Two rats were excluded during the acquisition phase because of the failure of catheter patiency. In the course of the escalation phase, three rats were excluded from the study because of the failure of catheter patiency at the end of the study, and one rat in the vehicle group died unexpectedly during the day of from cocaine self-administration before the study was completed, thus leaving n=6 rats/group for the final analysis. Te exclusion of those data did not affect the results of the statistical analysis.Te present study found that adolescent WIN exposure increased irritability-like behavior in adolescence, which persisted into adulthood, induced cross-sensitization to the locomotor-stimulating effect of cocaine in adolescence, which did not persist into adulthood, decreased the speed of acquisition but not the rate of cocaine self-administration in adulthood, and had no effect on the escalation of cocaine self-administration in adulthood. Overall, these results demonstrate that although cannabinoid exposure in adolescence induces irritability-like behavior and cross-sensitization to the psychostimulant effect of cocaine during adolescence, it does not promote cocaine self-administration once the animals reach adulthood. However, the effect of adolescent WIN exposure on cocaine self-administration in adolescence was not investigated in the present study because the animals reached adulthood by the time they had recovered from the surgeries that were required for self-administration. Reductions of both body weight and food intake were observed during WIN treatment. Although the activation of cannabinoid receptors typically produces an increase in food intake in adulthood,hydroponic drain table accumulating evidence suggests that adolescent exposure to THC or WIN in rats decreases food intake and body weight.
Te increase in water intake during WIN exposure in the present study confirms the role of cannabinoid receptors in homeostatic responses that regulate not only energy homeostasis but also fluid balance. Irritability, anxiety, and dysphoria are key negative emotional states that characterize the withdrawal syndrome in humans, which arises when access to the drug is prevented and contributes to drug relapse. Irritability has also been reported to be greater in adolescents at higher risk for substance use. Irritability-like behavior has also been shown to increase during withdrawal from alcohol and nicotine in rodents. However, to our knowledge, whether early exposure to cannabinoids affects irritability-like behavior has not been studied in animal models. In the present study, we found that WIN exposure induced irritability-like behavior in adolescence and adulthood, suggesting that cannabinoid exposure in adolescence induces long-lasting neurobehavioral adaptations that can persist months after WIN exposure. However, further studies are needed to investigate whether this finding has translational relevance. An alternative explanation is that, despite blind randomization of the subjects to the two groups, the increase in irritability-like behavior that was observed in WIN-treated rats may be attributable to preexisting differences in irritability-like behavior. Further studies are needed to investigate whether this finding has translational relevance. Numerous human studies demonstrate that early cannabis use is associated with greater vulnerability to the later development of drug addiction and psychiatric illness. A recent study reported a pivotal role for cannabinoid receptors as molecular mediators of adolescent behavior and suggested that cannabinoid receptors may be important in adolescent-onset mental health disorders. Chronic adolescent exposure to WIN has also been shown to induce anxiety-like behavior in rats. However, contradictory findings have also been published, with either no change or even a decrease in anxiety-like behavior after cannabinoid exposure in adolescence.Interestingly, a previous study also demonstrated that long-term cognitive and behavioral dysfunction that was induced by adolescent THC exposure could be prevented by concurrent cannabidiol treatment.
Importantly, WIN acts as a full cannabinoid receptor agonist, in contrast to THC, which only acts as a partial agonist. Moreover, cannabis is known to consist of dozens of additional phytocannabinoids apart from THC. Furthermore, different strains of cannabis differ in their THC content, and THC levels in cannabis have increased year after year because of consumer demand, thus making direct comparisons of human data across time and across studies difficult. Nevertheless, we chose this model of early cannabinoid exposure and followed it precisely because it has been shown to induce cocaine cross-sensitization, thus supporting the gateway hypothesis. Further studies are needed to investigate whether the long-term irritability-like behavior that was observed in the present study can be prevented by concurrent cannabidiol treatment or whether adolescent exposure to cannabis smoke induces long-lasting irritability-like behavior in rats. Epidemiological data consistently document that cannabis exposure precedes the use of other illicit drugs. However, epidemiological data cannot provide causal evidence of this sequence. Animal models are particularly useful for studying effects that are related to cross-sensitization because they allow sequential administrations of the studied drugs while controlling for confounding variables. Several studies have reported behavioral cross-sensitization between cannabinoids and stimulants in rodents. WIN treatment during adolescence in rats induces long-lasting cross-tolerance to morphine, cocaine, and amphetamine, potentiates amphetamine-induced psychomotor sensitization, and induces cocaine-induced psychomotor sensitization in adolescence. WIN exposure also leads to increases in methylenedioxymethamphetamine-induced and cocaine-induced conditioned place preference.
In the present study, WIN exposure in adolescence induced cross-sensitization to the stimulatory effect of cocaine in adolescence. However, this effect was no longer present in adulthood when the rats had self-administered cocaine for several weeks, suggesting that cannabinoid exposure in adolescence may increase the psychomotor effects of cocaine during the first exposure to cocaine, but this effect is not necessarily long-lasting. Cannabinoid exposure increased irritability-like behavior and the psychomotor effects of cocaine, but it did not promote the acquisition or escalation of cocaine self-administration. Indeed, we observed the slower acquisition of cocaine self-administration with 1-h short-access to cocaine in male rats with prior exposure to WIN compared with controls. In contrast, a previous study reported a trend toward an increase in cocaine self-administration during the short acquisition phase in female rats with prior exposure to the cannabinoid receptor agonist CP55,940 but not in male rats. However, this study did not discriminate between inactive and active levers, and no difference in cocaine self-administration was observed during the 14-day maintenance phase in either sex. A recent study showed that adolescent WIN exposure caused impairments in an attentional set-shifting task, a measure of cognitive fexibility, in adulthood. An alternative hypothesis is that the slower acquisition of cocaine self-administration in adulthood that was observed in the present study may be attributable to cognitive impairment that slows the acquisition of operant responding. In humans, several studies have indicated that the adolescent use of cannabis can lead to long-term cognitive deficits, including problems with attention and memory. During escalation, no differences were observed between the rats that were exposed to vehicle in adolescence and the rats that were exposed to WIN in adolescence. This suggests that if cognitive impairments affected the initial acquisition of self-administration, then they did not produce long-term deficits. Te model of long-access to cocaine self-administration is one of the most validated animal models of cocaine use disorder and drug addiction in general. This model has been shown to result in all seven of the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition , and seven of the 11 DSM-5 criteria, including most of the criteria that are required for severe use disorder: tolerance, withdrawal, substance taken in larger amount than intended, unsuccessful efforts to quit, considerable time spent to obtain the drug, important social, work,rolling benches hydroponics or recreational activities given up because of use, and continued use despite adverse consequences.
Te present study found no effect of adolescent cannabinoid exposure in the escalation model, suggesting that adolescent WIN exposure may not facilitate the acquisition, maintenance, or escalation of cocaine use in adulthood. An alternative hypothesis is that the effect of cannabinoid use may not be observed on cocaine intake per se; instead, cannabinoid exposure may produce an increase in the motivation for cocaine, leading to an increase in compulsive cocaine seeking. Indeed, prior exposure to another potential gateway drug, alcohol, was found to have no effect on subsequent cocaine self-administration per se but produced greater motivation and compulsive-like cocaine seeking under a PR schedule of reinforcement. However, we observed no differences between the WIN-exposed and control groups in adulthood when we used a PR schedule of reinforcement to examine whether rats with prior exposure to WIN express alterations of the motivation to self-administer cocaine.One limitation of long-term behavioral studies in adolescent rats, including the present study, is that puberty in rats is relatively short. Compared with adults, rats that are allowed to self-administer cocaine during adolescence have been shown to be more vulnerable to cocaine addiction. Unfortunately, in the model of cannabinoid exposure during adolescence , cocaine self-administration can only be studied starting in late adolescence and continuing into adulthood because rats exit puberty by PND60. Because of this limitation, one possibility is that cannabinoid exposure during adolescence may affect cocaine intake in adolescence. Te present results demonstrate that chronic exposure to cannabinoids does not facilitate the acquisition of cocaine self-administration or compulsive-like cocaine intake in adulthood, measured by the escalation of cocaine self-administration and PR responding in a relevant model of cocaine use disorder. These results suggest that cannabinoid exposure per se is unlikely to be causally responsible for the association between prior cannabis use and future cocaine use in adulthood as purported by the gateway hypothesis. However, we found that cannabinoid exposure produced long-lasting increases in irritability-like behavior, which may indirectly facilitate the emergence of social conflicts and other mental disorders that may contribute to the abuse of drugs other than cocaine. Additionally, the cross-sensitization between WIN and cocaine in adolescence—which was not observed in adulthood—may highlight a short-term increase in the vulnerability to cocaine-induced behaviors. In summary, the present results showed that cannabinoid exposure during adolescence in rats produced cross-sensitization to cocaine in adolescence and a long-lasting increase in irritability-like behavior in adulthood.
However, it did not facilitate the acquisition or escalation of cocaine self-administration or compulsive-like responding for cocaine in adulthood.SUD is a chronic, relapsing disease. CM is a behavioral treatment based on operant conditioning principles that involves providing incentives for meeting specified goals or engaging in target behaviors. CM related to SUD treatment generally involves giving patients tangible rewards such as prizes, cash, or vouchers to reinforce goal behaviors, such as abstinence, medication adherence, or greater/continued engagement with treatment. SUD services such as counseling are already a Medi-Cal covered benefit. CM is often intended as a way to improve the outcomes of these services. CM is not a benefit that directly covers a health care screening, treatment, service, or item. Rather it is an incentive, analogous to, for example, incentive payments for members participating in wellness programs to encourage healthy behaviors. The total cash value a patient could receive through CM ranges widely, with a mean of $914.46 and a median of $466 earned. CHBRP has assumed that CM for SUD treatment programs would be allowed for Medi-Cal beneficiaries .Treatments for SUD include residential, inpatient, and outpatient care using behavioral therapy, counseling, and/or prescription medication. Mutual help groups also support those with SUD to achieve and maintain sobriety. CM can be used as an adjunct to psychosocial treatments for SUD or as a standalone behavioral treatment. Descriptions of treatments for stimulant and cannabis use disorder follow. Stimulants are a class of drugs that includes prescription medications to treat ADHD as well as illicit drugs such as cocaine and methamphetamine. Repeated misuse of stimulants can lead to psychological consequences, such as hostility, paranoia, psychosis, as well as physical consequences of high body temperatures, irregular heartbeats, and the potential for cardiovascular failure or seizures. In California, it is estimated that 33% of all admissions to state- and county-contracted SUD programs are for stimulant use disorders – representing nearly 50,000 admissions annually. It is estimated that there are approximately 3,035 deaths from stimulant use disorder in California each year. Cannabis, also known as marijuana, is the most commonly used psychoactive drug in the United States, after alcohol. Acute effects of cannabis use include nausea, vomiting, and abdominal pain, while chronic impacts include cognitive impairment, pulmonary disease, and sleep disturbance.