatment option to reduce cocaine craving and helps to identify new molecular targets to treat cocaine addiction.

Impact of sleep on incubation of cocaine craving and dopamine terminal adaptations following abstinence

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Impact of sleep on incubation of cocaine craving and dopamine terminal adaptations following abstinence

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