Characterization of the decline in alcohol consumption by aminopeptidase inhibition.
Bestatin, an aminopeptidase inhibitor, prolongs the action of angiotensin and enkephalin. Previous studies have shown that bestatin can reduce alcohol intake in heterogeneous as well as genetically selected alcohol preferring 'P' rats, but more detailed studies of the characteristics of this effect have not yet been done. In experiment 1, daily injections of 10, 20 or 40 mg/kg bestatin for 12 days produced a uniform reduction in alcohol intake (approximately 40%) which did not recover following suspension of bestatin, but did recover following a 7 day period of morphine-stimulated alcohol drinking. In experiment 2, the lower end of the dose range was explored (2.5, 5, 10 mg/kg) and a dose-dependent effect was observed with a threshold dose of 5 mg/kg. Again, alcohol drinking did not recover following suspension of the 10 mg/kg dose of bestatin. Using a limited access procedure, bestatin reduced the intake of a preferred sodium chloride solution but not an avidly-consumed glucose solution indicating that while bestatin's effect was selective, it was not specific to alcohol. In the final experiment, the role of angiotensin and enkephalin was explored by pretreating animals with losartan (5, 10, 20 mg/kg), an angiotensin receptor blocker and naltrexone, (0.25, 0.5, 1 mg/kg) an opiate receptor blocker. Both agents produced significant but rather small attenuations in bestatin's effect suggesting that other factors are involved in its action. These findings further characterize the inhibitory effect of bestatin on alcohol intake in rodents. In addition, the novel finding of a carry-over inhibition of alcohol intake in the bestatin-free period adds further impetus to the recommendation that this drug, which has been safely used in humans, might be examined as a possible therapeutic agent for alcohol abuse.
Szczepanska
R
R
Department of Pharmacology, University of Toronto, Ontario, Canada.
Harding
S
S
Grupp
L A
LA
D000428:Alcohol Drinking; D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004327:Drinking Behavior / Q000187:drug effects; D004745:Enkephalins / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019808:Losartan; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000008:administration & dosage / Q000627:therapeutic use
D001713:Biphenyl Compounds; D004745:Enkephalins; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D009271:Naltrexone; D000626:Aminopeptidases; D007930:Leucine; C012211:ubenimex; D019808:Losartan