Behavioural and biochemical evidence for signs of abstinence in mice chronically treated with delta-9-tetrahydrocannabinol.
Tolerance and dependence induced by chronic delta-9-tetrahydrocannabinol (THC) administration were investigated in mice. The effects on body weight, analgesia and hypothermia were measured during 6 days of treatment (10 or 20 mg kg(-1) THC twice daily). A rapid tolerance to the acute effects was observed from the second THC administration. The selective CB-1 receptor antagonist SR 141716A (10 mg kg(-1)) was administered at the end of the treatment, and somatic and vegetative manifestations of abstinence were evaluated. SR 141716A administration precipitated several somatic signs that included wet dog shakes, frontpaw tremor, ataxia, hunched posture, tremor, ptosis, piloerection, decreased locomotor activity and mastication, which can be interpreted as being part of a withdrawal syndrome. Brains were removed immediately after the behavioural measures and assayed for adenylyl cyclase activity. An increase in basal, forskolin and calcium/calmodulin stimulated adenylyl cyclase activities was specifically observed in the cerebellum of these mice. The motivational effects of THC administration and withdrawal were evaluated by using the place conditioning paradigm. No conditioned change in preference to withdrawal associated environment was observed. In contrast, a conditioned place aversion was produced by the repeated pairing of THC (20 mg kg(-1)), without observing place preference at any of the doses used. This study constitutes a clear behavioural and biochemical model of physical THC withdrawal with no motivational aversive consequences. This model permits an easy quantification of THC abstinence in mice and can be useful for the elucidation of the molecular mechanisms involved in cannabinoid dependence.
Hutcheson
D M
DM
Département de Pharmacologie Moléculaire et Structurale, U266 INSERM, URA D1500 CNRS, Université René Descartes, Paris, France.
Tzavara
E T
ET
Smadja
C
C
Valjent
E
E
Roques
B P
BP
Hanoune
J
J
Maldonado
R
R
D000704:Analysis of Variance; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003213:Conditioning, Psychological / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D013759:Dronabinol / Q000494:pharmacology*; D004347:Drug Interactions; D006213:Hallucinogens / Q000494:pharmacology*; D007035:Hypothermia / Q000139:chemically induced; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009042:Motivation; D009294:Narcotics / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D000077285:Rimonabant; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
D006213:Hallucinogens; D009294:Narcotics; D010880:Piperidines; D011720:Pyrazoles; D013759:Dronabinol; D000242:Cyclic AMP; D000077285:Rimonabant