AN EXTENSION OF PLANARIAN BEHAVIORAL MODEL: CANNABINOID PHYSICAL DEPENDENCE AND WITHDRAWAL

Abstract

Background: Planarians have mammalian-like neurotransmitter systems and have been established as a novel in vivo model for neuropharmacology. In previous research, planarians exposed to the cannabinoid receptor (CB-R) agonist WIN 55,212-2 (10 μmol/L) for 1 h displayed a significant (p < 0.05) decrease in spontaneous locomotor velocity (pLMV) when subsequently tested in drug-free, but not in drug-containing, water. This demonstrated abstinence-induced withdrawal from a CB-R agonist as a manifestation of the development of physical dependence. Purpose: The purpose of the present study was to extend previous work and to further establish a cannabinoid behavioral model with planarians. Specifically, the goals included (i) confirm the work with WIN 55,212-2 and extend to a second agonist (ii) interfere with agonist-induced physical dependence using several CB-R antagonists, (ii) demonstrate antagonist-induced precipitated withdrawal behavior, and (iii) try to induce withdrawal behavior from CB-R agonists using UV light. Methods: Two CB agonists (WIN 55,212-2 and JWH251) and four CB antagonists (AM251, AM281, SLV319 and SR144528) were used. Planarians were placed individually in CB-R agonist or agonist + antagonist mixtures for 20 and 30 min of exposure (with or without UV radiation), and withdrawal was quantified by measuring pLMV in drug-free vs drug-containing water (with or without UV light irradiation). Results: (i) Four different CB1-R antagonists (AM251, AM281, SLV319 and SR144528) dose-relatedly blocked development of physical dependence induced by two different CB-R agonists (WIN 55,212-2 and JWH251). (ii) None of the same four antagonists (AM251, AM281, SLV319 and SR144528) precipitated withdrawal. (iii) Short wavelength (254 nm), but not long wavelength (366 nm), UV light attenuated abstinence-induced withdrawal from WIN 55,212-2, while short wavelength UV light induced moderate withdrawal behavior. Conclusions: The results confirm the use of a planarian model as a simple yet robust way to study development of physical dependence to cannabinoid agonists. The model is more rapid and sensitive than the usual rodent models. The effect of UV irradiation adds to the supposition that the results are receptor-related. The results also give rise to the surprising suggestion, within the limitations of the methodology, that development of cannabinoid physical dependence and antagonist-induced precipitated withdrawal might be separable phenomena in planarians.