Levetiracetam has opposite effects on alcohol- and cocaine-related behaviors in C57BL/6J mice.
The antiepileptic drug levetiracetam (LEV) is a potential treatment for alcohol use disorders, yet few preclinical studies exist on its effects in animal models relevant to drug or alcohol abuse. We investigated the effects of LEV on locomotor stimulation following acute and repeated administration of alcohol or cocaine and on alcohol- and cocaine-mediated changes in responding for brain stimulation reward (BSR) in C57BL/6J mice. LEV alone (10.0-100.0 mg/kg intraperitoneally) had no significant effect on locomotor activity or intracranial self-stimulation. Pretreatment with LEV reduced acute locomotor stimulation by 2.0 g/kg alcohol, attenuated the development of locomotor sensitization to alcohol with repeated exposure, and produced a shift in the dose-response curve for alcohol on BSR threshold without affecting maximum operant response rate (MAX). Conversely, LEV pretreatment enhanced both acute locomotor stimulation by 15 mg/kg cocaine and development of locomotor sensitization following repeated exposure and produced a leftward shift in the dose-response curve for cocaine on BSR threshold without affecting MAX. Electrophysiological recordings in vitro showed that LEV reduced excitatory currents in both ventral tegmental area (VTA) dopamine neurons and nucleus accumbens (NAc) medium spiny neurons, consistent with a presynaptic effect. The opposite effects of LEV pretreatment on alcohol- and cocaine-related behaviors may predict its clinical utility in the treatment of patients with alcohol, but not psychostimulant abuse disorders.
Laboratory of Developmental Neuropharmacology, Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7025, USA.
J Elliott
JE
Robinson
Meng
M
Chen
Alice M
AM
Stamatakis
Michael C
MC
Krouse
Elaina C
EC
Howard
Sara
S
Faccidomo
Clyde W
CW
Hodge
Eric W
EW
Fish
C J
CJ
Malanga
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000037:antagonists & inhibitors / Q000494:pharmacology; D059333:Central Nervous System Sensitization / Q000187:drug effects; D003042:Cocaine / Q000819:agonists* / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000819:agonists / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D000077287:Levetiracetam; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D012653:Self Stimulation / Q000187:drug effects*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology
D000927:Anticonvulsants; D002492:Central Nervous System Depressants; D018765:Dopamine Uptake Inhibitors; D000431:Ethanol; D000077287:Levetiracetam; D003042:Cocaine; D010889:Piracetam