A/L Murthy, Jayakumar
(2015)
Modulation of amygdalar glutamatergic neurotransmission during ethanol withdrawal induced anxiety-like syndrome via MGluR5-PKC epsilon mediated signalling pathway.
Masters thesis, Universiti Sains Malaysia.
Abstract
Abstinence from chronic ethanol consumption leads to the manifestation of a variety of
symptoms attributed to central nervous system hyperexcitability. Recent studies have
demonstrated the importance of metabotropic glutamate receptor 5 (mGluR5) in addictive
behaviours. This study investigated the role of amygdalar mGluR5-PKC epsilon mediated
signalling pathway in the manifestation of ethanol withdrawal (EW) induced anxiety. Male
Wistar rats were fed a Modified Liquid Diet (MLD) containing low fat cow’s milk, sucrose,
and maltodextrin with a gradual introduction of 2.4%, 4.8% and 7.2% ethanol for 20 days.
Six hours into EW, the rats were intraperitoneally injected with normal saline, MPEP (2.5,
5.0, 10, 20, 30 mg/kg) and ethanol (2.5g/kg, 20% v/v) and were assessed for EW induced
anxiety using an automated elevated plus maze (EPM) and an open field (OF). MPEP at 10
mg/kg significantly attenuated EW induced anxiety without any compromising effects on
locomotor activities of EW rats. However, low doses of MPEP (2.5, 5 mg/kg) significantly
compromised the locomotor activities of EW rats. High doses of MPEP (20 and 30 mg/kg)
and acute challenge of ethanol significantly attenuated withdrawal anxiety when tested in the
EPM but not OF. Administration of MPEP (2.5-30 mg/kg) has no significant compromising
effect on the locomotor activities of ethanol naive rats. Following Western Blot analysis,
significant increase in protein levels of mGluR5, total PKC epsilon and phosphorylated PKC
epsilon was seen in the amygdala of EW rats. MPEP (10mg/kg) produced significant
reduction in the protein levels of phosphorylated PKC epsilon. MPEP (2.5-30mg/kg) had no
significant effect on the total protein levels of PKC epsilon and mGluR5. Acute ethanol
challenge increased the protein expression of phosphorylated PKC epsilon in the amygdala
of EW rats but showed less alterations in the protein levels of total PKC epsilon and mGluR5
compared to EW rats. Following RT-PCR analysis, significant increase in mRNA levels of
mGluR5, NR1, NR2A, and NR2B subunits of NMDA receptors was recorded in the
amygdala of EW rats. EW had no significant effect on mRNA levels of PKC epsilon. MPEP
(10 and 30mg/kg) significantly reduced the gene expression of mGluR5 and NR2A subunit.
On the other hand, acute ethanol challenge significantly reduced the gene expression of
mGluR5 and NR2B. Overall, the results show that MPEP (10mg/kg) significantly attenuated
EW induced anxiety in the EPM and the OF through inhibition of mGluR5-PKC epsilon
signalling pathway which attenuated the EW induced glutamatergic hyperexcitability in the
amygdala by significantly reducing the abstinence induced increase in mGluR5 and NR2A
gene expression.
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