Effects of SR141716 and WIN 55,212-2 on tolerance to ethanol in rats using the acute and rapid procedures.
BACKGROUND
Our previous findings have shown rapid cross-tolerance between ethanol and Delta(9)-tetrahydrocannabinol and that intraperitoneal (i.p.) injection of cannabinoid receptor type 1 (CB1R) antagonist SR141716 (SR) does not interfere with tolerance to either of these drugs in mice.


OBJECTIVE
This study investigates the effects of SR, alone or in combination with the CB receptor agonist WIN 55,212-2 (WIN), on the development of acute and rapid tolerance to the incoordinating effect of ethanol in rats.


METHODS
Male Wistar rats received SR, through i.p. (0.5-2.0 mg/kg) or intracerebroventricular (i.c.v.) injections (0.5-4.0 microg), alone or together with WIN (1.0 microg, i.c.v.), in combination with ethanol (2.7 g/kg, i.p.). Another group received WIN (1.0 microg, i.c.v.) in combination with ethanol (2.3 g/kg), and the rats were tested for motor coordination. Rapid tolerance was assessed 24 h later by administering ethanol to all animals and retesting them under the same dose regimen. Acute tolerance was evaluated for 75 min after ethanol (3.0 g/kg, i.p.) in animals treated with SR or WIN (i.c.v.).


RESULTS
The reduced motor impairment on day 2 (i.e., rapid tolerance) was blocked by SR (i.p. and i.c.v.). WIN (1.0 microg, i.c.v.) facilitated rapid tolerance and also prevented the blockade of rapid tolerance by SR (1.0 microg, i.c.v.). In the acute tolerance procedure, SR did not affect the motor incoordination induced by ethanol.


CONCLUSIONS
The results suggest that the endocannabinoid system may contribute to the development of rapid tolerance to ethanol.
Lemos
Jose Inácio
JI
Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário Trindade, CCB, 88049-900, Florianopolis, SC, Brazil. gsmorato@farmaco.ufsc.br
Takahashi
Reinaldo Naoto
RN
Morato
Gina Struffaldi
GS
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D013997:Time Factors
D000701:Analgesics, Opioid; D048588:Benzoxazines; D002492:Central Nervous System Depressants; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000431:Ethanol; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant