Effects of the mGluR5 antagonist MPEP on ethanol withdrawal induced anxiety-like syndrome in rats

Abstract

Abstinence from chronic ethanol consumption leads to the manifestation of a variety of symptoms attributed to central nervous system hyperexcitability, such as increased irritability, anxiety, and restlessness. Recent studies have demonstrated the importance of metabotropic glutamate receptor 5 (mGluR5) in addictive behaviours. This study investigates the effects of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on ethanol withdrawal induced anxiety using two behavioural paradigms. Male Wistar rats were fed a Modified Liquid Diet (MLD) containing low fat cow milk, sucrose, and maltodextrin with a gradual introduction of 2.4%, 4.8% and 7.2% ethanol for 20 days. Six hours into ethanol withdrawal, the rats were intraperitoneally injected with normal saline and MPEP (2.5, 5.0, 10, 20, 30 mg/kg) and were assessed for ethanol withdrawal induced anxiety-like syndrome using an automated elevated plus maze and an open field. MPEP at 10 mg/kg significantly attenuated ethanol withdrawal induced anxiety without any compromising effects on locomotor activities. Despite reversing several indices of ethanol withdrawal induced anxiety in both the elevated plus maze and the open field, low doses of MPEP (2.5, 5 mg/kg) significantly compromised the locomotor activities of ethanol withdrawn rats. High doses of MPEP (20 and 30 mg/kg) significantly attenuated withdrawal anxiety when tested in the elevated plus maze but not in the open field. Administration of MPEP (2.5, 5, 10, 20, 30 mg/kg) has no significant compromising effect on the locomotor activities of ethanol naïve rats. Despite significantly reducing withdrawal anxiety in both behavioural paradigms at 10 mg/kg, the compromising effects of low and high doses of MPEP must be further explored along with the therapeutic efficiency of this drug for relieving withdrawal induced anxiety.

Simvastatin treatment reduces the cholesterol content of membrane/lipid rafts, implicating the N -methyl-D-aspartate receptor in anxiety: a literature review

“…In particular, the up-regulation of different subunits of the NMDA receptor may cause hyperexcitability of the CNS during withdrawal or negative emotions such as dysphoria, irritability, anxiety, and depression (BlancoGandía et al, 2015). In accordance with numerous data in the literature, ethanol withdrawal induces an anxiogenic effect in the elevated plus-maze (Kumar et al, 2013;Van Skike, Diaz-Granados, Matthews, 2015). However, these findings contrast our previous data indicating that lower doses of ethanol produce anxiolytic-like effects (Cruz et al, 2012a).…”

Voluntary induction and maintenance of alcohol dependence in rats using alcohol vapor self-administration

“…However, the analysis of closed arm entries did not indicate any differences between escalated, non-escalated, and naive rats. Additionally, evidence of a general reduction of motor function during alcohol withdrawal has been reported in rats (Kumar et al 2013; Williams et al 2012). The negative emotional state during acute withdrawal was also reflected by the development of mechanical hyperalgesia.…”

Group 1 mGlu-family proteins promote neuroadaptation to ethanol and withdrawal-associated hippocampal damage

“…This study also found that pretreatment with mGlu5 antagonist MPEP dose-dependently reduced binge ethanol consumption in rodents. Others have shown that MPEP administration (10 mg/kg) attenuated ethanol withdrawal anxiety-like behaviors (Kumar et al, 2013) or have shown a reduction in ethanol reinstatement following acute MPEP administration elicited by drug-associated cues (Bäckström et al, 2004), as well as attenuation of ethanol withdrawal-elicited behaviors in rodents (Blendov and Harris, 2008). …”