Effects of calcium channel blockade on intravenous self-administration of ethanol in rats.
In the present study the involvement of voltage-operated calcium channels (VOCCs) in the acquisition and maintenance of operant i.v. ethanol (EtOH) self-administration was investigated in rats. Rats readily learned to self-administer EtOH (unit dose range: 0.5-4% v/v) within five daily 2-h sessions, when infusions were made contingent upon nose-poking in a hole containing infrared sensors. Response rate was related to the EtOH concentration in an inverted U-shaped manner, the maximal rate and intake being observed at a unit dose of 1% v/v (0.27 mg EtOH/infusion). Self-administration of EtOH appeared to be behaviorally specific, as responding in the reinforced hole did not coincide with increased responding in a nonreinforced hole. Daily treatment with the dihydropyridine VOCC blocker nimodipine (2.5-20 mg/kg, i.p., t-15 min) dose-dependently attenuated acquisition of EtOH self-administration; the 5 mg/kg dose resulting in a partial, and the 10 and 20 mg/kg doses in a complete prevention of i.v. self-administration behavior. The effects of nimodipine (2.5-5.0 mg/kg) were considered to be relatively specific, as an inhibition of the reinforced responding could be demonstrated in the absence of a significant effect on nonreinforced responding. When tested in rats showing stable self-administration behavior (unit dose: 1% v/v EtOH), nimodipine showed biphasic dose-response effects; with 2.5 and 5 mg/kg resulting in a mild increase, and 10 and 20 mg/kg resulting in a decrease of self-administration behavior, respectively. The present study suggests that blockade of VOCCs attenuates the reinforcing stimulus effects of EtOH; and, as such, the data may offer an explanation for the previously reported EtOH intake-reducing effects of dihydropyridine calcium channel ligands obtained in two-bottle choice paradigms. Dihydropyridine derivatives, such as nimodipine, may therefore offer an interesting approach to the pharmacotherapy of alcoholism.
Kuzmin
A
A
Pavlov Medical University, St. Petersburg, Russia. alexander.kuzmin@fyfa.ke.se
Semenova
S
S
Zvartau
E
E
De Vry
J
J
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects; D020864:Calcium Channels, N-Type; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D009553:Nimodipine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D002492:Central Nervous System Depressants; D004095:Dihydropyridines; D000431:Ethanol; D009553:Nimodipine