Indiana University-Purdue University Indianapolis (IUPUI) / Cannabis (and its main psychoactive component, THC) is one of the most widely-used drugs in the world, and recent expansion of its legal status has made it available in a variety of formulations and at a potency unrivaled in history. While its medicinal properties are gaining scientific support, so too is its potential to lead to abuse and dependence. Both initiation of cannabis use and frequent cannabis use are most prevalent in adolescence, and compared to adults, cannabis use by adolescents is associated with a greater likelihood of developing cannabis dependence and cannabis use disorder. Given the ethical limitations surrounding research that provides cannabis to non-users or non-adults, animal models of drug use can be valuable tools for the study of causes and consequences related to drug use, as well as allowing for investigating brain mechanisms underlying these factors. However, only recently have models in which animals reliably use cannabis (THC) at levels above its respective vehicle and at levels which produce consistent behavioral and physiological effects become available, and in no case has age-related differences in this use been examined. Thus, one goal of the current study was to directly compare the self-administration of edible THC (a route of administration used by humans and a formulation increasing in popularity) between adolescent and adult mice. Adolescents also appear to be differentially sensitive to various effects of several classes of drugs, and they have been shown to be less sensitive to the aversive effects of cannabis, thereby putting them at greater risk for elevated and continued use. Evidence also suggests that, in addition to the risk associated with adolescent cannabis use, having initial positive subjective experiences resulting from its use is a strong predictor of subsequent cannabis dependence. Thus, the second goal of the current study was to use the place conditioning paradigm to examine the reward- (or aversion-) inducing properties of THC in adolescent and adult C57BL/6J mice, using both the traditional experimenter-administered THC (via injection) as well as edible THC self-administration. Prior to initiating these THC studies, sensitivity of the place conditioning procedure to age-related differences in drug-induced reward was validated using cocaine, yielding locomotor stimulation in both ages and a decreased sensitivity to cocaine’s rewarding properties in adolescent mice. When provided limited access to edible THC dough in doses ranging from 0.0 to 6.0 mg/kg, mice showed a dose-dependent reduction in consumption across access sessions, and this reduction was more rapid in adult mice at the highest doses, suggesting that adolescent mice might have been less sensitive to its aversive properties. These same mice, as well as a separate group of mice receiving injection (also 0.0 to 6.0 mg/kg THC), were given place conditioning sessions, alternating between THC dough and control dough or THC injection and vehicle injection, for 6 days per week and were tested once per week across a total of 3 weeks. Mice conditioned using edible THC showed a neutral response (neither reward nor aversion) at all doses. However, mice conditioned using injected THC showed a conditioned place aversion to the highest dose, which was more pronounced in adult mice. Interestingly, in mice self-administering edible THC, the dose of THC consumed was related to the outcome of place conditioning, such that a conditioned place preference was observed for adult mice which shifted their consumption of 3.0 mg/kg edible THC downward relative to those mice with full consumption of 3.0 mg/kg, and for adolescent mice which had the highest degree of consumption of 6.0 mg/kg edible THC relative to those mice with the lowest consumption of 6.0 mg/kg. Furthermore, initial place preference outcomes at the individual level at test 1 predicted subsequent doses of edible THC consumed, suggesting mice adjust their self-administration of edible THC based on the subjective experience it produces. Besides its impact in place conditioning, THC also had differential effects on body weight and locomotor activity based on age and route of administration. Collectively, this project demonstrates that adolescent mice are less sensitive to the hedonic properties of both cocaine and THC, and that differences in edible THC self-administration between ages, and between individuals within an age, are likely related the subjective experience of its rewarding and aversive properties.

Cannabis (and its main psychoactive component, THC) is one of the most widely-used drugs in the world, and recent expansion of its legal status has made it available in a variety of formulations and at a potency unrivaled in history. While its medicinal properties are gaining scientific support, so too is its potential to lead to abuse and dependence. Both initiation of cannabis use and frequent cannabis use are most prevalent in adolescence, and compared to adults, cannabis use by adolescents is associated with a greater likelihood of developing cannabis dependence and cannabis use disorder. Given the ethical limitations surrounding research that provides cannabis to non-users or non-adults, animal models of drug use can be valuable tools for the study of causes and consequences related to drug use, as well as allowing for investigating brain mechanisms underlying these factors. However, only recently have models in which animals reliably use cannabis (THC) at levels above its respective vehicle and at levels which produce consistent behavioral and physiological effects become available, and in no case has age-related differences in this use been examined. Thus, one goal of the current study was to directly compare the self-administration of edible THC (a route of administration used by humans and a formulation increasing in popularity) between adolescent and adult mice.<br><div> Adolescents also appear to be differentially sensitive to various effects of several classes of drugs, and they have been shown to be less sensitive to the aversive effects of cannabis, thereby putting them at greater risk for elevated and continued use. Evidence also suggests that, in addition to the risk associated with adolescent cannabis use, having initial positive subjective experiences resulting from its use is a strong predictor of subsequent cannabis dependence. Thus, the second goal of the current study was to use the place conditioning paradigm to examine the reward- (or aversion-) inducing properties of THC in adolescent and adult C57BL/6J mice, using both the traditional experimenter-administered THC (via injection) as well as edible THC self-administration.</div><div> Prior to initiating these THC studies, sensitivity of the place conditioning procedure to age-related differences in drug-induced reward was validated using cocaine, yielding locomotor stimulation in both ages and a decreased sensitivity to cocaine’s rewarding properties in adolescent mice. When provided limited access to edible THC dough in doses ranging from 0.0 to 6.0 mg/kg, mice showed a dose-dependent reduction in consumption across access sessions, and this reduction was more rapid in adult mice at the highest doses, suggesting that adolescent mice might have been less sensitive to its aversive properties. These same mice, as well as a separate group of mice receiving injection (also 0.0 to 6.0 mg/kg THC), were given place conditioning sessions, alternating between THC dough and control dough or THC injection and vehicle injection, for 6 days per week and were tested once per week across a total of 3 weeks. Mice conditioned using edible THC showed a neutral response (neither reward nor aversion) at all doses. However, mice conditioned using injected THC showed a conditioned place aversion to the highest dose, which was more pronounced in adult mice. Interestingly, in mice self-administering edible THC, the dose of THC consumed was related to the outcome of place conditioning, such that a conditioned place preference was observed for adult mice which shifted their consumption of 3.0 mg/kg edible THC downward relative to those mice with full consumption of 3.0 mg/kg, and for adolescent mice which had the highest degree of consumption of 6.0 mg/kg edible THC relative to those mice with the lowest consumption of 6.0 mg/kg. Furthermore, initial place preference outcomes at the individual level at test 1 predicted subsequent doses of edible THC consumed, suggesting mice adjust their self-administration of edible THC based on the subjective experience it produces. Besides its impact in place conditioning, THC also had differential effects on body weight and locomotor activity based on age and route of administration. Collectively, this project demonstrates that adolescent mice are less sensitive to the hedonic properties of both cocaine and THC, and that differences in edible THC self-administration between ages, and between individuals within an age, are likely related the subjective experience of its rewarding and aversive properties.</div>