Vol. 275, Issue 5, R1647-R1653, November 1998
Stimulation of rat hypothalamus by microdialysis with
K+: increase of ACh release
elevates plasma glucose
Akira
Takahashi,
Eiko
Kishi,
Hirohisa
Ishimaru,
Yasushi
Ikarashi, and
Yuji
Maruyama
Department of Neuropsychopharmacology (Tsumura), Gunma University
School of Medicine, Maebashi, Gunma, 371, Japan
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ABSTRACT |
The
effects of stimulation of the ventromedial hypothalamus (VMH) or
lateral hypothalamus (LH) with potassium chloride through a
microdialysis probe were studied. The concentrations of ACh and
norepinephrine (NE) in the dialysate obtained from the hypothalamic nuclei and plasma glucose concentration were measured. Stimulation of
the hypothalamic nuclei, VMH and LH, with potassium increased the
plasma glucose level as well as the extracellular concentrations of ACh
and choline. Addition of atropine, a muscarinic ACh receptor antagonist, into the potassium solution reduced the increase in the
level of plasma glucose. Cholinergic stimulation of these nuclei with
neostigmine increased the extracellular concentrations of ACh and
plasma glucose. Stimulation of the nuclei with potassium also increased
the release of NE. However, stimulation of the VMH or LH with NE
and/or pargyline, a monoamine oxidase inhibitor, through the
dialysis probe membrane did not significantly increase the plasma
glucose concentration. These results suggest that activation of the
muscarinic cholinergic or ACh-receptive neurons in the hypothalamic
nuclei, VMH and LH, contribute to the elevation of plasma glucose
level.
ventromedial hypothalamus; lateral hypothalamus; stimulation with
potassium; acetylcholine release
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INTRODUCTION |
THE HYPOTHALAMUS IS REGARDED as the autonomic center,
and it is also recognized as the critical locus for metabolic
integration. In neural glucoregulation, the importance of hypothalamic
noradrenergic and cholinergic neurons has been made clear by a variety
of experiments. Analysis of the hypothalamic content of
neurotransmitters and hypothalamic metabolites has indicated that the
noradrenergic and cholinergic systems contribute to
glucoregulation. A positive correlation between the
increased norepinephrine (NE) metabolite-to-NE ratio in the medial
basal hypothalamus and blood glucose level has been reported (12, 21,
22). The neuroglycopenic agent 2-deoxyglucose (2-DG) causes
hyperglycemia, associated with a dose-dependent decrease of ACh content
and a corresponding increase in choline content in the ventromedial
hypothalamus (VMH) and lateral hypothalamus (LH) (24, 26). Chemical
stimulation studies also have shown a significant role of both neurons
in glucoregulation. Microinjection of NE into VMH (10, 19) and of an
ACh esterase inhibitor, such as neostigmine, into VMH and LH elevates
blood glucose level (2, 6). The above reports indicate the involvement of the hypothalamic noradrenergic and cholinergic systems in the regulation of peripheral glucose metabolism by the central nervous system.
An increase in the ratio of neurotransmitter metabolites to
neurotransmitter has been frequently used as a proof of
individual neuronal activity. However, neuronal activity in the
individual brain nuclei is not always reflected in the ratio of
neurotransmitter metabolites to neurotransmitters or in the content of
neurotransmitters. The relationship between an increase of ACh or NE
release, i.e., intrinsic cholinergic or noradrenergic activity, in VMH
or LH and fluctuation of plasma glucose level has not been previously examined. In addition, the chemical stimulation study does not account
for an incidental effect on other neuronal systems and other adjacent
nuclei. For instance, the intraventricular injection of neostigmine
also activates hypothalamic noradrenergic and dopaminergic systems (5,
29). Moreover, the neuronal activity in the nuclei may be modulated by
administration of NE or by ACh itself through an action at
prejunctional receptors. Recently, using microdialysis, we showed that
2-DG administration increased extracellular concentrations of both ACh
and choline, i.e., increase of ACh release, in the hypothalamus (27).
Application of microdialysis makes neuronal stimulation and
simultaneous analysis of neuronal activity possible. At present, in
vivo microdialysis is one of the most effective techniques for the
analysis of functional neuroactivity in a specified region of the
brain.
In this study, to clarify the relationship between the increase of
cholinergic and noradrenergic activity in the VMH or LH and the
increase of plasma glucose concentration, we used microdialysis for
stimulation of the bilateral hypothalamic nuclei with potassium through
the probe membrane and simultaneous analysis of the ACh and NE release.
This approach enabled us to determine the contribution of endogenous
ACh and NE release in the hypothalamic nuclei to glucoregulation.
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METHODS |
All experimental procedures involved in these studies were approved by
the Committee for Animal Experimentation at the Gunma University School
of Medicine and meet the guidelines of the Japanese Association for
Laboratory Animal Science.
Female Wistar rats weighing 250-280 g were used. They were kept at
24°C under a 12:12-h light-dark cycle (lights on from 0700). The
animals were fed ad libitum with laboratory food and water. One week
before the experiment, rats under pentobarbital sodium anesthesia (45 mg/kg ip) were stereotaxically implanted with guide cannulas into both
sides of either the VMH or LH [coordinates: VMH
anterior-posterior (AP) 0.0, lateral (L) 0.75, depth from dura 7.5 mm;
LH AP 0.0, L 2.0, depth 7.0 mm; according to atlas of Pellegrino et al.
(14a)] for in vivo brain microdialysis. Two guide cannulas were
anchored firmly to the skull in each rat by dental adhesive and acrylic
resin. After implantation of the guide cannula, a heart catheter (1-mm
OD and 0.5-mm ID silicone tube) was inserted through the right jugular
vein to facilitate blood sampling without disturbing the behavior of
unanesthetized rats. The residual segment of the silicone tubing was
passed under the skin and pulled out from the back of the neck.
One week later, two microdialysis probes, 2 mm in length and 0.5 mm OD
(CMA 10; Carnegie Medicine, Stockholm, Sweden), with dialysis membranes
were inserted into both sides of the VMH or LH through guide cannulas.
The pointed ends of the probes reached a 9.5- or 9.0-mm depth from the
dura. The brain microdialysis was performed without disturbing the
behavior of unanesthetized rats. Animals were deprived of food and
water throughout the microdialysis. The probes were perfused with
Ringer solution (in mM: 147 sodium, 4.0 potassium, and 3.0 CaCl2) containing 20 µM
eserine at 2 µl/min using a microinfusion pump. Generally, ACh in
microdialysis dialysate is not detectable without the use of an ACh
esterase inhibitor (11), and ACh concentration in the dialysate is
Ca2+ dependent and sensitive to
TTX, a sodium channel blocker (9, 13). After an equilibration period of
3 h, the perfusate was collected every 15 min. Five baseline fractions
were collected. After the measurement of initial basal concentrations
of extracellular ACh and NE in the hypothalamic nuclei, the perfusion
medium was changed to the medium containing 100 or 50 mM potassium
chloride for 45 min. On occasion, atropine sulfate was added to the
perfusion medium containing 100 mM potassium. The effects of
cholinergic stimulation with 1 mM neostigmine were also studied. In the
course of this study, we had ascertained the TTX-sensitive nature of the dialysate ACh. Addition of 10 µM TTX to the perfusion solution produced a >80% reduction in the basal ACh concentration and
45-50% reduction in the 100 mM potassium-induced increase of
dialysate ACh concentration. Thus perfusion of a high concentration of
potassium chloride through the microdialysis probe is effective for
neural stimulation. In addition, to study the effects of
hypothalamic stimulation with potassium chloride on the plasma glucose
concentration, 100 or 500 µM or 2 mM of NE and equal amounts of
pargyline, a monoamine oxidase inhibitor, were added to Ringer solution
and delivered to the VMH or LH through the microdialysis probes.
Concentrations of ACh, choline, and NE in the dialysate were analyzed
using two HPLC systems equipped with electrochemical detectors, as
reported previously (24, 29). Recovery rate of ACh and choline with the
microdialysis probe in vitro was 12.1 ± 0.4%, and that of NE was
10.2 ± 0.3% (n = 12). The
recovery was tested by placing the probe in Ringer solution containing 1 pmol/µl each of ACh, choline, and NE and then perfusing the probe
at a flow rate of 2 µl/min at 37.5°C.
During microdialysis, ~0.15-ml samples of blood were withdrawn from
the heart catheter for analysis of plasma glucose concentration. After
each sample was taken, 0.15 ml of isotonic saline was injected through
the catheter. The blood samples were transferred to microcentrifuge tubes containing trace amounts of heparin, and plasma was separated by
centrifugation and kept frozen until analysis. Plasma glucose concentration was determined by the glucose oxidase method. After the
experiments, an overdose of pentobarbital sodium was injected from the
heart catheter in each animal. The brain was removed and kept in a
solution of 4% buffered neutral paraformaldehyde for several days.
Individual coronal sections were taken on a cryostat and stained with
Mayer's hematoxylin. Figure 1 shows schematically the position of the tips of the microdialysis probes for
six bilateral VMH-perfused and six bilateral LH-perfused rats used
successfully for the experiment in the perfusion with 100 mM potassium
chloride. The microdialysis membrane was located and penetrated the VMH
or LH. The positions of the microdialysis probes in other experiments
were also verified under microscopy.
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Fig. 1.
Localization of tips of microdialysis probes. Frontal sections of brain
were schematically illustrated at levels of 5.8 and 6.0 mm anterior to
interaural line, according to atlas of Pellegrino et al. (14a).  ,
Ventromedial hypothalamus (VMH) stimulation with 100 mM KCl;  ,
lateral hypothalamus (LH) stimulation with 100 mM KCl. DMH, dorsomedial
hypothalamus; FX, fornix; OT, optic tract.
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All values are presented as means ± SE. The data were evaluated by
a one-way ANOVA with Bonferroni's post hoc analysis.
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RESULTS |
Effects of bilateral hypothalamic stimulation with potassium on ACh
and NE release and plasma glucose level.
Bilateral perfusion of 100 mM potassium chloride to the VMH or LH
through microdialysis probes increased plasma glucose concentrations, as shown in Fig. 2. The plasma glucose
level gradually increased during perfusion of potassium chloride and
decreased after cessation of the perfusion. The concentrations reached
~120% of their respective initial values at 45 min. Figure
3 shows the effect of 0.2, 2, and 5 mM
atropine, a muscarinic antagonist, on the potassium-induced rise in
plasma glucose. Addition of atropine into the perfusion medium reduced
the potassium-induced rise in plasma glucose level. In both VMH and LH
perfusions, at 45 min, 55-60% of the rise in plasma glucose was
reduced by the addition of 2 and 5 mM atropine, although the
potassium-induced increase of plasma glucose was not completely
suppressed by the atropine. Addition of 2 mM atropine alone had no
significant effect on plasma glucose concentration.
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Fig. 2.
Effects of bilateral VMH and LH stimulation with 100 mM KCl through
microdialysis probes on plasma glucose level. Stimulation of VMH and LH
was carried out as described in
METHODS. Values are means ± SE for
6 rats. Solid bar on abscissa indicates duration of
stimulation of VMH and LH. * Significantly different from initial
basal levels at P < 0.01.
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Fig. 3.
Effects of addition of atropine into dialysis medium on potassium
stimulation-induced increase of plasma glucose level. Values are
increase of plasma glucose concentration at 45 min relative to
respective initial basal levels. Values are means ± SE for 6 rats.
* Significantly different from values in 100 mM KCl stimulation
and atropine alone at P < 0.01.
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ACh and choline concentrations in the dialysate of the VMH are shown in
Fig. 4. The basal extracellular levels of
ACh and choline in the dialysate were 0.42 ± 0.03 and 20.8 ± 0.9 pmol/50 µl, respectively, without correction for recovery across
the probe membrane. ACh concentration increased rapidly to ~6-7
times the basal level within 15 min after the beginning of 100 mM
potassium perfusion, and the level decreased rapidly after cessation of the perfusion. A similar response to the perfusion was obtained by
changing the choline concentration. The response in ACh preceded the
response in choline. ACh and choline concentrations in the LH dialysate
are shown in Fig. 5. The basal
concentrations of ACh and choline were higher than those of the VMH
dialysate, and the values were 1.26 ± 0.08 and 41.9 ± 1.3 pmol/50 µl, respectively. Also, ACh in the dialysate of the LH
increased rapidly to ~3-4 times the basal level. The choline
concentration increased slightly. The increase of extracellular choline
in addition to ACh concentration indicates the intrinsic increase of
ACh release.
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Fig. 4.
Changes of extracellular concentrations of ACh and choline in
VMH after bilateral VMH stimulation (horizontal bars) with 100 mM KCl
through microdialysis probes. Values are means ± SE for 6 rats.
* Significantly different from initial basal levels at
P < 0.01.
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Fig. 5.
Changes of extracellular concentrations of ACh and choline in LH after
bilateral LH stimulation (horizontal bars) with 100 mM KCl through
microdialysis probes. Values are means ± SE for 6 rats.
* Significantly different from initial basal levels at
P < 0.01.
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Figure 6 shows the increase of ACh in the
dialysate of the VMH and LH and plasma glucose concentrations at 45 min
by perfusion of 50 and 100 mM potassium chloride. The effect of the
dose-dependent nature of the potassium perfusion on the increase of ACh
and plasma glucose concentration was observed.
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Fig. 6.
Increase of plasma glucose and microdialysis dialysate ACh
concentrations after bilateral VMH and LH stimulation with 50 and 100 mM KCl through microdialysis probes. Values are increases of plasma
glucose and dialysate ACh concentration at 45 min relative to
respective initial basal level. Values are means ± SE for 6 rats.
* Significantly different from initial basal levels at
P < 0.01.
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NE concentration in the VMH dialysate was increased by stimulation with
potassium, and the increase was about two times the basal value at 45 min (Fig. 7). Extracellular concentration
of NE in the LH also increased with the potassium stimulation, as shown in Fig. 7. This increase of extracellular NE indicates
increases of NE release. The NE concentration decreased gradually after cessation of the perfusion.
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Fig. 7.
Changes of extracellular concentrations of norepinephrine (NE) in VMH
and LH after bilateral stimulation (horizontal bars) with 100 mM KCl
through microdialysis probes. Values are means ± SE for 6 rats. * Significantly different from initial basal levels at
P < 0.01.
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Effects of bilateral hypothalamic stimulation with neostigmine on
plasma glucose level and ACh release.
Stimulation of the bilateral hypothalamic nuclei with neostigmine by
using the microdialysis probes increased the extracellular concentrations of ACh and plasma glucose. In both the VMH (Fig. 8) and LH (Fig.
9) stimulation, glucose concentrations were
elevated along with the increase of ACh level after the beginning of
neostigmine perfusion. The basal values of ACh and choline were 0.63 ± 0.03 and 22.3 ± 0.9 pmol/50 µl, respectively, in the VMH
and 1.21 ± 0.06 and 40.5 ± 2.2 pmol/50 µl, respectively, in
the LH. Extracellular ACh level increased rapidly to ~3-4 times
the basal value. Different from the potassium stimulation, neostigmine
stimulation in the VMH or LH did not involve the increase of choline
concentration. The choline level decreased gradually during the
neostigmine perfusion; choline concentration was ~75% of its basal
value at 45 min (17.1 ± 2.0 and 30.5 ± 2.1 pmol/50 µl in VMH
and LH, respectively). This shows that the increase of ACh
concentration in the dialysate with neostigmine perfusion is caused by
inhibition of ACh hydrolysis and is not attributable to increase of ACh
release.
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Fig. 8.
Effects of bilateral VMH stimulation (horizontal bar) with
neostigmine through microdialysis probes on extracellular ACh
concentration in VMH and on plasma glucose level. Values are
means ± SE for 6 rats. * Significantly different from
initial basal levels at P < 0.01.
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Fig. 9.
Effects of bilateral LH stimulation (horizontal bar) with
neostigmine using microdialysis probes on extracellular ACh
concentration in LH and on plasma glucose level. Values are means ± SE for 6 rats. * Significantly different from initial basal
levels at P < 0.01.
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On the other hand, bilateral stimulation of the VMH or LH with 100 µM
to 2 mM NE and/or pargyline, a monoamine oxidase inhibitor, through the microdialysis probes did not significantly increase the
plasma glucose level (data not shown).
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DISCUSSION |
Our present data show that bilateral stimulation of the hypothalamic
nuclei, VMH or LH, with potassium through the microdialysis probe
membrane increases the plasma glucose concentration as well as
extracellular concentration of ACh in the hypothalamic nuclei (Figs. 2
and 4-6), and addition of atropine, a muscarinic antagonist, into
the potassium dialysis medium reduced the potassium-induced increase of
plasma glucose level (Fig. 3). Cholinergic stimulation of these nuclei
with neostigmine using microdialysis probes simultaneously increased
extracellular concentration of ACh in the hypothalamic nuclei and
plasma glucose level (Figs. 8 and 9). Our results strongly point to the
involvement of the hypothalamic cholinergic system in glucoregulation.
The present data confirm that activation of the muscarinic cholinergic
or ACh-receptive neurons in the hypothalamic nuclei, VMH and LH,
contributes to the elevation of the plasma glucose level.
The stimulation with potassium through the microdialysis probe is not
specific to cholinergic neurons. It is possible that potassium
stimulation affects many hypothalamic neurotransmitter/neuromodulator systems that may be involved in acute glucoregulation. In our data, a
considerable part (40-45%) of the increase of plasma glucose concentration remains even in the presence of 2-5 mM atropine (Fig. 3). Therefore, in addition to the hypothalamic cholinergic or
ACh-receptive neurons, other neurotransmitter and neuropeptide systems
may partially contribute to the stimulation-induced increase of plasma
glucose level. On the other hand, it has been reported that
intracerebroventricular neostigmine injection-induced hyperglycemia is
suppressed by coadministration of atropine (8).
The contribution of the hypothalamic cholinergic system to the
regulation of peripheral glucose metabolism has been elucidated through
the study of chemical stimulation and the analysis of hypothalamic
neuronal activity. Cholinergic neurons are adjacent to the third
ventricle, which includes the VMH and LH (7, 23). In the
chemical stimulation, microinjection of neostigmine into the VMH and LH
increased the blood glucose level (2, 6). We have also shown that the
cholinergic activity in both the VMH and LH, evaluated by extracellular
concentration of ACh using microdialysis and hypothalamic contents of
ACh and choline, is elevated in 2-DG-induced hyperglycemia (27). The
VMH is considered to be a sympathetic center with a close relation to
the splanchnic nerves. Electrical stimulation of the VMH increases NE
turnover of sympathetically innervated organs (15), and stimulation of the VMH increases blood glucose concentration via the neural
innervation of the liver (28) and the increase in epinephrine and
glucagon secretion. These neural and hormonal factors after activation of the hypothalamic cholinergic system probably contribute to the
hyperglycemic response in stimulation of the VMH with potassium. On the
other hand, the LH is supposed to be closely related to the vagus
nerves. In the regulation of carbohydrate metabolism in the liver,
reciprocal functions of the VMH and LH have been reported (18-20). LH
stimulation causes a decrease in the efferent activity of the
sympathetic nerves, with a concomitant increase in vagal nerve activity
(14). In stimulatory effects of 2-DG on feeding and gastric secretion,
the main site of the action was supposed to be the LH (3). However, the
LH contains several cell condensations, and the connections of the LH
are complex. It has been reported that stimulation of the middle part
of the LH increases efferent activity of the adrenal sympathetic nerves (30). Electrical stimulation of the LH can elevate
adrenomedullar activity and epinephrine turnover without
affecting sympathetic nerve activity and NE turnover in other organs
(15). A dissociation of the activities of the two components of the
sympathoadrenal system has been shown to occur under certain conditions
(31). In addition, it has been reported that activation of cholinergic receptor mechanisms within the LH induce hyperglycemia by promoting an
increase in adrenomedullar activity (17). Thus the increase of blood
glucose induced by LH stimulation with potassium and neostigmine (Figs.
2 and 9) may be attributable to adrenal epinephrine.
The participation of the hypothalamic noradrenergic system in
glucoregulation has already been accepted (4, 16, 19, 20), although the
evidence of a direct relationship between the activity of the
noradrenergic processes in the VMH and the glucoregulatory function is
not necessarily sufficient. In our present analytic system, NE in the
VMH dialysate, i.e., extracellular level or NE release, was also
increased by stimulation with potassium and decreased gradually after
the cessation of the stimulation (Fig. 7). These results might support
the involvement of the hypothalamic noradrenergic processes in
hyperglycemic response. However, stimulation of the VMH or LH with
0.1-2 mM NE and/or pargyline, a monoamine oxidase
inhibitor, using microdialysis probes did not significantly increase
plasma glucose concentration. The activation of the hypothalamic noradrenergic system alone does not induce a remarkable hyperglycemia such as hyperglycemia induced by the activation of the cholinergic system with neostigmine. In consideration of our present data, it seems
unlikely that the hyperglycemic responses with potassium are
attributable to hypothalamic noradrenergic activity. Rather, the
noradrenergic system in the hypothalamic nuclei may be related to a
long-time energy regulation, energy intake, and expenditure. Indeed,
destruction of the ventral noradrenergic bundle induces hyperphagia and
obesity (1), and hypothalamic NE content decreases in VMH
lesion-induced obese rats (26). On the other hand, activation of the
cholinergic system in the hypothalamic nuclei may be an essential
process causing hyperglycemia. It appears that muscarinic cholinergic
or ACh-receptive neurons of the hypothalamic nuclei influence certain
aspects of acute regulation of the energy substrate glucose.
Perspectives
Relatively few areas in the hypothalamus, including the VMH and LH,
have been identified as sites of glucoregulation. Chemical stimulation
studies have shown the importance of the cholinergic and noradrenergic
system in hypothalamic glucoregulation. However, the relationship
between an increase of ACh and NE release in the hypothalamic nuclei
and an increase of plasma glucose concentration has not been
sufficiently explored. Using in vivo microdialysis, we stimulated the
VMH and LH with 100 or 50 mM potassium through microdialysis probes and
simultaneously analyzed the extracellular concentration of ACh and NE.
Perfusion of the hypothalamic nuclei with potassium chloride increased
the plasma glucose level as well as the extracellular concentration of
ACh and choline, i.e., increased ACh release. Addition of atropine to
the perfusion medium containing potassium reduced the potassium-induced
increase of plasma glucose level, and the perfusion with neostigmine
increased the plasma glucose level. The extracellular concentration of
NE also increased with potassium stimulation, but the perfusion with NE
and pargyline through microdialysis probes did not increase the plasma
glucose level. Our results suggest that activation of the muscarinic
cholinergic system in the VMH and LH contributes to the elevation of
plasma glucose concentration. The approach taken in this study is one
effective method to elucidate relationships between physiological or
biological responses and the activity of central neurons as well as the
release of endogenous neurotransmitter and neuroactive substances in
specific brain nuclei or regions.
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FOOTNOTES |
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: A. Takahashi, Dept. of
Neuropsychopharmacology (Tsumura), Gunma Univ. School of Medicine,
3-39-22 Showa-Machi, Maebashi, Gunma 371, Japan.
Received 4 February 1998; accepted in final form 28 July 1998.
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Abstract
Introduction
