Effect of low doses of Δ9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats
- 577 Downloads
Using the place-preference conditioning paradigm, we evaluated the potential of the two most prominent cannabinoids found in marijuana, the psychoactive component Δ9-tetrahydrocannabinol (Δ9-THC) and the nonpsychoactive component cannabidiol (CBD), to potentiate extinction of a cocaine-induced and an amphetamine-induced conditioned place preference in rats.
To determine the effects of pretreatment with Δ9-THC or CBD on extinction, a cocaine-induced and amphetamine-induced place preference was first established. Rats were then given an extinction trial, during which they were confined to the treatment-paired floor for 15 min. Thirty minutes prior to the extinction trial, they were injected with a low dose of Δ9-THC (0.5 mg/kg), CBD (5 mg/kg) or vehicle. The potential of the CB1 receptor antagonist, SR141716, to reverse the effects of Δ9-THC or CBD was also evaluated. To determine the hedonic effects of CBD, one distinctive floor was paired with CBD (5 mg/kg) and another with saline. Finally, to determine the effect of Δ9-THC or CBD on the establishment and/or the expression of a place preference during four cycles of conditioning trials, rats were injected with Δ9-THC (0.25–1 mg/kg), CBD (5 mg/kg) or vehicle 25 min prior to receiving an injection of amphetamine followed by placement on the treatment floor; on alternate days, they received injections of vehicle followed by saline and placement on the nontreatment floor. The rats then received two test trials; on one trial they were pretreated with the cannabinoid and on the other trial with vehicle.
Δ9-THC and CBD potentiated the extinction of both cocaine-induced and amphetamine-induced conditioned place preference learning, and this effect was not reversed by SR141716. The cannabinoids did not affect learning or retrieval, and CBD was not hedonic on its own.
These results are the first to show that both Δ9-THC, which acts on both CB1 and CB2 receptors, and CBD, which does not bind to CB1 or CB2 receptors, potentiate the extinction of conditioned incentive learning.
KeywordsMemory Cannabinoids Δ9-Tetrahydrocannabinol Cannabidiol Extinction Cocaine Amphetamine Conditioned place-preference learning Incentive Classical conditioning
The research in Canada was supported by the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research; the Research in Jerusalem was supported by the Israel Science Foundation and the National Institute on Drug Abuse (US).
- Bardo MT, Neisewander JL, Miller JS (1986) Repeated testing attenuates conditioned place preference with cocaine. Psychopharmacology 89:239–243Google Scholar
- Brodkin J, Moerschbaecher JM (1997) SR 141716A antagonizes the disruptive effects of cannabinoid ligands on learning in rats. J Pharm Exp Ther 282:1526–1532Google Scholar
- Calcagnetti DJ, Schechter MD (1993) Extinction of cocaine-induced place approach in rats: a validation of the “biases” conditioning procedure. Brain Res Bull 30:696–700Google Scholar
- Cunningham CL (1998) Drug conditioning and drug-seeking behavior. In: O’Donohue W (ed) Learning and Behavior Therapy. Allyn & Bacon, Boston, MA, pp 518–44Google Scholar
- Heyser CJ, Hampson RE, Deadwyler SA (1993) Effects of delta-9-tetrahydrocannabinol on delayed match to sample performance in rats: alterations in short-term memory associated with changes in task specific firing of hippocampal cells. J Pharm Exp Ther 264:294–307Google Scholar
- Iversen LL (2000) The Science of Marijuana. Oxford University Press, NYGoogle Scholar
- Kwiatkowska M, Parker LA, Burton P, Mechoulam R (2004) A comparative analysis of the potential of cannabinoids and ondansetron to suppress cisplatin-induced emesis in the Suncus murinus (house musk shrew). Psychopharmacology (in press)Google Scholar
- Lichtman AH, Martin BR (1996) Δ-9-Tetrahydrocannabinol impairs spatial memory through a cannabinoid receptor mechanism. Psychopharmacology 126:125–131Google Scholar
- Mallet PE, Beninger RJ (1998a) The cannabinoid CB1 receptor antagonist SR 141716A attenuates the memory impairment produced by Δ9-tetrahydrocannabinol or anandamide. Psychopharmacology 140:11–19Google Scholar
- Varvel SA, Hamm RJ, Martin BR, Lichtman AH (2001) Differential effects of Δ9-THC on spatial reference and working memory in mice. Psychopharmacology 157:142–150Google Scholar