Calcium channel agonist (-)-BAY k 8644 suppresses free and limited access intake of alcohol in genetic drinking rats.
Drugs which possess selective actions on a given voltage operated calcium (Ca2+) channel (VOCC) are reportedly involved in the pharmacological actions of alcohol. Recently it was shown that the 1,4-dihydropyridine (-)-BAY k 8644, an L-type VOCC agonist, reduces alcohol intake relatively selectively in the genetic drinking AA rat. This study determined whether (-)-BAY k 8644 would alter volitional alcohol drinking in two other genetic models of alcoholism, male P rats and a new strain of male and female high ethanol preferring (HEP) rats. By use of a standard 10-day preference test for water versus 3 to 30% alcohol, the maximally preferred concentration of alcohol was first determined for each rat individually, i.e. 9%, 13% or 15%. Then the rats were allowed free access over 24 h or limited access to alcohol for only 2 h, during which time the intakes of water and preferred solution of alcohol were recorded. After the drinking patterns stabilized for 4 days, saline, a solutol vehicle solution or (-)-BAY k 8644 was administered: (1) in a dose of 0.125, 0.25 or 0.5 mg/kg given intraperitoneally twice daily for 4 days during free access to alcohol; and (2) for 3 days in a dose of 0.125 or 0.25 mg/kg given subcutaneously 30 min prior to 2 h of limited access to alcohol. Fluid intakes were recorded for either 4 or 8 days after limited and free access conditions, respectively. Whereas the control solutions were without effect during 24 h access, (-)-BAY k 8644 caused a significant dose-dependent suppression of up to 80% in absolute g/kg and proportion of alcohol to total fluid consumed; this decline persisted in the post drug period. During the limited access paradigm, (-)-BAY k 8644 similarly reduced alcohol drinking maximally within the first 15 min of presentation of alcohol; again, this reduction persisted over the remaining 105 min of alcohol access. Also, individual levels of blood alcohol declined concurrently with the suppression of drinking. These results demonstrate that (-)-BAY k 8644 possesses a short latency of action on alcohol intake and that its salutary effects on drinking persist after the drug is terminated. Finally, the hypothesis that L-type calcium channel agonists may be useful as a therapeutic adjunct in the treatment of alcoholism is extended.
West
M W
MW
Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC 27858-4354, USA.
Biggs
T A
TA
Schreiber
R
R
De Vry
J
J
Myers
R D
RD
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology* / Q000627:therapeutic use; D000428:Alcohol Drinking / Q000188:drug therapy / Q000378:metabolism; D000437:Alcoholism / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D000438:Alcohols / Q000097:blood; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D000438:Alcohols; D002120:Calcium Channel Agonists; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester