Available online at www.sciencedirect.com
Drug and Alcohol Dependence 96 (2008) 16–21
Expression of N-methyl-d-aspartate (NMDA) receptor subunits and splice
variants in an animal model of long-term voluntary alcohol
self-administration
Hanna Raeder
a
, Sabine M. Holter
b
, Annette M. Hartmann
a
, Rainer Spanagel
c
,
Hans-Juergen Moller
a
, Dan Rujescu
a,∗
a
Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany
b
Max-Planck-Institute of Psychiatry, Munich, Germany
c
Department of Psychopharmacology, Central Institute of Mental Health, Mannheim, Germany
Received 27 February 2006; received in revised form 21 December 2007; accepted 7 April 2008
Available online 21 March 2008
Abstract
Long-term, free-choice, alcohol self-administration with repeated alcohol deprivation phases is known to enhance N-methyl-d-aspartate (NMDA)
receptor activity. We hypothesized that this might not only reflect an increase in NMDA receptor density, but that differential transcriptional
regulation and alternative splicing of the various subunits comprising the NMDA receptor may lead to changes in receptor composition and
subsequent function. We, therefore, aimed to further investigate this effect in various brain regions. The relative mRNA expression of exon 5
inclusion/exclusion variants of the NR1 subunit, and the relative expression of NR2A, NR2B and NR2C subunits was examined in rats subjected to
long-term free-choice, alcohol self-administration with repeated alcohol deprivation phases. We observed a relative decrease of the NR2C/NR2A
mRNA ratio and an increase of NR1 splice variants including exon 5 (NR1 + E5) in the striatum but not in the cortex, hippocampus or cerebellum
in the experimental group. Our results demonstrate that long-term voluntary alcohol self-administration, affects the regulation of genes encoding
the various subunits and splice variants of the NMDA receptor in a brain regional-specific manner.
© 2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: Alcohol; Ethanol; Addiction; NMDA-subunits; mRNA splicing; Deprivation
1. Introduction
In order to study the molecular mechanisms of alcohol addic-
tion, appropriate animal models are warranted. Although current
animal models are generally unable to incorporate all aspects and
criteria of alcohol dependence seen in humans, they can at least
reflect some of the criteria given in the fourth edition of Diag-
nostic and Statistical Manual of Mental Disorders (DSM-IV) of
the American Psychiatric Association (1994). Here we used a
rat model of long-term, free-choice, alcohol self-administration
with repeated alcohol deprivation phases (Spanagel and Holter,
1999; Sanchis-Segura and Spanagel, 2006). These animals show
∗
Corresponding author at: Division of Molecular and Clinical Neurobiology,
Department of Psychiatry, Ludwig-Maximilians-University, Nussbaumstr. 7, D-
80336 Munich, Germany. Tel.: +49 89 5160 5756; fax: +49 89 5160 5779.
E-mail address: Dan.Rujescu@med.uni-muenchen.de (D. Rujescu).
certain characteristics: (i) they exhibit relapse-like drinking
behavior (=alcohol deprivation effect/ADE), (ii) they have a
high, even compulsive motivation to consume alcohol during
an ADE, (iii) they show tolerance to some effects of alcohol and
have mild symptoms of physical withdrawal during the onset of
abstinence, and (iv)during abstinence they exhibit psychological
withdrawal symptoms consisting of enhanced anxiety-related
behaviour and hyper-reactivity to stressful stimuli (Spanagel
and Holter, 1999; Sanchis-Segura and Spanagel, 2006). In sum-
mary, these behavioral characteristics are very similar to those
observed in alcohol dependent patients and therefore this ani-
mal model can be used for studying molecular mechanisms of
alcohol addiction.
The N-methyl-d-aspartate (NMDA) receptor is a ligand-
gated ion channel complex which belongs to the family of
glutamate receptors. The receptor contains distinct ligand recog-
nition sites sustaining both Na
+
and Ca
2+
currents and is
essentially involved in learning and memory and is implicated
0376-8716/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.drugalcdep.2007.12.013