Discriminative Stimulus Properties of Δ⁹‐Tetrahydrocannabinol: Mechanistic Studies

Abstract

Δ9‐Tetrahydrocannabinol (THC) produces a multiplicity of pharmacologic effects including analgesic, antiinflammatory, anticonvulsant, antidiarrheal, antiglaucoma, antihypertensive, and sedative effects. Efforts to elucidate the neurochemical systems mediating the THC effects have used these and related endpoints. However, animal models useful for evaluating the mechanisms by which THC produces its unique subjective effects have only recently been established. The use of drugs as discriminative stimuli provides a means for studying such mechanisms, since generalization data from this test closely correlate with subjective properties observed in clinical studies. The present study examined the ability of various drugs to mimic or block the cue produced by THC In rats. In animals trained to discriminate 3.2 mg/kg THC from vehicle, generalization occurred consistently with cannabinoids such as 11‐OH‐THC, HHC, and nabilone. Stereoselective generalization was also obtained with isomers of a potent analgesic, nantradol; potencies were consistent with results from other endpoints. In contrast, THC cueing was not produced by agents acting on adrenergic, cholinergic, serotonergic, GABAergic, or opiate systems. Similarly, a number of drugs previously reported to antagonize various nonunique effects of THC uniformly failed to block its subjective properties. These results indicate that the subjective properties of THC are mediated through as yet unidentified neurochemical systems.

Discriminative stimulus functions in rats of AM1346, a high-affinity CB1R selective anandamide analog

“…This is congruent with previous reports evaluating these agents in rats discriminating between 3.0 to 3.2 mg/kg Δ 9 -THC and vehicle (Barrett et al 1995; for overviews, see Balster and Prescott 1992;Browne and Weissman 1981;Järbe and Mathis 1992;Weissman 1978;Wiley 1999). Limited drug-like responding in tests with D-amphetamine and morphine also occurred in rats trained with lower (1.8 mg/kg) and higher (5.6 mg/kg) doses of Δ 9 -THC, as well as in rats trained with 10 mg/kg mAEA (Järbe et al 1998a(Järbe et al , 2006).…”

Endocannabinoid system involvement in brain reward processes related to drug abuse

“…Surprisingly, AM-404, an inhibitor of endogenous cannabinoid transport, which also did not increase dopamine levels in the nucleus accumbens shell by itself, did not enhance or prolong the effects of intravenously injected anandamide (72). Although dopamine elevations in the nucleus accumbens shell are believed to play an important role in the reinforcing effects of THC (24,29,31), the fact that a number of differences between the dopamine-increasing profile and the discriminative stimulus profiles of endogenous cannabinoids were found (72) and that dopaminergic compounds do not produce THC-like discriminative effects (88) indicates that the behavioral effects of cannabinoids are only partially mediated by the dopaminergic system.…”

“…A protocol that we and others have used to characterize the abuse-related effects of cannabinoids is the two-lever choice drug discrimination procedure with THC or other cannabinoid CB1 agonists as the training drug (78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88). Rats or monkeys readily learn to discriminate even relatively low doses of THC from vehicle, although the development of stable discrimination performance usually requires 30 sessions or more.…”

The Endogenous Cannabinoid Anandamide Produces δ-9-Tetrahydrocannabinol-Like Discriminative and Neurochemical Effects That Are Enhanced by Inhibition of Fatty Acid Amide Hydrolase but Not by Inhibition of Anandamide Transport

“…A way to investigate whether exogenous and endogenous cannabinoids produce qualitatively similar effects is to use drugdiscrimination procedures (Solinas et al, 2006b), with THC as the baseline training drug (Browne and Weissman, 1981;Wiley et al, 1995;Burkey and Nation, 1997;Jarbe et al, 2001;Solinas et al, 2003;Alici and Appel, 2004).…”