Upregulation of glutamate receptor subtypes during alcohol withdrawal in rats

Department of Psychiatry, University Hospital Rigshospitalet, Copenhagen, Denmark.
Alcohol and Alcoholism (Impact Factor: 2.89). 11/2004; 40(2):89-95. DOI: 10.1093/alcalc/agh117
Source: PubMed


To investigate glutamate receptor subtypes during alcohol withdrawal.
Rats were exposed to severe alcohol intoxication for 84 h and then decapitated at 0, 12 and 36 h after the last alcohol dose (n = 7 per group). Alcohol was administered five times a day by intragastric intubation. The densities of N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors were studied in membranes from the forebrain by using the specific ligands [3H]MK-801 and [3H]AMPA, respectively.
Although no change in the maximal density (B(max)) of [3H]MK-801 binding sites was observed at the time of withdrawal, [3H]MK-801 binding was increased by 49% 12 h into the withdrawal reaction compared with the control group. At 36 h post alcohol the B(max) of the [3H]MK-801 binding was still increased by 24% compared with the control group; however, this difference was not statistically significant. When investigated at the time of withdrawal from chronic alcohol intoxication, no significant alterations in the B(max) of the [3H]AMPA binding was detected, but 12 h into the withdrawal reaction the [3H]AMPA binding was markedly increased by 94%. At 36 h post alcohol the [3H]AMPA binding had returned to control levels. No significant alterations in the dissociation constant (K(D)) of either [3H]MK-801 or [3H]AMPA binding was observed at any time point.
NMDA and AMPA receptors are involved in the cerebral hyperactivity of alcohol withdrawal.

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Available from: Steven Haugbøl, Aug 21, 2015
    • "In particular , changes observed after chronic alcohol exposure include a reduction in number, function and sensitivity to GABA of the GABA A receptors (down-regulation)[14,16,17]and an increase in number, sensitivity and affinity for glutamate of NMDA receptors (up-regulation)[10,14,18]. More recently, an up-regulation of the glutamate receptors a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate has been described during AWS[19,20]. The abrupt reduction or cessation of alcohol intake produces an acute imbalance due to both the acute reduction of GABA activity and the increase of glutamatergic action, with consequent hyperexcitability and development of AWS symptoms, which may start as early as a few hours after the last alcohol intake[13]. "
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    ABSTRACT: Symptoms of alcohol withdrawal syndrome (AWS) may develop within 6-24 h after the abrupt discontinuation or decrease of alcohol consumption. Symptoms can vary from autonomic hyperactivity and agitation to delirium tremens. The gold-standard treatment for AWS is with benzodiazepines (BZDs). Among the BZDs, different agents (i.e., long-acting or short-acting) and different regimens (front-loading, fixed-dose or symptom-triggered) may be chosen on the basis of patient characteristics. Severe withdrawal could require ICU admission and the use of barbiturates or propofol. Other drugs, such as α2-agonists (clonidine and dexmetedomidine) and β-blockers can be used as adjunctive treatments to control neuroautonomic hyperactivity. Furthermore, neuroleptic agents can help control hallucinations. Finally, other medications for the treatment for AWS have been investigated with promising results. These include carbamazepine, valproate, sodium oxybate, baclofen, gabapentin and topiramate. The usefulness of these agents are discussed.
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    • "Our results differ in that we examine NMDARs in a specific region, the VTA, rather than in the whole brain. Also, our studies involved a relatively brief period of EtOH intake relative to previous work (Chen et al., 1997; Haugbøl et al., 2005). "
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    • "Chronic exposure of animals to alcohol can lead to a compensatory increase in NMDAR functionality through increased expression of NMDAR subunits; however, the experimental paradigm used can greatly influence which subunit is affected and the magnitude of the change. The largest alteration in expression occurs during withdrawal following a constant exposure or repeated deprivation protocol (Gulya et al., 1991; Darstein et al., 2000; Nixon et al., 2004; Haugbol et al., 2005; Nelson et al., 2005; Raeder et al., 2008). The influence of sex on molecular changes has not been extensively studied in human brain, despite its vulnerability (Harper et al., 1990). "
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