Induction of glucose intolerance by acute administration of rimonabant.
OBJECTIVE
Rimonabant is a cannabinoid CB1 receptor antagonist. Other CB1 antagonists have biphasic effects on blood glucose levels following acute administration. We therefore tested the effects of rimonabant on glucose tolerance following acute administration.


METHODS
We tested the effects of oral and intracerebroventricular administration of rimonabant on blood glucose and gastrointestinal transit in mice following oral and intravenous glucose challenge.


RESULTS
We found a dose-dependent increase in blood glucose from oral doses of rimonabant of 3 mg/kg and above. WIN55,212-2 (3 mg/kg), a cannabinoid receptor agonist, did not influence blood glucose in the presence or absence of rimonabant. Rimonabant did not induce release of glucose from isolated rat hepatocytes or modify serum insulin concentration in mice. Intracerebroventricular administration of rimonabant caused increases in blood glucose and gastrointestinal transit, suggesting a central nervous system site of action. Increases in blood glucose by rimonabant were partially blocked by the dopamine receptor antagonist haloperidol and significantly blocked by the 5-hydroxytryptophan(5-HT) depleting agent p-CPA and the 5-HT 3 receptor antagonist ondansetron.


CONCLUSIONS
Rimonabant causes dose-dependent increase in glucose profile upon glucose challenge partially mediated by the central nervous system control of gastrointestinal carbohydrate absorption through pathways that are modulated by both 5-HT and dopamine.
Sun Pharma Advanced Research Company Limited, Vadodara, India. sanjay.mandhane@sunpharma.com
Sanjay
S
Mandhane
Prasanta
P
Nayak
Durgesh
D
Soni
Shakti
S
Jain
John C
JC
Ashton
Thennati
T
Rajamannar
D000284:Administration, Oral; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D010134:Fenclonine / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D018149:Glucose Intolerance / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D006220:Haloperidol / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D057967:Infusions, Intraventricular; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D017294:Ondansetron / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors*; D011954:Receptors, Dopamine / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D000077285:Rimonabant; D012702:Serotonin Antagonists / Q000494:pharmacology
D048588:Benzoxazines; D001786:Blood Glucose; D018492:Dopamine Antagonists; D007328:Insulin; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017294:Ondansetron; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D005947:Glucose; D006220:Haloperidol; D010134:Fenclonine; D000077285:Rimonabant