Effects of the Non‐Competitive NMDA Receptor Antagonist Memantine on the Volitional Consumption of Ethanol by Alcohol‐Preferring Rats

Abstract

Potent N-methyl-D-aspartate (NMDA) receptor antagonists decrease volitional consumption of ethanol by rats. This study examined the effects of memantine, a low-affinity, open channel NMDA antagonist, on volitional consumption of ethanol by alcohol-preferring rats and potential locomotor, sedative and hypothermic effects. Volitional consumption of ethanol in a 24-hr two-choice paradigm was determined for male Myers' high-ethanol-preferring (mHEP) rats. Effects of memantine (0.3, 1.0, 3.0 and 10.0 mg ⁄ kg, i.p., b.i.d. [twice daily] for 3 days) or vehicle on volitional consumption of ethanol, proportion of ethanol to total fluids consumed, total fluid intake and consumption of food were observed. Potential sedating and locomotor effects of memantine (10.0 mg ⁄ kg, i.p., b.i.d.) were determined using an elevated plus maze and an Auto-Track Opto-Varimex activity monitoring system. Rectal temperature was measured to determine if memantine (10.0 mg ⁄ kg, i.p.) produces a hypothermic effect. The results indicate that memantine dose-dependently decreased the amount of ethanol and proportion of ethanol to total fluids consumed daily, reaching 48% and 24%, respectively, at the highest dose. These effects did not appear to be anti-caloric. Memantine (10.0 mg ⁄ kg) partially reversed both the sedation and the reductions in locomotor activity induced by ethanol. This dose did, however, produce a small, partially reversible hypothermic effect. In conclusion, memantine may decrease ethanol consumption with fewer side effects than other NMDA receptor antagonists, such as phencyclidine (PCP), MK 801 and ketamine.In the Diagnostic and Statistical Manual, 4th Edition (DSM-IV), the American Psychiatric Association has defined alcohol abuse and alcohol dependence as maladaptive patterns of alcohol use leading to clinically significant impairment or distress [1]. Cloninger and colleagues [2] have divided alcoholism into two subtypes based on distinct alcohol-related symptoms, personality traits, ages of onset and patterns of inheritance. Type 1 alcoholics are characterized by anxious (passive-dependent) personality traits and rapid development of tolerance and dependence on the anti-anxiety effects of alcohol. These drinkers lose control, have difficulty ending binges once they begin, feel guilty and experience liver complications following socially encouraged exposure to alcohol use. Type 2 alcoholics are characterized by anti-social personality traits and persistent seeking of alcohol for its euphoriant effects. These drinkers experience an early onset of inability to abstain entirely from alcohol use and are involved in fighting and arrests when drinking [2].Ethanol inhibits glutamatergic neurotransmission at the ionotropic N-methyl-d-aspartate (NMDA) receptor [3][4][5][6] which suggests that NMDA antagonists may be effective drugs for treating alcohol dependence and ⁄ or alcohol abuse. Previously, our laboratory demonstrated that LY 274614, a competitive NMDA antagonist, dizocilpine (MK 801), a non-competitive NMDA rece...

Alternative Splicing of AMPA Subunits in Prefrontal Cortical Fields of Cynomolgus Monkeys Following Chronic Ethanol Self-Administration

“…An integral role of iGluR transmission is further implicated by several demonstrations that modulators at these receptors affect alcohol intake and reinstatement. Ethanol self-administration is reduced by competitive and non-competitive NDMA receptor antagonists (Rassnick et al, 1992; Bienkowski et al, 1999; Holter et al, 2000; Malpass et al, 2010) and competitive AMPA/kainate receptor antagonists (Stephens and Brown, 1999). Cue-induced reinstatement of ethanol maintained responding is reduced by lamotrigine, a glutamate release inhibitor (Vengeliene et al, 2007), competitive NMDA receptor antagonists (Backstrom and Hyytia, 2004; Bachteler et al, 2005), the NMDA receptor modulator acamprosate (Bachteler et al, 2005) as well as competitive AMPA/kainate antagonists (Backstrom and Hyytia, 2004; Sanchis-Segura et al, 2006), including topiramate (Knapp et al, 2007; Lynch et al, 2011).…”

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

“…Furthermore, inhibition of the NR2B subunit of NMDA in the dorsal medial striatum has been shown to significantly decrease alcohol consumption in chronically exposed rats, which is indicative of NR2B NMDA receptor subunit playing a crucial role in alcohol consumption (Wang et al, 2010). Additionally, studies have shown that memantine and MK-801, NMDA receptor antagonists, affect several behavioral aspects associated with alcohol consumption such as alcohol sensitization, locomotor activities and sedative properties (Malpass et al, 2010; Meyer and Phillips, 2003; Paoletti et al, 2013; Shen and Phillips, 1998). Memantine also exhibited promising results in attenuating motor impairment as well as preventing cerebellar cell loss, thus indicating its neuroprotective effects (Idrus et al, 2011).…”

“…However, memantine was not able to improve the learning deficit associated with binge alcohol consumption (Idrus et al, 2011). Interestingly, a study performed on male Myers’ high-alcohol-preferring (mHEP) rats reported that memantine dose-dependently decreased alcohol consumption in a 24-hour two-choice volitional consumption paradigm (Malpass et al, 2010). However, a study reported that memantine administration heightened the aggressive behavior associated with alcohol consumption (Newman et al, 2012).…”

Interactions of a Dopamine D1 Receptor Agonist with Glutamate NMDA Receptor Antagonists on the Volitional Consumption of Ethanol by the mHEP Rat

“…memantine on the consumatory behavior of the mHEP rat. These doses were chosen as being minimal effective doses for a decrease in the consumption of ethanol [16,27]. As can be seen, there were small decreases in consumption with either drug alone, but no additivity when the drugs were combined, only a 17.3% decrease in the amount consumed compared to the pre-treatment baseline.…”

“…Drugs that target this receptor to reduce glutamate activation will reduce the volitional consumption of ethanol by selectively bred high ethanol preferring rats. Thus, a drug that directly inhibits the binding of glutamate to this ligand-operated channel, LY 274614 (3 SR ,4a RS ,6 SR ,8a RS -6-[phosphonomethyl]-decahydroisoquinoline-3-carboxylic acid), drugs that inhibit the binding of glycine to an accessory site on the receptor, (+)-HA-966 (3-amino-1-hydroxy-2-pyrrolidone) and ACPC (1-aminocyclo-propane-1-carboxylic acid), a drug that binds to the “PCP-site” to potently and non-competitively inhibit, dizolcipine (MK-801), or a drug that blocks the opened channel, memantine, all will decrease volitional consumption at doses with insignificant or small effects on food intake and motor performance [15,16]. In humans, pre-treatment of moderate drinkers with memantine reduced the craving for alcohol prior to their receiving alcohol, but not afterwards [17,18].…”