ACTIVATION OF BRAIN HISTAMINERGIC NEUROTRANSMISSION: A MECHANISM FOR COGNITIVE EFFECTS OF MEMANTINE IN ALZHEIMER’S DISEASE. M. MOTAWAJ, A. BURBAN, E. DAVENAS and J-M. ARRANG

2 a) Running Title : Memantine activates histamine neurons in vivo. This article has not been copyedited and formatted. The final version may differ from this version. ABSTRACT We previously reported that some NMDA-receptor antagonists enhanced histamine neuron activity in rodents. Here, we have investigated the effects of memantine, an NMDA-receptor antagonist used for the treatment of Alzheimer's disease, on histaminergic neurotransmission. In vitro, memantine antagonized native NMDA receptors with a micromolar potency, but had no effect at recombinant human histamine receptors. In vivo, acute administration of memantine increased histamine neuron activity, as shown by the 60 % increase of tele-methylhistamine (t-MeHA) levels observed in the brain of mice. This increase occurred with an ED 50 of 0.3 ± 0.1 mg/kg, similar to that found on inhibition of ex vivo [ 3 H]MK-801 binding (1.8 ± 1.3 mg/kg). Two days after pre-treatment of mice with memantine at 5 mg/kg twice daily for 5 days, t-MeHA levels were enhanced by 50 ± 7 % (p<0.001), indicating a long-lasting activation of histamine neurons. Quantitative PCR analysis was used to explore genes involved in this persistent effect. H 3-receptor mRNAs were strongly increased, but the density of H 3-receptor binding sites was increased solely in hypothalamus (by 141 ± 24 %). Up-regulations of BDNF and NMDA-receptor 1 subunit mRNAs were also found, but were restricted to hippocampus. mRNA expression of alpha7-nicotinic receptors remained unchanged in any region. Considering the well-established cognitive effects of histamine neurons, the increase in brain t-MeHA levels after acute or repeated administration of therapeutic doses of memantine suggests that the drug exerts its beneficial effects on cognitive deficits of Alzheimer's disease, at least partly, by activating histamine neurons. This article has not been copyedited and formatted. The final version may differ from this version.