Dataset Information

Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice.

ABSTRACT: Adolescence represents a developmental period with the highest risk for initiating cannabis use. Little is known about whether genetic variation in the endocannabinoid system alters mesolimbic reward circuitry to produce vulnerability to the rewarding properties of the exogenous cannabinoid ?9-tetrahydrocannabinol (THC). Using a genetic knock-in mouse model (FAAHC/A) that biologically recapitulates the human polymorphism associated with problematic drug use, we find that in adolescent female mice, but not male mice, this FAAH polymorphism enhances the mesolimbic dopamine circuitry projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and alters cannabinoid receptor 1 (CB1R) levels at inhibitory and excitatory terminals in the VTA. These developmental changes collectively increase vulnerability of adolescent female FAAHC/A mice to THC preference that persists into adulthood. Together, these findings suggest that this endocannabinoid genetic variant is a contributing factor for increased susceptibility to cannabis dependence in adolescent females.

SUBMITTER: Burgdorf CE

PROVIDER: S-EPMC7015690 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice.

Burgdorf Caitlin E CE Jing Deqiang D Yang Ruirong R Huang Chienchun C Hill Matthew N MN Mackie Ken K Milner Teresa A TA Pickel Virginia M VM Lee Francis S FS Rajadhyaksha Anjali M AM

Science advances 20200212 7

Adolescence represents a developmental period with the highest risk for initiating cannabis use. Little is known about whether genetic variation in the endocannabinoid system alters mesolimbic reward circuitry to produce vulnerability to the rewarding properties of the exogenous cannabinoid Δ<sup>9</sup>-tetrahydrocannabinol (THC). Using a genetic knock-in mouse model (FAAH<sup>C/A</sup>) that biologically recapitulates the human polymorphism associated with problematic drug use, we find that in ...[more]

PMID: 32095523

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Project description:Circadian rhythm disturbances have long been associated with the development of psychiatric disorders, including mood and substance use disorders. Adolescence is a particularly vulnerable time for the onset of psychiatric disorders and for circadian rhythm and sleep disruptions. Preclinical studies have found that circadian rhythm disruption (CRD) impacts the brain and behavior, but this research is largely focused on adult disruptions. Here, we sought to determine the long-term behavioral and neurobiological effects of CRD during early adolescence by exposing mice to 12 h shifts in the light/dark cycle. We hypothesized that adolescent CRD would have a greater effect on psychiatric-related behaviors, relative to adult disruption. To identify possible mechanisms, we also measured gene expression in brain regions relevant to circadian rhythms, mood and reward. We found that disruption during early adolescence, but not adulthood, persistently increased exploratory drive (risk-taking behavior) and cocaine preference when tested later in life. Interestingly, we found sex differences when intravenous cocaine self-administration was tested. While female mice with a history of adolescent CRD had a greater propensity to self-administer cocaine, as well as increased motivation and cue-induced reinstatement, male adolescent CRD mice had reduced motivation and extinction responding. Overall, adolescent CRD in mice caused persistent increases in risky behavior, cocaine reward and cocaine self-administration, which suggests that CRD during adolescence may predispose individuals towards substance use disorders. Importantly, we found that many transcripts were affected by adolescent CRD and these were largely distinct across sex and brain region. Future research is required to elucidate how adolescent CRD affects behaviors relevant to mood- and substance use-related disorders across the 24-hour day, as well as to identify intervention strategies to alleviate disruption during adolescence and novel therapeutic approaches once symptoms have begun.

Dataset Information

Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice.

Publications

Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice.

Similar Datasets

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