Background: Recent work has demonstrated that acute administration of the novel positive allosteric modulator of the GABA_B receptor, COR659, reduces several alcohol-related behaviors in rodents. Objective: To assess whether COR659 continues to lessen alcohol intake after repeated administration, a fundamental feature of drugs with therapeutic potential. Methods: Male C57BL/6J mice (n = 40) were exposed to daily 2-hour drinking sessions (20% (v/v) alcohol) under the 1-bottle “drinking in the dark” protocol and male Sardinian alcohol-preferring rats (n = 40) were exposed to daily 1-hour drinking sessions under the 2-bottle “alcohol (10%, v/v) vs water” choice regimen. COR659 (0, 10, 20, and 40 mg/kg in the mouse experiment; 0, 5, 10, and 20 mg/kg in the rat experiment) was administered intraperitoneally before 7 consecutive drinking sessions. Results: Alcohol intake in vehicle-treated mice and rats averaged 2.5–3.0 and 1.5–1.6 g/kg/session, respectively, indicative of high basal levels. In both experiments, treatment with COR659 resulted in an initial, dose-related suppression of alcohol intake (up to 70–80% compared to vehicle treatment; P < .0005 and P < .0001 in mouse and rat experiments, respectively). The magnitude of the reducing effect of COR659 on alcohol drinking diminished progressively, until vanishing over the subsequent 2–4 drinking sessions. Conclusion: COR659 effectively reduced alcohol intake in two different rodent models of excessive alcohol drinking. However, tolerance to the anti-alcohol effects of COR659 developed rapidly. If theoretically transposed to humans, these data would represent a possible limitation to the clinical use of COR659.

Substance use disorder is associated with accelerated disease progression in people with human immunodeficiency virus (HIV; PWH). Problem opioid use, including high-dose opioid therapy, prescription drug misuse, and opioid abuse, is high and increasing in the PWH population. Oxycodone is a broadly prescribed opioid in both the general population and PWH. Here, we allowed HIV transgenic (Tg) rats and wildtype (WT) littermates to intravenously self-administer oxycodone under short-access (ShA) conditions, which led to moderate, stable, “recreational”-like levels of drug intake, or under long-access (LgA) conditions, which led to escalated (dependent) drug intake. HIV Tg rats with histories of oxycodone self-administration under LgA conditions exhibited significant impairment in memory performance in the novel object recognition (NOR) paradigm. RNA-sequencing expression profiling of the medial prefrontal cortex (mPFC) in HIV Tg rats that self-administered oxycodone under ShA conditions exhibited greater transcriptional evidence of inflammation than WT rats that self-administered oxycodone under the same conditions. HIV Tg rats that self-administered oxycodone under LgA conditions exhibited transcriptional evidence of an increase in neuronal injury and neurodegeneration compared with WT rats under the same conditions. Gene expression analysis indicated that glucocorticoid-dependent adaptations contributed to the gene expression effects of oxycodone self-administration. Overall, the present results indicate that a history of opioid intake promotes neuroinflammation and glucocorticoid dysregulation, and excessive opioid intake is associated with neurotoxicity and cognitive impairment in HIV Tg rats.

Background: Chronic cannabis use (CU) can result in subtle deficits in cognitive performance that may be linked with alterations in underlying neural functioning. However, these network alterations are not well-characterized following monitored abstinence. Here, we evaluate differences in functional brain network activity associated with CU patterns in adolescents/young adults.Methods: Functional connectomes were generated using resting-state fMRI data collected from 83 healthy young adults (44 male) following two weeks of monitored cannabis abstinence. Network topology metrics were calculated for each of the 7 Yeo 2011 intrinsic connectivity networks (ICNs) and on the whole-brain level. Multiple linear regressions were used to evaluate whether CU (regular-users, n = 35 vs. non-using controls, n = 40) was associated with network topology metric differences after controlling for past-year alcohol use, age, sex, and cotinine levels; moderation by sex was also investigated. Regressions were run within CU group to test for associations between cannabis use patterns (lifetime CU, age of CU initiation, and past-year CU) and network topology. Finally, a network-based statistic (NBS) approach was used to search for connectome subcomponents associated with CU group, CU*sex, and patterns of CU.Results: No significant association between CU groups and ICN topology was observed. Sex moderation was observed; within male cannabis users, higher past-year CU was associated with significantly higher frontoparietal and ventral attention network (VAN) efficiency. Within female cannabis users, higher past-year CU was associated with significantly lower Default Mode Network assortativity. Within individuals who initiated CU before the age of 17, males had lower assortativity in the VAN and Somatomotor network. NBS analyses indicated that connectivity strength within a primarily right-lateralized subnetwork distributed throughout the connectome was significantly and reliably associated with past-year CU).Conclusion: The present findings suggest that subtle differences in resting-state network topology associated with CU may persist after an extended period of abstinence in young adults, particularly males, especially those with heavier past-year use and those who initiated CU earlier in life. While further replication is required in larger samples, these findings suggest potential neuroimaging correlates underlying long-term changes in brain network topology associated with CU.

Adolescence is characterized by rapid neurobehavioral development. The endocannabinoid (eCB) system modulates several co-developing neurotransmitter systems and is well-implicated in preclinical substance use (SU) models. Few studies, however, have investigated associations between the eCB system and SU in adolescence. The present study evaluated associations between circulating eCB lipids and SU, impulsivity, and behavioral approach endophenotypes. Concentrations of eCBs [2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)] and related small bioactive lipids were quantified in serum samples from a substudy of youth (n = 432) enrolled in the Adolescent Brain Cognitive Development Study using liquid chromatography-mass spectrometry. Youth completed the UPPS-P Impulsive Behavior and Behavioral Inhibition/Behavioral Approach System Scales, a SU interview, and questionnaire on factors that impact circulating eCBs. Generalized additive models assessed for associations and sex interactions between eCB concentrations and behaviors. 2-AG and 2-oleoylglycerol were broadly associated with behavioral approach and urgency, while AEA and other N-acylethanolamines were associated with higher-order functions like perseverance and planning, with several sex interactions observed. 2-AG and AEA were negatively associated with low-level substance use and full-unit substance use, respectively. Although relationships between serum eCBs and concentrations in brain are not known, the associations observed between peripheral eCB concentrations and substance use behaviors could reflect differences in eCB homeostasis in the brain. Observed sex differences may suggest hormonal or sex-specific eCB influences on brain development. Further work using direct measures of eCB concentrations in the brain are needed to validate these speculations. Future studies should investigate these mechanisms longitudinally.