INTERACTION OF MEMANTINE WITH ETHANOL CONSUMPTION AND DOPAMINERGIC FUNCTION IN HIGH ETHANOL PREFERRING RATS

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Gloria Elaine Malpass (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: ABSTRACT  Gloria E. Malpass. INTERACTION OF MEMANTINE WITH ETHANOL CONSUMPTION  AND DOPAMINERGIC FUNCTION IN HIGH ETHANOL PREFERRING RATS. (Under  the supervision of Dr. Brian A. McMillen) Department of Pharmacology and Toxicology,  November 2009.  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.  

Additional Information

Publication

Dissertation

Language: English

Date: 2009

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