Interaction of memantine with ethanol consumption and dopaminergic function in high ethanol preferring rats

Abstract

N-methyl-D-aspartate (NMDA) receptor antagonists have been reported to decrease ethanol consumption in rodents, but these drugs often produce adverse side effects. Memantine is a neuroprotective and low-affinity, noncompetitive NMDA receptor antagonist shown to be an effective treatment for Alzheimer's disease with a favorable clinical profile. This study investigated effects of memantine on volitional ethanol consumption in the Myers' high ethanol preferring (mHEP) rat using a two-choice 24 hour access paradigm. Memantine was found to reduce ethanol consumption in an apparent dose-dependent manner. Behavioral experiments indicated that memantine, at a dose shown to decrease ethanol consumption, did not adversely affect locomotor ability and activity, induce sedation, or add to ethanol-induced hypothermia. Previously, ethanol has been shown to alter levels of dopamine metabolism (DA) in brain regions receiving DA input in the DA reward pathway. Therefore, high performance liquid chromatrography (HPLC) was used to compare levels of DA metabolism in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and striatum (STR) of rats treated with saline, memantine (10.0 mg/kg, i.p.) and/or ethanol (1.0 or 2.5 g/kg, i.p.). No significant treatment effects were detected in levels of DA or its metabolite, 3,4- dihydroxyphenylacetic acid (DOPAC). Ethanol (2.5 g/kg) increased striatal DOPAC to levels bordering on significance, but mematine clearly produced no effect. To determine if memantine alters ethanol intake via signaling downstream of activation of the DA D1 receptor, Western blots were used to compare effects of the same treatments on levels of DARPP-32, a protein implicated as an intracellular regulator in ethanol reward, and its phosphorylation at Thr34 and Thr75 sites in the mPFC, NAc, and STR. Bands for phospho-DARPP-32 (Thr34) in the mPFC were undetectable. All other blots indicated no significant treatment effects on levels of DARPP-32 or its phosphorylation at Thr34 and Thr75 sites. Together, these results suggest that mechanisms which do not involve glutamate and the NMDA receptor may also activate ethanol reward in the mHEP rat, and a mechanism not downstream of the DA D1 receptor is involved. The effect of memantine on consumption of ethanol does not involve modification of the DA/DARPP- 32 signaling system.