Discriminative stimulus properties of Δ9-tetrahydrocannabinol (THC) in C57Bl/6J mice

Abstract

Primarily, rats have served as subjects in Δ 9 -tetrahydrocannabinol's (THC) discrimination studies although other species such as monkeys and pigeons have been used. While the introduction of the knockout and transgenic mice has vastly stimulated the study of the discriminative stimulus effects of drugs there is only a single published report of mice trained to discriminate THC. Thus, this study extended those results by providing a systematic replication that THC serves as an effective discriminative stimulus in mice and by further investigating the mechanisms of action involved in the THC discrimination model in the mouse. Male C57BL/6J mice were trained to discriminate 10 mg/kg THC from vehicle in 2-lever drug discrimination. THC fully and dose dependently substituted for itself. Cannabinoid indoles, except one with low cannabinoid CB 1 receptor affinity, substituted for THC. Anandamide failed to substitute for THC when administered alone but completely substituted when administered with the non-specific fatty acid amide hydrolase inhibitor, phenylmethylsulphonyl fluoride. As expected, nicotine failed to substitute for THC. Lastly, the cannabinoid CB 1 receptor antagonist rimonabant blocked THC's discriminative stimulus effects.Taken together these studies demonstrate THC's ability to produce discriminative stimulus effects as well as demonstrate its pharmacological specificity and mechanism of action in a two-lever drug discrimination mouse model.

AB-CHMINACA, AB-PINACA, and FUBIMINA: Affinity and Potency of Novel Synthetic Cannabinoids in Producing Δ9-Tetrahydrocannabinol–Like Effects in Mice

“…For each session, percentage of responses on the drug-associated manipulandum and response rate (responses/s) were calculated. Full substitution was defined as $80% responding on the drug-associated manipulandum (Vann et al, 2009). ED 50 values were calculated on the linear part of the drug manipulandum selection dose-response curve for each drug using least squares linear regression analysis, followed by calculation of 95% confidence intervals (CI).…”

“…Two groups of adult male mice were trained to discriminate D 9 -THC in standard operant chambers, as described previously (Vann et al, 2009). Mice were trained to press one of two levers following intraperitoneal administration of 5.6 mg/kg D 9 -THC and to press the other lever after intraperitoneal vehicle injection.…”

Discriminative Stimulus Properties of the Endocannabinoid Catabolic Enzyme Inhibitor SA-57 in Mice

“…Curiously, THC produces reinforcing effects in some (Gardner et al, 1988;Lepore et al, 1996;Justinova et al, 2003Justinova et al, , 2005, but not all (Vlachou et al, 2007;Wiebelhaus et al, 2015), preclinical laboratory animal models. In contrast, THC serves as a reliable discriminative stimulus in the drug-discrimination paradigm (Henriksson et al, 1975;Järbe, 1989;Wiley et al, 1997;Vann et al, 2009), an assay that is highly predictive of drug psychoactivity in humans (Chait et al, 1988;Kamien et al, 1993;Lile et al, 2012).…”

Differential Drug–Drug Interactions of the Synthetic Cannabinoids JWH-018 and JWH-073: Implications for Drug Abuse Liability and Pain Therapy

“…-THC discrimination training and testing in mice were based on previous work by McMahon et al (2008) and Vann et al (2009). Food-maintained responding was established as previously described (see FoodMaintained Responding), and discrimination training began after mice reliably worked at FR10 to earn all possible reinforcements in five consecutive training sessions.…”