Schizophrenia is a mental disorder characterized by a series of positive, negative or cognitive symptoms but with also the particularity of exhibiting a high rate of co-morbid use of drugs of abuse. While more than 80% of schizophrenics are smokers, the second most consumed drug is alcohol, with dramatic consequences on frequency and intensity of psychotic episodes and on life expectancy. Here we investigated the impact of light alcohol intake during adolescence on the subsequent occurrence of alcohol addiction-like behavior in neonatal ventral hippocampal lesion (NVHL) rats, a neurodevelopmental model of schizophrenia. Our findings demonstrated an increased liability to addictive behaviors in adult NVHL rats after voluntary alcohol intake during adolescence. NVHL rats displayed several signs of alcohol use disorder such as a loss of control over alcohol intake and high motivation to consume alcohol, associated with a higher resistance to extinction. In addition, once NVHL rats relapsed, they maintained higher drinking levels than controls. We finally showed that the anti-addictive drug naltrexone is efficient in reducing excessive alcohol intake in NVHL rats. Our results are in accordance with epidemiological studies underlying the particular vulnerability to alcohol addiction after adolescent exposure to alcohol and highlight the fact that schizophrenic subjects may be particularly at risk even after light alcohol consumption. Based on these results, it seems particularly relevant to prevent early onset of alcohol use in at-risk subjects and thus to reduce the incidence of co-morbid alcohol abuse in psychotic patients.

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.