Lifelong substance abuse is often initiated during adolescence; yet, most pre-clinical research in this area has been conducted in adult animals. Substantial evidence exists that the brain development that continues throughout adolescence may result in pharmacological responses that differ in a crucial manner from those of adults. The goal of this study was to evaluate age differences in motor activity following acute and repeated administration of drugs that are commonly abused by adolescents, including cocaine, Δ 9 -tetrahydrocannabinol (Δ 9 -THC), and the club drugs, ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Adolescent and adult male rats were injected once daily with saline or with a dose of one of the test drugs for two 5-day dosing periods, separated by a 2-day drug holiday during which they remained in their home cages. Following each injection, rats were placed in a locomotor chamber for a 20-minute session. The potencies of cocaine, ketamine and MDMA for producing motor stimulation were less in male adolescents than in male adults. Furthermore, sensitization to the club drug, ketamine, developed after repeated dosing in adults, but not adolescents. In contrast, adolescents were initially more sensitive to the stimulatory effects of low doses of Δ 9 -THC than were adults, although rapid tolerance occurred. These results suggest that adolescents are less sensitive to the acute and repeated stimulant effects of some, but not all, of the drugs that are preferentially abused by this age group. This differential sensitivity may contribute to the different patterns of use that have been noted in adolescent versus adult drug abusers.

Adolescents and young adults of both sexes are the primary consumers of "club" drugs; yet, most of the mechanistic preclinical research in this area has been performed in adult male rodents. The purpose of this study was to evaluate the acute and repeated effects of drugs that are commonly abused by adolescents in female adolescent and adult rats in a rodent model of behavioral sensitization. During two five-day periods separated by a two-day break, rats were injected daily with saline or with one of the following drugs: cocaine (7 or 15 mg/kg), ketamine (3 or 10 mg/kg), 3,4-methylenedioxymethamphetamine (MDMA) (3, 10, or 30 mg/kg), or Δ(9)-tetrahydrocannabinol (THC) (0.03, 0.1, 0.3 or 1 mg/kg) and their locomotor activity was measured. Cocaine increased activity across days in both age groups. Whereas ketamine produced progressive increases in activity with repeated administration in rats of both ages, MDMA increased, and then decreased, activity in the chronic dosing regimen in female adolescents only. Tolerance to the initial stimulatory effects of low doses of THC was observed at both ages. The results with THC are similar to those obtained for male rats tested under identical conditions in a previous study; however, in contrast with the present results in females, male adolescent rats in the previous study failed to develop behavioral sensitization to ketamine. Together, these results suggest that age and sex strongly influence the progressive adaptive changes that occur with repeated administration of some, but not all, of these commonly abused substances.

The endogenous cannabinoid system has been noted for its therapeutic potential, as well as the psychoactivity of cannabinoids such as Δ9-tetrahydrocannabinol (THC). However, less is known about the psychoactivity of anandamide (AEA), an endocannabinoid ligand. Thus, the goals of this study were to establish AEA as a discriminative stimulus in transgenic mice lacking fatty acid amide hydrolase (i.e., FAAH −/− mice unable to rapidly metabolize AEA), evaluate whether THC or oleamide, a fatty acid amide, produced AEA-like responding, and assess for CB1 mediation of AEA’s discriminative stimulus. Mice readily discriminated between 6 mg/kg AEA and vehicle in a two-lever drug discrimination task. AEA dose-dependently generalized to itself. THC elicited full AEA-like responding, whereas oleamide failed to substitute. The CB1 antagonist rimonabant attenuated AEA- and THC-induced AEA-appropriate responding, demonstrating CB1 mediation of AEA’s discriminative stimulus. These findings suggest that, in the absence of FAAH, AEA produces intoxication comparable to THC, and consequently to marijuana.

Anandamide (AEA), an endocannabinoid (eCB), shares some, but not all, pharmacological properties with THC. This pharmacological dissociation is in part due to the rapid catabolism of AEA by fatty acid amide hydrolase (FAAH). With inhibitors of FAAH, studies have demonstrated that AEA shares THC's discriminative stimulus (DS) properties providing the leading evidence for the involvement of the eCB system in the subjective effects of marijuana. However, this remains to be fully elucidated without demonstrating that these DS effects are cross symmetrical. Thus, the current study investigated whether FAAH (−/−) mice, those lacking the ability to breakdown AEA, could be trained to discriminate AEA (6 mg/kg) versus VEH in a 2‐lever discrimination. AEA was successfully trained and dose dependently generalized. THC fully and dose dependently substituted whereas oleamide, another FAA, failed to substitute. THC's and AEA's DS effects were blocked by SR141716. This study demonstrates that: AEA's DS can be trained in FAAH (−/−) mice, THC and AEA cross generalize, and these effects are CB1 receptor mediated. Oleamide's lack of AEA‐like DS effects provides further support for the specificity of this model. Taken together, this research demonstrates that THC or AEA activation of the eCB system results in similar DS effects. Research supported by NIH grant DA‐09789.

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