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.

Long‐lasting effect of NMDA receptor antagonist memantine on ethanol‐cue association and relapse

“…Such an indirect and very long-lasting effect (for several weeks) of drug treatment on gene expression and relapse behaviour was recently observed by us by applying a glycine transporter inhibitor (Vengeliene et al 2010). In addition, long-lasting effects of memantine on operant behaviour (up to 30 h) has already been demonstrated in previous studies, showing that this drug may also alter gene expression and protein synthesis (Jeanblanc et al 2014;Alaux-Cantin et al 2015), and thus causing long-lasting behavioural changes. Fig.…”

“…In addition, long‐lasting effects of memantine on operant behaviour (up to 30 h) has already been demonstrated in previous studies, showing that this drug may also alter gene expression and protein synthesis (Jeanblanc et al . ; Alaux‐Cantin et al . ), and thus causing long‐lasting behavioural changes.…”

Metabotropic and ionotropic glutamate receptors as potential targets for the treatment of alcohol use disorder

“…However, a study reported that memantine administration heightened the aggressive behavior associated with alcohol consumption (Newman et al, 2012). It is noteworthy that memantine treatments exerted the ability to reduce self-administration to alcohol (Jeanblanc et al, 2014). …”

BDNF Val66Met and reward-related brain function in adolescents: role for early alcohol consumption

“…Previous animal and human studies suggest that BDNF is associated with alcohol consumption (e.g., Jeanblanc, Coune, Botia, & Naassila, 2014;Jeanblanc et al, 2009). However, investigations on this association in adolescence, a risk period where alcohol consumption starts to develop to possibly problematic (ab)use (Chambers, Taylor, & Potenza, 2003), are missing.…”