title: Brain-derived neurotrophic factor mediates the suppression of alcohol self-administration by memantine.
abstract: Brain-derived neurotrophic factor (BDNF) within the striatum is part of a homeostatic pathway regulating alcohol consumption. Memantine, a non-competitive antagonist of N-methyl-D-aspartate receptors, induces expression of BDNF in several brain regions including the striatum. We hypothesized that memantine could decrease ethanol (EtOH) consumption via activation of the BNDF signalling pathway. Effects of memantine were evaluated in Long-Evans rats self-administering moderate or high amounts of EtOH 6, 30 and 54 hours after an acute injection (12.5 and 25 mg/kg). Motivation to consume alcohol was investigated through a progressive ratio paradigm. The possible role for BDNF in the memantine effect was tested by blockade of the TrkB receptor using the pharmacological agent K252a and by the BDNF scavenger TrkB-Fc. Candidate genes expression was also assessed by polymerase chain reaction array 4 and 28 hours after memantine injection. We found that memantine decreased EtOH self-administration and motivation to consume EtOH 6 and 30 hours post-injection. In addition, we found that inhibition or blockade of the BDNF signalling pathway prevented the early, but not the delayed decrease in EtOH consumption induced by memantine. Finally, Bdnf expression was differentially regulated between the early and delayed timepoints. These results demonstrate that an acute injection of memantine specifically reduces EtOH self-administration and motivation to consume EtOH for at least 30 hours. Moreover, we showed that BDNF was responsible for the early effect, but that the delayed effect was BDNF-independent.
authors: Groupe de Recherche sur l'Alcool et les Pharmacodépendances - INSERM ERI 24, UFR de Pharmacie, Université de Picardie Jules Verne, SFR CAP Santé, France.
authors: Jérôme
authors: J
authors: Jeanblanc
authors: Fabien
authors: F
authors: Coune
authors: Béatrice
authors: B
authors: Botia
authors: Mickaël
authors: M
authors: Naassila
mesh_terms: D000428:Alcohol Drinking / Q000517:prevention & control*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000502:physiology*; D002227:Carbazoles / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D026121:Indole Alkaloids / Q000494:pharmacology; D007267:Injections; D008297:Male; D008559:Memantine / Q000008:administration & dosage / Q000494:pharmacology*; D009042:Motivation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects; D020318:Rats, Long-Evans; D020813:Receptor, trkB / Q000037:antagonists & inhibitors; D012646:Self Administration; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D002492:Central Nervous System Depressants; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D026121:Indole Alkaloids; D000431:Ethanol; C049985:staurosporine aglycone; D020813:Receptor, trkB; D008559:Memantine
keywords: Alcohol consumption; BDNF; memantine; prefrontal cortex; self-administration; striatum