Δ 9-Tetrahydrocannabinol During Adolescence Reprograms the Nucleus Accumbens Transcriptome, Affecting Reward Processing, Impulsivity, and Specific Aspects of Cocaine Addiction-Like Behavior in a Sex-Dependent Manner

Abstract

Background Cannabis exposure during adolescence is associated with emotional and motivational alterations that may entail an enhanced risk of developing psychiatric disorders. In rodent models, exposure to cannabinoids during adolescence leads to increased self-administration of opiates and cocaine, however, the psychological and neural mechanisms and the sex-specificity of this phenomenon are largely unknown. Methods We exposed male and female adolescent rats to Δ9-tetrahydrocannabinol (THC) and studied at adulthood the effects of such treatment on psychological processes related to reward, such as Pavlovian conditioned approach, Pavlovian to instrumental transfer, habit formation and waiting impulsivity. In the light of these data and given the involvement of the nucleus accumbens in the processes examined, we performed an RNASeq transcriptomic study and assessed cocaine addiction-like behavior. Results THC exposure increased goal-tracking (in males and females) and enhanced Pavlovian to instrumental transfer (especially in males) but did not affect habit formation. THC-exposed rats exhibited subtle, state-dependent changes in premature responding in the 2-CSRTT task. RNASeq data showed gene expression alterations in a marked sex-specific manner. While no effects were found on the acquisition of cocaine self-administration or punished drug-seeking, rats exposed to THC self-administered more cocaine under a progressive ratio schedule (males), had a higher rebound upon returning to continuous access to the drug (females) and showed reduced drug-seeking after 30 days of withdrawal (females). Conclusions Adolescent THC affects specific aspects of reward- (and cocaine-) guided behavior and the function of a key brain region mediating these effects, in a remarkable sex-specific manner.

Long-term effects of THC exposure on reward learning and motivated behavior in adolescent and adult male rats

“…The use of hunger to inflate reward value in Experiment 1 may have provided a more sensitive (albeit less selective) test of motivation, thereby unmasking a potentially more subtle motivational enhancement related to adolescent-THC exposure that was not expressed in Experiment 2. This is in line with other recent studies showing that adolescent THC exposure enhances cue-motivated behavior under chronic food restriction (Kruse et al 2019; Orihuel et al 2021).…”

“…Interestingly, both treatments tended to increase, rather than decrease, the vigor of instrumental performance for palatable food reward. This latter finding is consistent with recent reports that cue-motivated behavior is elevated in adulthood following adolescent exposure to relatively low doses of THC (Kruse et al 2019; Orihuel et al 2021). Such findings suggest that heavy and more moderate THC dosing regimens may have distinct long-term effects on reward processing and motivated behavior.…”

“…Mice given repeated THC exposure as adults have been reported to display insensitivity to reward devaluation under conditions that support flexible, goal-directed behavior in controls (Nazzaro et al 2012). In other more recent studies, rats with a history of adolescent cannabinoid exposure displayed normal or even enhanced sensitivity to reward devaluation (Ferland et al 2022;Orihuel et al 2021). Importantly, these studies were focused on the transition from goal-directed to habitual control and therefore employed simple instrumental testing protocols that promote habit formation.…”

“…Such findings are notable because anhedonia -i.e., diminished interest in healthy, reward-seeking activities -is a common feature of depression, anxiety, and other psychiatric disorders (Husain and Roiser 2018). In contrast, repeated adolescent exposure to lower doses of THC (2.5-5 mg/kg/day) have often been seen to elevate, rather than suppress, rewardmotivated behavior (Kruse et al 2019;Orihuel et al 2021). Further research on the effects of more moderate THC dosing regimens is therefore warranted, particularly given their relevance to modeling early-stage, cannabis use in humans (Poulia et al 2021;Ruiz et al 2021;Torrens et al 2020).…”

Long-Term Outcomes of Adolescent THC Exposure on Translational Cognitive Measures in Adulthood in an Animal Model and Computational Assessment of Human Data

“…Preclinical models allow for potential causal interpretations about certain risk factors and have shown that adolescent THC exposure can precipitate addictionlike behaviors and changes in reward learning . Although these studies have delineated effects on behaviors critical to the development of substance use disorders, few have investigated decision-making and impulsivity and whether dose plays a role in these cognitive phenotypes. In this translational study, we assessed the association of adolescent low-dose or high-dose THC exposure with decision-making and impulsivity using a validated preclinical analogue of the IGT, the Rat Gambling Task (rGT) .…”