Comparative effects of pulmonary and parenteral Δ9-tetrahydrocannabinol exposure on extinction of opiate-induced conditioned aversion in rats

Abstract

Rationale: Evidence suggesting that the endogenous cannabinoid (eCB) system can be manipulated to facilitate or impair extinction of learned behaviours has important consequences for opiate withdrawal and abstinence. We demonstrated that the fatty acid amide hydrolase (FAAH) inhibitor URB597, which increases eCB levels, facilitates extinction of a naloxone-precipitated morphine withdrawal-induced conditioned place aversion (CPA). Objectives: The potential of the exogenous CB1 ligand, Δ9-tetrahydrocannabinol (Δ9-THC), to facilitate extinction of this CPA was tested. Effects of both pulmonary and parenteral Δ9-THC exposure were evaluated using comparable doses previously determined. Methods: Rats trained to associate a naloxone-precipitated morphine withdrawal with a floor cue were administered Δ9-THC - pulmonary (1, 5, 10 mg vapour inhalation) or parenteral (0.5, 1.0, 1.5 mg/kg intraperitoneal injection) - prior to each of 20 to 28 extinction/testing trials. Results: Vapourized Δ9-THC facilitated extinction of the CPA in a dose- and time-dependent manner: 5 and 10 mg facilitated extinction compared to vehicle and 1 mg Δ9-THC. Injected Δ9-THC significantly impaired extinction only for the 1.0-mg/kg dose: it prolonged the CPA fourfold longer than the vehicle and 0.5- and 1.5-mg/kg doses. Conclusions: These data suggest that both dose and route of Δ9-THC administration have important consequences for its pharmacokinetic and behavioural effects; specifically, pulmonary exposure at higher doses facilitates, whereas pulmonary and parenteral exposure at lower doses impairs, rates of extinction learning for CPA. Pulmonary-administered Δ9-THC may prove beneficial for potentiation of extinction learning for aversive memories, such as those supporting drug-craving/seeking in opiate withdrawal syndrome, and other causes of conditioned aversions, such as illness and stress.