Behavioural PharmacologyDiscriminative stimulus properties of Δ9-tetrahydrocannabinol (THC) in C57Bl/6J mice
Introduction
Mapping of the mouse genome has allowed rapid advances in the development of techniques for mutagenesis of specific genes, as seen in the creation of knockout and transgenic mice (see Picciotto and Wickman, 1998). Although genotype is relatively easy to verify, determination of phenotypic differences is often more difficult, particularly if expression of the mutant phenotype primarily involves behavior. Consequently, recent years have seen increased emphasis on development of novel behavioral techniques for mice as well as alteration of existing procedures (often developed in rats) for use in mice. Since differences in the functional consequences of manipulation of genes that encode for specific receptors or steps in neurotransmission processes may not be evident through use of strictly observational measures, more complicated operant procedures have often been used to measure constructs such as learning and memory. In addition, pharmacological challenge often is employed.
Drug discrimination is increasingly being used in mice as a method to tease out pharmacologically selective differences in behavioral phenotypes. In drug discrimination, a subject is trained to make one response if administered a specific psychoactive drug (i.e., the training drug) and to make another response if administered vehicle or a drug that does not share the same psychoactive properties. In mice, the typical response requirement is a lever press or a head poke on a drug- or vehicle-associated side, respectively, with correct responses resulting in delivery of reinforcement (an appetitive reinforcer such as food pellet or sweetened milk). Previous studies have demonstrated that mice can be trained to discriminate a variety of psychoactive drugs, including clozapine (Philibin et al., 2005), ethanol (Bowen and Balster, 1997), pentobarbital (Balster and Moser, 1987), and nicotine (Varvel et al., 1999). Moreover, knockout mice have been used to gain further insights regarding the discriminative stimulus effects of drugs such as nicotine with alpha 7 knockout mice (Stolerman et al., 2004) and cocaine with dopamine D5 knockout mice (Elliot et al., 2003).
Δ9-Tetrahydrocannabinol (THC), the principal psychoactive substituent of the marijuana plant (Cannabis sativa), has also been used as a discriminative stimulus in laboratory animals, including rats (Burkey and Nation, 1997, Järbe et al., 1998, Solinas et al., 2007, Vann et al., 2007, Wiley et al., 1995a), rhesus monkeys (Wiley et al., 1995c), pigeons (Henriksson et al., 1975), and gerbils (Järbe et al., 1975). Collectively, these studies have revealed that the discriminative stimulus effects of THC are pharmacologically selective for psychoactive cannabinoids (Wiley et al., 1995b) and are blocked by administration of rimonabant and other antagonists of cannabinoid (CB1) receptors in the brain, but not by an antagonist of cannabinoid CB2 receptors (Järbe et al., 2001, Järbe et al., 2006, Wiley et al., 1995c). Further, centrally active cannabinoids of various structural classes substitute for THC with strong correlation between potency for substitution and affinity for cannabinoid CB1 receptors (Compton et al., 1993). Moreover, the discriminative stimulus effects of cannabinoids in animals correspond to the subjective effects of cannabinoids that have been assessed in humans (Chait et al., 1988, Lile et al., 2008); hence, THC discrimination represents an animal model of marijuana intoxication (Balster and Prescott, 1992).
Recently, McMahon et al. (2008) reported the first successful training of a 2-nose poke THC versus vehicle discrimination in C57BL/6J mice. In this initial manuscript, the structurally dissimilar cannabinoids, CP 55940 and WIN 55212-2, substituted for THC in mice trained whereas the metabolically stable anandamide analog methanandamide and noncananbinoid drugs (ketamine, cocaine and ethanol) did not. The present study extends the findings of that study and provides additional findings regarding the mechanisms of action of a 2-lever THC versus vehicle discrimination in C57BL/6J mice through a variety of techniques, including co-administration of antagonists or metabolic inhibitors, substitution tests with a non-cannabinoid compound (nicotine), and preliminary assessment of structure–activity relationship with indole-derived cannabinoids (Table 1).
Section snippets
Subjects
Male C57B1/6J mice (20–25 g) obtained from Jackson Laboratories (Bar Harbor, ME) were housed individually in clear plastic cages (18 × 29 × 13 cm) with steel wire fitted tops and wood-chip bedding in a temperature-controlled (20–22 °C) vivarium. Water was available ad libitum except while the mice were in the operant chambers. Training and test sessions were conducted at similar times during the light phase of a 12-h light/dark cycle. Completion of the entire study required sequential training of
THC discrimination
Acquisition to criteria of the THC discrimination required an average of 78.2 (range = 53–93) and 68.8 training sessions (range = 53–91) for the mice tested with JWH compounds and for nicotine–anandamide group, respectively. THC fully and dose dependently substituted for itself with similar patterns of generalization and with nearly identical ED50 values (Table 1) in both groups of THC-trained mice (Fig. 1, Fig. 2, top panels). Repeated measures ANOVA conducted on the response rate data from the
Discussion
Rats have been the chosen species for the majority of previous drug discrimination studies in rodent models; however, the importance of training drug discrimination in mice has greatly increased in recent years due, in part, to the growing body of research using genetically modified mice. Basic characterization of mouse models of discrimination with different drug classes is necessary in order to determine how best to maximize benefits of models and to facilitate the most effective comparisons
Acknowledgements
Research supported by National Institute on Drug Abuse grants DA-03672, DA-09789 and DA03590.
References (50)
- et al.
Δ9-Tetrahydrocannabinol discrimination in rats as a model for cannabis intoxication
Neurosci. Biobehav. Rev.
(1992) - et al.
Desflurane, enflurane, isoflurane and ether produce ethanol-like discriminative stimulus effects in mice
Pharmacol. Biochem. Behav.
(1997) - et al.
Anandamide amidohydrolase activity in rat brain microsomes. Identification and partial characterization
J. Biol. Chem.
(1995) - et al.
Delta 9-tetrahydrocannabinol produced discrimination in pigeons
Pharmacol. Biochem. Behav.
(1975) - et al.
1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles
Bioorg. Med. Chem. Lett.
(2005) - et al.
Delta9-tetrahydrocannabinol and pentobarbital as discriminative cues in the Mongolian Gerbil (Meriones unguiculatus)
Pharmacol. Biochem. Behav.
(1975) - et al.
Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs
Pharmacol. Biochem. Behav.
(1991) - et al.
The role of nicotinic receptor beta-2 subunits in nicotine discrimination and conditioned taste aversion
Neuropharmacology
(2002) - et al.
The role of nicotinic receptor alpha 7 subunits in nicotine discrimination
Neuropharmacology
(2004) - et al.
Discriminative stimulus (DS) properties of nicotine in the C57BL/6 mouse
Pharmacol. Biochem. Behav.
(1999)
Cannabis: discrimination of “internal bliss”?
Pharmacol. Biochem. Behav.
Discriminative stimulus effects of CP 55,940 and structurally dissimilar cannabinoids in rats
Neuropharmacology
Pharmacological specificity of the discriminative stimulus effects of delta 9-tetrahydrocannabinol in rhesus monkeys
Drug Alcohol Depend.
Evaluation of cannabimimetic discriminative stimulus effects of anandamide and methylated fluoroanandamide in rhesus monkeys
Pharmacol. Biochem. Behav.
Evaluation of cannabimimetic effects of structural analogs of anandamide in rats
Eur. J. Pharmacol.
Influence of phenylmethylsulfonyl fluoride on anandamide brain levels and pharmacological effects
Life Sci.
Evaluation of the role of the arachidonic acid cascade in anandamide's in vivo effects in mice
Life Sci.
Comparative effects of dextromethorphan and dextrorphan on nicotine discrimination in rats
Pharmacol. Biochem. Behav.
Evaluation of the role of nicotinic acetylcholine receptor subtypes and cannabinoid system in the discriminative stimulus effects of nicotine in rats
Eur. J. Pharmacol.
Evaluation of cannabinoid receptor binding and in vivo activities for anandamide analogs
J. Pharmacol. Exp. Ther.
Pentobarbital discrimination in the mouse
Alcohol Drug Res.
Pharmacological specificity of delta 9-tetrahydrocannabinol discrimination in rats
Psychopharmacology
Complex discriminative stimulus properties of (+)lysergic acid diethylamide (LSD) in C57Bl/6J mice
Psychopharmacology
(R)-methanandamide, but not anandamide, substitutes for delta 9-THC in a drug-discrimination procedure
Exp. Clin. Psychopharmacol.
Discriminative stimulus and subjective effects of smoked marijuana in humans
Psychopharmacology
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