Corticostriatal mechanisms of action learning and habit formation

National Institute On Alcohol Abuse And Alcoholism

Investigators

Linked publications, trials & patents

Abstract

Chronic Exposure to Delta-9 Tetrahydrocannabinol Disrupts Sleep, Hedonic Function and Cognition Drugs derived from Cannabis sativa, such as marijuana and hashish, are among the most widely used psychoactive substances worldwide. The major psychoactive ingredient in cannabis-derived drugs in delta-9 tetrahyrocannabinol (THC), which acts as a partial agonist of the cannabinoid type 1 receptor (CB1) that is among the most abundant G protein-coupled receptors (GPCRs) in the brain. Indeed, the CB1 receptor mediates the majority of the psychoactive effects of cannabis drugs, and other CB1 agonists can mimic THC actions. Like many psychoactive drugs, the cannabis-derived drugs have the potential for misuse. The American Psychiatric Association has defined the symptoms of Cannabis Use Disorder (CUD). Among these symptoms is a series of behavioral and cognitive changes observed following cessation of heavy cannabis use, known as Cannabis Withdrawal Syndrome (CWS). To examine effects of chronic THC exposure in C57Bl6J mice, we used an established procedure consisting of 6 days of intraperitoneal drug injection (at 10 mg/kg) that is known to produce tolerance to THC actions. As previously demonstrated, the initial THC injection enhanced non-rapid-eye movement (NREM) sleep as measured with polysomnography and automated sleep-state scoring. This acute THC action was eliminated following the 6-day chronic THC procedure, indicating tolerance to the somnolescent effect of the drug. In the first two days following cessation of the chronic THC exposure regimen, fragmentation of NREM sleep (shorter bouts of NREM) was observed in male, but not female, mice. The NREM values in male mice returned to baseline levels by days 5-6 after cessation of chronic THC treatment. These effects were not observed following chronic treatment with the vehicle used to dilute THC. To determine if chronic THC-treated mice show changes in hedonic behavior we examined preference for sucrose-containing water relative to water alone using a two-bottle choice paradigm. Once again, the male mice showed a modest but significant decrease in sucrose preference relative to vehicle-treated male mice over the first two days following cessation of THC treatment, while preference in the female mice was unaffected by the THC exposure regimen. As with the NREM disruption, sucrose preference returned to baseline levels in male mice within 5-6 days following THC cessation. To assess if reward-driven behavior and stimulus associations with reward were altered by chronic THC treatment, we tested mice in a cue-driven rewarded lever-pressing task before and after the drug treatment procedure. In male mice THC treatment induced longer latencies to respond to the cue light, as well as poorer cue discrimination. No such deficits were observed in female mice. In the bottle brush test designed to examine responses to an irritating stimulus, male mice showed increased aggressive responses to brush presentation, especially 5-6 days following cessation of THC treatment. Female THC-treated mice showed a small decrease in these responses at the same time points. No changes in defensive behaviors were observed in either sex at any time point following treatment. Both male and female mice exhibited decreased weight during abstinence. Food and water intake were reduced after the first THC injection, but recovered to normal levels after subsequent injections and after treatment cessation in both sexes. We also measured locomotor activity in an open field chamber. As expected, the initial dose of THC reduced locomotion in both male and female mice, but activity levels were similar to vehicle-injected mice at the end of the treatment regimen. No locomotor activity differences were observed following treatment cessation in mice of either sex. We also measured blood corticosterone as a physiological index of stress in the mice during the period following cessation of THC exposure. Small increases in corticosterone were observed in male, but not female mice, during the first two days after the end of the treatment period. No changes were observed on days 5-6 after THC cessation. This finding indicates that male mice might experience more stress associated with THC withdrawal. It must be noted that the increase in corticosterone levels in the male mice was modest, and not outside the range of normal diurnal fluctuations in levels of this hormone. Overall, our findings indicate that a number of affective and cognitive functions are altered in male mice following a chronic THC exposure period known to produce tolerance to the drug. Interestingly, female mice appeared to be resilient to these withdrawal-induced behavioral changes and did not show changes in corticosterone levels, unlike the male mice. The lack of significant THC-induced changes in female mice does not appear to be due to greater variability in the measures obtained. Sex differences in the stressful effects of THC exposure and withdrawal (as indicated by the elevated corticosterone in males but not females) may contribute to the behavioral differences. We are currently examining neurobiological mechanisms that could contribute to the effects of drug withdrawal and the observed sex differences. The neurotransmitter dopamine is known to contribute to activity, arousal and sleep/vigilance states. Thus, we are examining effects of THC and withdrawal using fast-scan cyclic voltammetry to measure dopamine release in slices from different striatal regions of male and female mice. Our findings to date indicate that dopamine release is elevated in dorsolateral and dorsomedial striatum, as well as the nucleus accumbens, in female mice in the first two days following cessation of THC treatment. Later in withdrawal release levels are similar to those observed in controls. In contrast, slices from male mice only show an increase in dopamine release in the dorsomedial striatum on days 5-6 following THC treatment cessation, with no change earlier in withdrawal. These intriguing new findings suggest that elevated dopamine release could contribute to the resilience of female mice to effects of THC treatment/withdrawal. For example, the lack of impairment in females in the cue-driven rewarded lever-pressing task may involve enhanced dopamine contributions to vigilance, action initiation and/or decision making. We can examine these hypotheses in future studies by combining experimental manipulations of the dopaminergic system with THC treatment and behavioral tests.