Upregulation of glutamate receptor subtypes during alcohol withdrawal in rats

Article (PDF Available)inAlcohol and Alcoholism 40(2):89-95 · November 2004with18 Reads
DOI: 10.1093/alcalc/agh117 · Source: PubMed
Abstract
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.
Alcohol & Alcoholism Vol. 40, No. 2, pp. 89–95, 2005 doi:10.1093/alcalc/agh117
Advance Access publication 29 November 2004
UPREGULATION OF GLUTAMATE RECEPTOR SUBTYPES DURING
ALCOHOL WITHDRAWAL IN RATS
STEVEN ROSENZWEIG HAUGBØL
1
, BJARKE EBERT
2
and JAKOB ULRICHSEN
1
*
1
Neuropsychiatric Research Group, Department of Psychiatry 6234, University Hospital Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen,
Denmark and
2
Department of Neurobiology, Biological Research, Lundbeck A/S, Ottiliavej 9, DK 2500 Valby, Denmark
(Received 30 May 2004; first review notified 11 August 2004; in revised form 19 September 2004; accepted 19 September 2004)
Abstract Aims: To investigate glutamate receptor subtypes during alcohol withdrawal. Methods: 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 [
3
H]MK-801
and [
3
H]AMPA, respectively. Results: Although no change in the maximal density (B
max
) of [
3
H]MK-801 binding sites was observed
at the time of withdrawal, [
3
H]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 [
3
H]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 [
3
H]AMPA binding was detected, but 12 h into the withdrawal reaction the [
3
H]AMPA binding
was markedly increased by 94%. At 36 h post alcohol the [
3
H]AMPA binding had returned to control levels. No significant alterations
in the dissociation constant (K
D
) of either [
3
H]MK-801 or [
3
H]AMPA binding was observed at any time point. Conclusions: NMDA
and AMPA receptors are involved in the cerebral hyperactivity of alcohol withdrawal.
Alcohol & Alcoholism Vol. 40, No. 2 © Medical Council on Alcohol 2005; all rights reserved
*Author to whom correspondence should be addressed at: Department of
Psychiatry, Gentofte University Hospital, Niels Andersens Vej 65, DK-2900,
Hellerup, Denmark. Tel.: +45 3977 3658; Fax: +45 3977 7600; E-mail:
jakob.ulrichsen@mail.dk
89
INTRODUCTION
The amino acid glutamate is quantitatively the most important
excitatory neurotransmitter in the central nervous system
(CNS). It exerts its effects through specific receptors, which
can be categorized into two groups, i.e. the metabotropic and
ionotropic receptors. The metabotropic receptors are coupled
to intracellular G proteins and when activated, they are
involved in the production of secondary messengers in the
activated neuron. The ionotropic receptors are ion channels,
which, upon activation, allow a transmembranous passage of
cations such as sodium, potassium and calcium, which results
in a lowering of the membrane potential. The ionotropic
glutamate receptors are further divided into the subtypes
2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA), N-methyl-D-aspartate (NMDA) and kainic acid
according to their selective agonists (Watkins et al., 1990;
Nakanishi, 1992; Sommer and Seeburg, 1992). For more than
a decade several studies have indicated that glutamate may
play an important role in the effects of alcohol in the brain
including hyperactivity, which is seen during withdrawal from
longterm intoxication. When administered acutely, alcohol in
pharmacologically relevant concentrations causes a
suppression of the NMDA receptor function in vitro. This has
been demonstrated in electrophysiology studies in which
NMDA-activated currents were inhibited by alcohol (Lovinger
et al., 1989, 1990; White et al., 1990) and in biochemical
experiments where alcohol resulted in inhibition of NMDA-
induced Ca
2+
uptake (Dildy and Leslie, 1989; Hoffman et al.,
1989). On the other hand, when exposed chronically to
alcohol the NMDA receptor function seems to be increased,
perhaps as a result of adaptation to the inhibiting effects of
acute alcohol administration. Thus, chronic alcohol
administration resulted in increased ligand binding to the
NMDA receptor (Grant et al., 1990; Gulya et al., 1991; Sanna
et al., 1993; Hu and Ticku, 1995) and enhanced NMDA-
stimulated increase in intracellular Ca
2+
concentration (Iorio
et al., 1993; Blevins et al., 1995; Hu and Ticku, 1995;
Smoothers et al., 1997). In addition, administration of NMDA
to animals withdrawing from chronic alcohol exposure results
in an increase in seizure activity (Grant et al., 1990; Sanna
et al., 1993), mortality (Davidson et al., 1993; Sanna et al.,
1993) and morphological damage (Davidson et al., 1995)
compared with control animals, whereas the NMDA
antagonist dizocilpine (MK-801) has been shown to inhibit
alcohol withdrawal seizures in mice (Grant et al., 1990) and
rats (Morrisett et al., 1990). Furthermore, mice bred to express
a severe reaction to alcohol withdrawal have an increased
density of NMDA receptor binding sites in hippocampus
compared with mice bred to express a mild alcohol withdrawal
reaction (Valverius et al., 1990).
The involvement of the AMPA and kainic acid receptors in
the cerebral effects of alcohol has not been studied to the same
extent as the NMDA receptor and the results are less
consistent. Martin et al. (1995) demonstrated that alcohol
inhibited AMPA and kainic acid induced depolarization in
hippocampus. A similar finding was shown by Lovinger et al.
(1989) but in this study the NMDA receptors were inhibited to
a much higher degree by alcohol than the AMPA and kainic
acid receptors. An increased sensitivity to NMDA and AMPA
on the firing rate of the neurons was detected in alcohol
withdrawing rats in the locus coeruleus, whereas the
sensitivity to kainic acid was unchanged as compared with
control animals (Engberg and Hajos, 1992). Binding studies in
rats have shown that the densities of AMPA and kainic acid
receptors in hippocampus were unaffected by a single episode
of chronic alcohol intoxication (Rudolph et al., 1997), whereas
kindling by alcohol withdrawal decreased the regional AMPA
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90 S. R. HAUGBØL et al.
binding without affecting the regional densities of the kainic
acid receptor (Ulrichsen et al., 1996).
Although the majority of the studies that have been
conducted recently are in agreement with the theory that
chronic alcohol administration results in an increased NMDA
receptor function, there seems to be disagreement about
the time course of the receptor alterations that, in part, may be
due to interspecies variations. Thus, in mice, the density of the
NMDA receptor seems to be upregulated at the time at which
alcohol administration is terminated (Grant et al., 1990; Gulya
et al., 1991), i.e. the changes take place during the alcohol
intoxication period, whereas in rats it was shown that the NMDA
receptor binding was unchanged at the end of the alcohol
intoxication period but increased markedly during the
subsequent withdrawal reaction (Sanna et al., 1993). In order
to shed more light on these inconsistent results and to study
the AMPA receptor in alcohol dependence further, the present
binding experiment was performed to study the time course of
the NMDA and AMPA receptors during the alcohol
withdrawal reaction in rats.
MATERIALS AND METHODS
Animals and intoxication procedure
Eighty male Wistar rats (Møllegaard, Køge, Denmark) were
housed in a room with a 12 h light/dark cycle (lights on at
07:00 h) and had free access to food pellets and water. The
body weight was initially 180–200 g. The animals were
exposed to severe alcohol intoxication for 84 h. Alcohol was
administered five times a day between 08:00 h and 24:00 h by
the intragastric intubation method (Majchrowicz, 1975).
Before each feeding session the degree of alcohol intoxication
was assessed by using the following rating scale.
(0) Neutrality: no signs of intoxication.
(1) Sedation: reduced muscle tone, dulled appearance and
slow locomotor activity but no impairment of gait or
coordination.
(2) Ataxia 1: slight gait impairment and slight motor
incoordination but able to elevate abdomen and pelvis.
(3) Ataxia 2: clearly impaired staggering gait and impaired
motor coordination, some elevation of abdomen and
pelvis.
(4) Ataxia 3: slowed righting reflex, heavily impaired motor
coordination, no elevation of abdomen and pelvis.
(5) Loss of righting reflex (LRR): unable to right itself when
placed on its back, other reflexes still present.
(6) Coma: no signs of movement; no response to pain stimuli;
no blinking reflex; spontaneous breathing.
The alcohol dose was adjusted individually according to the
degree of intoxication. Neutral rats received 5–7 g/kg whereas
animals with LRR received 0–1 g/kg. The aim was to reach an
intoxication level of 3–5 g (ataxia 2–LRR) within 8 h and to
keep this level for the rest of the intoxication period. The
alcohol solution consisted of: 200 g/l of ethanol, 300 g/l of
sucrose and 4 ml/l of multivitamin mixture in Ringer’s
solution, the sucrose being added in order to prevent
hypoglycaemia and ketosis (Hemmingsen and Chapman,
1980). Control animals received an isocaloric amount of
sucrose instead of alcohol and the same amount of water and
food as the alcohol treated rats. The blood concentration of
alcohol was not measured in the present study, but previous
studies have shown that it is 3–5 g/l during most of the
intoxication period (Majchrowicz, 1975; Ulrichsen et al.,
1995, 1998).
Nine animals died due to alcohol intoxication. After the last
alcohol dose, 21 of the 71 surviving alcohol treated animals
were randomly selected for glutamate receptor binding and the
remaining animals were used in other experiments. The 21
animals were randomly allocated to three groups (n = 7 per
group), which were decapitated at 0, 12 or 36 h after the last
alcohol dose, respectively. After decapitation, which was
performed under light halothane anaesthesia, the brains were
rapidly removed and frozen in isopentane cooled by a bath of
acetone and dry ice (80C). The whole brains were stored at
80C. The control animals (n = 7) were decapitated 12 h
after the last alcohol dose was administered to the
experimental animals.
Before the animals were decapitated, the severity of the
withdrawal reaction was assessed openly by scoring the three
individual items: intentional tremor, rigidity and hyperactivity/
irritability on a 4 level scale (0–3). The sums of these scores
(0–9) were used as a quantitative measurement of the severity
of the withdrawal reaction (Ulrichsen et al., 1986). The level
of alcohol intoxication was measured by using the rating scale
mentioned above (0–6).
All animals were weighed immediately before the first and
last alcohol dose.
Membrane preparation
The whole brains were thawed and the cerebellum and
midbrain removed. The remaining cerebrum was divided
longitudinally and each half was used for either [
3
H]MK-801
binding or [
3
H]AMPA binding. Tissue preparation was
performed as described by Ransom and Stec (1988). Briefly,
the tissue was homogenized (500 r.p.m.) in 10 volumes (w/v)
of ice-cold 0.32 M sucrose by eight strokes of a glass-teflon
homogenizer. The homogenate was centrifuged at 1000 g for
10 min and the supernatant was then centrifuged at 20 000 g
for 20 min at 4C. The resulting pellet was then resuspended
in 20 volumes of ice-cold distilled water and homogenized
(100 r.p.m.) with a glass-teflon homogenizer. The homogenate
was centrifuged at 8000 g for 20 min at 4C. The supernatant
and buffy coat was decanted and recentrifuged at 48 000 g for
20 min at 4C. The pellet was resuspended in 20 volumes of
ice-cold distilled water and centrifuged at 48 000 g for 20 min
at 4C. The last step was repeated once and the pellet was
frozen at 20C for at least 18 h.
On the day of the assay, the membrane pellet was thawed at
room temperature for 45 min, suspended in 75 volumes of
5 mM Tris–HCl buffer (pH 7.4 at 25C) using a thurax
homogenizer (2 10 s) and centrifuged for 20 min (48 000 g)
at 4C. This step was repeated three times. The membranes
were resuspended in the assay buffer prior to the final
centrifugation step.
[
3
H]MK-801 binding
[
3
H]MK-801 binding was performed with modifications as
described previously (Ransom and Stec, 1988). The assay was
carried out in a volume of 1 ml. This volume was made up of:
750 µl of membrane suspension; 100 µl of [
3
H]ligand; 100 µl
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GLUTAMATE RECEPTOR SUBTYPES AND ALCOHOL WITHDRAWAL 91
of test substance and 50 µl of buffer or modulator.
Determinations were carried out in triplicate.
Well washed membranes were resuspended in 5 mM
Tris–HCl buffer (pH 7.4) corresponding to ~12 mg of original
tissue per well. Binding experiments were carried out at 25C
and under maximum stimulation, i.e. a final concentration of
30 µM (S)-glutamate and 1 µM glycine. Construction of a
saturation curve was carried out using a combined increase of
radioactive ligand and isotope dilution (Ebert et al., 1991).
Radioligand concentrations between 0.1 and 3 nM were
obtained by increasing concentrations of [
3
H]MK-801 (specific
activity 22.5 Ci/mmol), whereas concentrations >3 nM were
obtained by isotope dilution of 3 nM [
2
H]MK-801 with non-
radioactive MK-801 (total ligand concentration ranged from 0.1
to 12 nM). Non-specific bound [
3
H]MK-801 was determined
using 100 µM 1-[1-(2-thienyl)cyclohexyl] piperidine (TCP).
After incubation for 4 h, binding was determined by
filtration through Whatman GF/B filters (presoaked for at least
2 h in 0.1% polyethylenimine solution) using a Brandell
M-48R cell harvester and washed three times using 2 ml of
ice-cold buffer.
For each total MK-801 concentration (i.e. radioactive and
non-radioactive) specific bound ligand was calculated as
described previously (Ebert et al., 1999). Based on the result-
ing saturation curves B
max
and K
D
was determined for each
animal using the non-linear curvefitting program Grafit 5.0
(Erithacus Software, Staines, UK).
[
3
H]AMPA binding
[
3
H]AMPA binding was performed with modifications as
described previously (Honore and Nielsen, 1985). The assay
was carried out in a volume of 250 µl. This volume was made
up of: 200 µl of membrane suspension; 25 µl of [
3
H]-ligand
and 25 µl of test substance. Determinations were carried out
in triplicate.
Well washed membranes were resuspended in 30 mM
Tris–HCl (pH 7.1) containing 2.5 mM CaCl
2
and 100 mM
potassium thiocyanate (KSCN) corresponding to ~9 mg
original tissue per well. The binding experiments were carried
out at 0–4C. Construction of a saturation curve was carried out
using a combined increase of radioactive ligand and isotope
dilution (Ebert et al., 1991). Radioligand concentrations
between 1 and 9 nM were obtained by increasing concen-
trations of [
3
H]AMPA (specific activity 52 Ci/mmol), whereas
concentrations >9 nM were obtained by isotope dilution of
9 nM [
3
H]AMPA with non-radioactive AMPA (total ligand
concentration ranged from 1 to 109 nM). Non specific binding
was determined using 1 mM (S)-glutamate. After incubation
for 30 min, bound ligand was separated from free using a
Packard Filtermate 96-well cell harvester and washed three
times with 250 µl of ice-cold buffer.
For each total AMPA concentration (i.e. radioactive and
non radioactive) specific bound ligand was calculated as
described previously (Ebert et al., 1999). Based on the
resulting saturation curves B
max
and K
D
was determined for
each animal using the non-linear curvefitting program Grafit
5.0 (Erithacus Software, Staines, UK).
Ligands
[
3
H]MK-801 and TCP was purchased from Sigma,
Copenhagen, Denmark and [
3
H]AMPA was kindly delivered
by Professor Povl Krogsgaard-Larsen, from Danish University
of Pharmaceutical Sciences.
Statistical analysis
Binding was first investigated by one-way analysis of variance
(ANOVA). If a significant group effect was found, the experi-
mental groups were subsequently compared with the control
group by two sided t-tests. Data are presented as mean (SEM).
The level of significance was set everywhere to 5%.
Ethics
The study was approved by the Danish Animal Experiment
Inspectorate, Ministry of Justice.
RESULTS
The alcohol dose, mean intoxication score and the intoxication
and withdrawal score at the time of decapitation is shown in
Table 1. All experimental animals were severely intoxicated
during the alcohol intoxication phase. A weight loss of 13%
(0.4) was observed in the control animals, whereas the alcohol
treated animals decapitated at 0, 12 and 36 h post alcohol had
a weight loss of 15% (0.5%), 14% (0.7%) and 13% (0.5%),
respectively.
K
D
and B
max
for cerebral [
3
H]MK-801 binding to NMDA
receptors in alcohol-dependent rats and isocalorical fed
controls are shown in Table 2. No significant group effects
were found for the dissociation constant K
D
, whereas ANOVA
revealed a significant group effect for the density of NMDA
receptors. [
3
H]MK-801 binding was not affected by chronic
alcohol intoxication per se, but during the withdrawal
Table 1. Alcohol intoxication parameters for the 84 h intoxication
period in rats decapitated during alcohol intoxication or during the
alcohol withdrawal reaction at 12 or 36 h post alcohol
Intoxication Withdrawal Withdrawal
(n = 7) (12 h) (n = 7) (36 h) (n =7)
Daily ethanol dose 12.6 (0.3) 11.8 ± 0.2 12.1 ± 0.2
(g/kg/24 h)
Mean intoxication score 2.9 (0.05) 3.0 ± 0.2 3.0 ± 0.05
Intoxication score at 2.7 (0.1) 1.2 ± 0.2 0.0 ± 0.0
decapitation (0–6)
Withdrawal score at 0.0 (0.0) 2.8 ± 0.4 3.0 ± 0.2
decapitation (0–9)
Data represent mean ± SEM.
Table 2. [
3
H]MK801 binding in cerebrum of rats exposed to 84 h severe
alcohol intoxication; the rats were decapitated during alcohol intoxication
or during the alcohol withdrawal reaction at 12 or 36 h post alcohol
Number of B
max
(pmol/mg
Group animals K
D
(nM) protein)
Control 6 0.99 ± 0.2 6.17 ± 0.5
Intoxication 6 1.19 ± 0.06 5.97 ± 0.3
Withdrawal (12 h) 5 1.23 ± 0.03 9.21 ± 0.6*
Withdrawal (36 h) 6 1.23 ± 0.06 7.68 ± 0.7
ANOVA Non significant P = 0.0017
Data represent mean ± SEM. A statistical significant difference from
control value is indicated by *P < 0.05 (t-test).
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92 S. R. HAUGBØL et al.
differences in MK-801 binding in alcohol-dependent rats, but
as binding was investigated at the time of withdrawal these
results are consistent with the current results. In another study
in which alcohol-dependent rats were investigated 48 h into
the withdrawal reaction, no changes in [
3
H]MK-801 binding
were detected compared with the control group (Tremwel et al.,
1994). In the current experiment, we did not investigate the
animals later than 36 h into the withdrawal reaction, but it is
reasonable to speculate that the increase in [
3
H]MK-801
binding had levelled off to control values if decapitation had
occurred 48 h after the last alcohol dose. Ligand binding
experiments in alcohol-dependent mice have consistently
shown an upregulation of the NMDA receptor but these
changes in the density of binding sites took place during the
alcohol intoxication phase rather than during the withdrawal
phase. Thus, the density of MK-801 binding sites was
increased in hippocampal membranes in mice chronically
exposed to alcohol intoxication and investigated when still
intoxicated (Grant et al., 1990; Valverius et al., 1990), and in
an autoradiography study an upregulation of MK-801 binding
was demonstrated in hippocampus, cortex, striatum and
thalamus in mice at the time of withdrawal (Gulya et al.,
1991). In this study, the time course of changes in MK-801
binding in hippocampal membranes showed that the increased
NMDA binding persisted 10 h into the withdrawal reaction
whereas the NMDA receptors had returned to control levels
20 h after the last alcohol dose (Gulya et al., 1991). In these
experiments, alcohol was administered as liquid diet to the
mice, a technique which does not provide quite the same blood
alcohol concentration as the intragastric intubation method of
Majchrowicz in which maximal tolerable doses of alcohol is
administered (Majchrowicz and Hunt, 1976). Although the
discrepancies in the time course of NMDA receptor binding
between the current study and Sanna et al. (1993) on the one
hand and Grant et al. (1990), Valverius et al. (1990) and Gulya
et al. (1991) on the other hand could theoretically be due to
differences in alcohol administration, we find it more likely
that they are brought about by interspecies variation. It is
therefore important to investigate species other than rodents
in order to understand the role of the NMDA receptor in
alcohol-dependent humans.
An earlier autoradiography experiment from our laboratory
does not agree with the current results, as we failed to detect
regional changes in [
3
H]MK-801 binding in rats exposed to
severe alcohol intoxication for 2 days and investigated 10–12 h
after the last alcohol dose (Ulrichsen et al., 1996). As the
withdrawal reaction is much more severe after 4 days rather
than 2 days of severe alcohol intoxication (Ulrichsen et al.,
1998), the NMDA receptor may not be changed if the
withdrawal reaction is relatively mild. The seizure component
of the withdrawal reaction may be particularly related to an
increased density of NMDA binding sites. Thus, seizures are
not observed in rats exposed to severe alcohol intoxication
for 2 days while 25–35% show spontaneous withdrawal
seizures after 4 days of alcohol intoxication (Ulrichsen et al.,
1996, 1998).
It has been postulated that physical dependence on alcohol
is developed as a cerebral response to the depressant effects of
alcohol in order that the brain may restore normal function
despite the presence of alcohol (i.e. tolerance) and that when
the suppression of the brain activity is terminated by
reaction, binding of [
3
H]MK-801 was upregulated. Thus, 12 h
into withdrawal a significant increase (of 49%) in the density
of NMDA binding sites was detected compared with the
control level. In the animals that were decapitated 36 h into
the withdrawal reaction, the density of NMDA binding sites
was still increased compared with the control animals
(by 24%), but the difference did not reach statistical
significance (P = 0.1).
The K
D
and B
max
for cerebral [
3
H]AMPA binding in
alcohol-dependent rats and isocaloric fed controls are
summarized in Table 3. K
D
did not differ across groups.
A significant group effect was observed for the B
max
of AMPA
binding sites. The density of AMPA binding sites was not
affected by chronic alcohol intoxication per se, but 12 h into
withdrawal this variable was increased significantly (by 94%)
compared with the control animals. Later during the
withdrawal reaction, i.e. 36 h post alcohol, the density of
AMPA binding sites had returned to control levels.
DISCUSSION
The upregulation of the NMDA receptors during the
withdrawal reaction found in the present study is consistent
with the theory that the cerebral hyperactivity, which follows
longterm alcohol intoxication, in part is due to an excessive
stimulation of the NMDA receptors (Glue and Nutt, 1990).
Although we detected no alterations when the animals were
still intoxicated, the density of the NMDA binding sites was
increased by 49% 12 h into the withdrawal reaction. During
the next 24 h the enhancement of binding sites was reduced to
a 24% increase compared with control levels; a difference
which did not reach statistical significance. This time course is
in agreement with the study by Sanna et al. (1993) in which an
alcohol paradigm similar to the present study was used . These
researchers also failed to detect changes in the MK-801
binding in hippocampus when the rats were tested early during
the withdrawal phase, i.e. 1–3 h post alcohol, while the density
of binding sites was increased by 25% 12–24 h into
withdrawal as compared with the sucrose treated control
animals (Sanna et al., 1993). In addition, alterations in the
NMDA-induced convulsive behaviour showed the same time
course. Thus, the seizure activity was unchanged 3 h post
alcohol but markedly increased 12–24 h into the withdrawal
reaction (Sanna et al., 1993). Using a variety of alcohol
paradigms, Rudolph et al. (1997) failed to detect major
Table 3. [
3
H]AMPA binding in cerebrum of rats exposed to 84 h severe
alcohol intoxication; the rats were decapitated during alcohol intoxication
or during the alcohol withdrawal reaction at 12 or 36 h post alcohol.
Number of B
max
(pmol/mg
Group animals K
D
(nM) protein)
Control 7 125 ± 16 5.36 ± 0.4
Intoxication 6 122 ± 18 4.27 ± 0.4
Withdrawal (12 h) 7 229 ± 77 10.4 ± 1.7*
Withdrawal (36 h) 7 106 ± 11 5.24 ± 0.5
ANOVA Non significant P = 0.0002
Data represent mean ± SEM. A statistical significant difference from
control value is indicated by *P < 0.05 (t-test).
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GLUTAMATE RECEPTOR SUBTYPES AND ALCOHOL WITHDRAWAL 93
withdrawal of alcohol, these cerebral alterations give rise to a
rebound hyperactivity in the brain (Kalant et al., 1971). This
theory is elegant and easily understood but it may not be
applicable to the glutamatergic neurotransmission, as the
current results suggest that upregulation of glutamate receptor
subtypes specifically occurs during the withdrawal phase
rather than the preceding episode of intoxication. It has been
shown using microdialysis that intracerebral administration of
NMDA in vivo results in a marked increase in extracellular
glutamate concentration. Thus, Rossetti et al. (1999) showed
that in saline treated control animals the glutamate
concentration in striatum was increased to 268% of baseline
values after NMDA administration. In alcohol-dependent
animals investigated at the time of withdrawal no effect was
observed, while 12 h into the withdrawal reaction, NMDA
administration resulted in a 6-fold (598%) increase of the
baseline glutamate levels. The increase in glutamate output
was blocked by the non-competitive NMDA receptor
antagonist MK-801. Assuming that the presence of alcohol at
the time of withdrawal inhibited the NMDA receptors
(Dildy and Leslie, 1989; Hoffman et al., 1989; Lovinger et al.,
1989, 1990; White et al., 1990), the results of Rossetti et al.
(1999) are in agreement with the present binding results and
similarly to our findings, they also suggest that the
supersensitivity of the NMDA receptor is developed during
the withdrawal phase rather than during the period of
intoxication. Alcohol affects a variety of neurotransmitters
of which, gamma-amino butyric acid (GABA) along with
glutamate, are probably the most widely studied. In
accordance with Morrow et al. (1988), Sanna et al. (1993)
detected a reduced ability of GABA and flunitrazepam to
stimulate
36
Cl
uptake in cortical vesicles prepared from
neurons of alcohol-dependent rats when still intoxicated.
However, when the animals showed clinical signs of
withdrawal, the GABA- and flunitrazepam-induced
36
Cl
uptake had returned to control levels (Sanna et al., 1993).
These results indicate that the GABA
A
receptor is involved in
alcohol tolerance but not in the cerebral hyperactivity of the
alcohol withdrawal reaction. Upon withdrawal of alcohol, the
abnormal function of GABA (and other neurotransmitter
systems involved in tolerance) returns to habitual conditions
(Sanna et al., 1993), but it is likely that this process of
restoring the impaired GABAergic inhibition results in
secondary CNS alterations, for instance, in the activity of the
glutamatergic neurotransmission. Hence, the upregulation of
the density of NMDA binding sites in the present study may
represent an attempt by the brain to counteract alterations,
which occur in GABAergic (and other neurotransmitter)
systems involved in alcohol tolerance, as the overall CNS
inhibition by GABA is increased after alcohol is withdrawn.
Therefore, the cerebral mechanisms of the alcohol withdrawal
reaction may not be directly related to tolerance as suggested
by Kalant et al. (1971), but rather develop secondarily to
the process of tolerance reduction upon termination of
alcohol intake.
Experiments using genetic animal models provide further
evidence for an involvement of the NMDA receptor in the
alcohol withdrawal reaction but not in the mechanisms of
alcohol tolerance. In mice that were selectively bred to be
tolerant to alcohol no difference in central MK-801 binding
was detected compared with non-tolerant animals (Näkki
et al., 1995) whereas mice bred to be sensitive to alcohol
withdrawal seizures exhibited an upregulation of MK-801
binding sites in hippocampus compared with the seizure
resistant line (Valverius et al., 1990).
Cloning studies have shown that the NMDA receptors are
composed of multiple subunits designated NR1, NR2a, NR2b,
NR2c and NR2d (or NMDAR1, NMDAR2a,b,c,d). The NR1
subunit is required to generate functional NMDA receptors,
whereas co-expression with various NR2 subunits results in
the assembly of ion channels that resemble native NMDA
receptors (reviewed by Davis and Wu, 2001). Recent studies
have shown that chronic alcohol intoxication affects the
NMDA receptor subunits and the mRNA encoding for these
proteins. An increase in NR1 receptor subunit immuno-
reactivity was found in membranes from whole brain (Chen
et al., 1997) and hippocampus (Trevisan et al., 1994) of rats
fed a liquid ethanol diet for 15 days and 12 weeks,
respectively. Upregulation of NR1, NR2a and NR2b receptor
subunits was detected in cerebral cortex and hippocampus
(Kalluri et al., 1998) in rats intoxicated by the intragastric
intubation method for 6 days. In a previous study from the
same laboratory, an increase in the levels of the mRNA
encoding for the NR2a and NR2b subunits was demonstrated,
whereas the expression of NR1 mRNA was unchanged
compared with the control animals (Follesa and Ticku, 1995).
NR1 and NR2a proteins were upregulated in alcohol-
dependent mice whereas no alterations were detected in the
mRNA levels for these subunits (Snell et al., 1996). These
results suggest that upregulation of NMDA receptors in
alcohol-dependent rodents is brought about by an increase in
both NR1 and NR2 protein subunits and that the mechanisms
behind these changes may be different. In the former case, a
decrease in receptor protein degradation may be responsible
for the alterations whereas an increased mRNA formation
leading to an elevated protein synthesis may result in
increased expression of NR2a and NR2b receptor subunits.
These speculations are tentative and more research into the
regulation of the NMDA receptor subunits is needed to
elucidate the mechanisms involved in the upregulation of
NMDA receptors in alcohol dependence.
As was the case with the NMDA receptor, the AMPA
receptor was also upregulated during the alcohol withdrawal
reaction, and to an even larger extent, as the density of the
AMPA binding was increased by 94% compared with the
control group. Therefore this receptor may also be involved in
the hyperactivity of alcohol withdrawal. The AMPA receptors
conduct mainly Na
+
currents and mediate fast excitatory
synaptic transmission, whereas the NMDA receptors display
high Ca
2+
permeability and voltage-dependent Mg
2+
block.
Since Mg
2+
blocks the ion channel the NMDA receptor is
relatively insensitive to glutamatergic and aspartergic stimula-
tion at resting membrane potential, but as the membrane
potential is decreased, for instance, by activation of AMPA
receptors, Mg
2+
causes less blockade, allowing for an increase
in Ca
2+
influx and further depolarization upon agonist
activation (Nakanishi, 1992; Sommer and Seeburg, 1992).
Therefore, the upregulation of the NMDA and AMPA receptors
during the withdrawal reaction may act synergistically to
increase the excitatory neurotransmission. To our knowledge,
this is the first study in which upregulation of AMPA binding
sites in alcohol dependence has been demonstrated. In one
by guest on June 1, 2013http://alcalc.oxfordjournals.org/Downloaded from
94 S. R. HAUGBØL et al.
ligand binding experiment in rats in which several alcohol
paradigms were employed, no changes in AMPA binding were
observed (Rudolph et al., 1997), but as all binding experiments
were conducted on animals that were still intoxicated, the
negative results are in agreement with our current findings. No
change in AMPA binding densities was observed (Freund and
Anderson, 1996) in human alcoholics who had been sober for
at least 2 weeks. In contrast to the present results, we did not
find significant changes in regional [
3
H]AMPA binding in
rats exposed to 2 days of severe alcohol intoxication
investigated 10–12 h into the withdrawal reaction compared
with sucrose treated controls (Ulrichsen et al., 1996).
However, in the same study, alcohol withdrawal kindled rats
exposed to multiple episodes of alcohol intoxication and
withdrawal showed a significant downregulation of [
3
H]AMPA
binding in several regions, perhaps as an adaptive response to
kindling induced cerebral hyperactivity. In consensus with the
current results it was shown in an electrophysiology study that
the sensitivity to AMPA was increased in locus coeruleus of
alcohol withdrawing rats (Engberg and Hajos, 1992). Obviously
the literature concerning the AMPA receptors in alcohol
dependence is limited and more research is needed to clarify
the mechanisms by which these receptors are regulated during
alcohol intoxication and withdrawal.
In conclusion, the present study showed that the densities of
NMDA and AMPA binding sites were upregulated during
the withdrawal reaction, whereas no changes were observed
at the time of withdrawal. These alterations may play an
important role in the cerebral hyperactivity of the withdrawal
reaction.
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    • "Finally, we recognize that the severity of alcohol withdrawal cannot be predicted by the levels of unblocked NMDARs alone. For example, the neuroinhibitory system (especially GABA A receptors) has been implicated in the brain's response to alcohol [1,36,37]. A complete representation of withdrawal would require incorporation of these additional systems. "
    [Show abstract] [Hide abstract] ABSTRACT: N-methyl-D-Aspartate (NMDA) and its receptors (NMDAR) play a critical role in glutamatergic neurotransmission. Ethanol molecules inhibit these receptors, and if the brain is exposed to ethanol chronically, NMDA-induced glutamatergic changes can result in physical dependence to ethanol in order to sustain normal brain function. In these cases, removal of ethanol from the system results in excitotoxic withdrawal. One compensatory mechanism the brain uses to regulate extracellular glutamate concentration is modulating the number of NMDARs at the synapse. Previous work has shown that the number of functional NMDARs at the synapse can be changed by three mechanisms: additional receptors can be synthesized and inserted, receptors can be recruited to the synapse from extrasynaptic regions, or the functionality of existing receptors can be modified. In this study, we consider the dynamic relocation control of NMDARs in response to chronic alcoholism and withdrawal. Specifically, we (1) propose and construct a mathematical model of the relocation control as a negative feedback system with an explicit set point, (2) investigate the effect of various ethanol consumption and withdrawal profiles on the NMDAR population, and (3) propose and calculate quantitative measures for the extent of withdrawal based on modeled NMDAR populations. A relocation-only model with an explicit set point was developed. The model was shown to apply across a wide range of controller parameters. The results suggest that withdrawal severity does not depend upon the dynamics involved in the development of dependence, and that regulating the blood alcohol level throughout the progression of withdrawal can minimize excitotoxic withdrawal symptoms. The negative feedback control system produced characteristic behaviors of NMDAR populations in response to simulations of alcohol dependence and abrupt withdrawal. The model can also predict the severity of excitotoxic withdrawal following various alcohol consumption and/or withdrawal patterns in order to generate testable hypotheses regarding ameliorating withdrawal.
    Full-text · Article · May 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]. "
    [Show abstract] [Hide abstract] 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.
    Article · Mar 2015
    • "Glutamate represents the most common excitatory neurotransmitter in the human brain and acts on several types of receptors in the central nervous system (CNS) of which, the N-methyl-D-aspartate (NMDA) receptor is the most ef- fected [53]. In addition, recent evidence shows that other ionotropic glutamate receptors may be involved in the pathophysiology of alcohol withdrawal syndrome (AWS), including the α-amino-3-hydroxy-5-methylisox- azole-4-propionic acid (AMPA) and the kainate subtypes of glutamate receptors [54] [55]. GABA is the major inhibitory neurotransmitter and binds to a fast-acting receptor complex GABA-A, which hyperpolarizes the cell membrane and inhibits neuroactivity [53] . "
    [Show abstract] [Hide abstract] ABSTRACT: Antiepileptic drugs (AEDs), have demonstrated efficacy treating a number of acute conditions, encompassing a broad range of symptoms and syndromes, in addition to being first-line treatment for epilepsy. Clinically, since their inception, AEDs have been used off-label for acute and chronic medical conditions, both as primary and as adjuvant therapies. In this review, we describe the observed clinical effectiveness of AEDs across a set of commonly encountered acute conditions in the general hospital: traumatic brain injury, pain, alcohol withdrawal. In describing the individual benefits and usages of specific agents, the applicability of these agents to other common neuropsychiatric conditions may be further explored.
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