A blocker of N- and T-type voltage-gated calcium channels attenuates ethanol-induced intoxication, place preference, self-administration, and reinstatement.
There is a clear need for new therapeutics to treat alcoholism. Here, we test our hypothesis that selective inhibitors of neuronal calcium channels will reduce ethanol consumption and intoxication, based on our previous studies using knock-out mice and cell culture systems. We demonstrate that pretreatment with the novel mixed N-type and T-type calcium channel antagonist 1-(6,6-bis(4-fluorophenyl)hexyl)-4-(3,4,5-trimethoxybenzyl)piperazine (NP078585) reduced ethanol intoxication. NP078585 also attenuated the reinforcing and rewarding properties of ethanol, measured by operant self-administration and the expression of an ethanol conditioned place preference, and abolished stress-induced reinstatement of ethanol seeking. NP078585 did not affect alcohol responses in mice lacking N-type calcium channels. These results suggest that selective calcium channel inhibitors may be useful in reducing acute ethanol intoxication and alcohol consumption by human alcoholics.
Newton
Philip M
PM
Department of Neurology, Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville, California 94608, USA.
Zeng
Lily
L
Wang
Victoria
V
Connolly
Jacklyn
J
Wallace
Melisa J
MJ
Kim
Chanki
C
Shin
Hee-Sup
HS
Belardetti
Francesco
F
Snutch
Terrance P
TP
Messing
Robert O
RO
D000435:Alcoholic Intoxication / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D020864:Calcium Channels, N-Type / Q000172:deficiency / Q000502:physiology*; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D012054:Reinforcement, Psychology; D045442:Rotarod Performance Test; D012646:Self Administration; D013315:Stress, Psychological / Q000503:physiopathology
C534047:1-(6,6-bis(4-fluorophenyl)hexyl)-4-(3,4,5-trimethoxybenzyl)piperazine; C500963:Cacna1b protein, mouse; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D002492:Central Nervous System Depressants; D010879:Piperazines; D000431:Ethanol