Cannabinoid-Elicited Conditioned Place Preference in a Modified Behavioral Paradigm

Abstract

Cannabinoids are the active ingredients in marijuana, which is among the most widely used addictive drugs despite the well-documented harmfulness related to its abuse. The mechanism underlying cannabinoid addiction remains unclear, which is attributed partially to the difficulty in behavioral testing of high-dose cannabinoids using the conditioned place preference (CPP) model. Here, we optimized conditions for establishing CPP with the synthetic cannabinoid HU210 intraperitoneally administered at a high dose. We found that the natural place preference of rats could be exploited for establishing a biased CPP model, and that the adverse effect of HU210 could be ameliorated by adding four daily pre-injections before the conditioning program. Thus, 0.1 mg/kg HU210 induced CPP when pre-injections were administered before traditional conditioning with HU210 administration paired with the non-preferred compartment. The present study provides a useful CPP model for behavioral measurement of the rewarding effects of cannabinoids.Key words cannabinoid; conditioned place preference (CPP); drug reward Psychotropic drugs are characterized by their ability to elicit a rewarding effect, which eventually leads to abuse and addiction.1) Behavioral testing of animals is the classic approach for monitoring the rewarding effects of these drugs and is indispensable for dissecting the mechanisms underlying drug addiction.2,3) The conditioned place preference (CPP) model detects the rewarding effect of drugs after a conditioning procedure that builds an enforced connection between the motivational effect of addictive drugs and the place where the drug is administered.4) The CPP model is among the most popular paradigms for drug reward research and has been used in numerous studies examining many addictive drugs. [4][5][6] Cannabinoids have been well-documented for both their addictive effects and the harmfulness of their abuse. 7) Although the rewarding effect of cannabinoids, for example, Δ9-tetrahydrocannabinol (Δ9-THC), HU210, and other cannabinoid agonists, has been studied using the CPP paradigm, the results of these test are controversial. 3,6,8) This controversy may reflect the multiple experimental factors that affect the outcome of drug-place coupling, and the involvement of different brain regions and neurotransmitters, including the ventral tegmental area dopamine (DA) neurons as well as the glutamatergic and γ-aminobutyric acid (GABA)ergic inputs to the nucleus accumbens and ventral tegmental area, in the neural circuitry of cannabinoid reward. [9][10][11] In addition, the potential adverse effects on learning and memory and the reported anxiolytic property of cannabinoids may also underlie these discrepancies. 12,13) In the present study, the potential factors that may affect cannabinoid CPP models, such as cannabinoid doses, animal strains, and conditioning protocols, were considered and analyzed. We found CPP in response to cannabinoid administration after drug pre-injections combined with a biased protocol design. The ...

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Synthetic Pot: Not Your Grandfather’s Marijuana

“…Interestingly, as previously demonstrated with Δ 9 -THC, prior exposure to Δ 9 -THC was required to “unmask” rewarding effects of JWH-018 [94] and pre-exposure to HU-210 prior to CPP conditioning sessions was necessary to obtain place preference with HU-210. [95]. At the time of this writing, very few SCBs have been tested in CPP experiments.…”