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Introduction
Recently, the differentiation of functions along the
longitudinal axis of the hippocampus (dorsal-ventral in the rat
and posterior-anterior in humans) has attracted
interest[1,2]. Anatomically, the hippocampus includes CA1, CA2, CA3,
and dentate gyrus subfields, with the pattern of efferent and
afferent connectivity changing between the dorsal and
ventral hippocampus[3]. Identification of distinct functional roles
for the dorsal and ventral hippocampus may help to resolve
differences among the various theoretical accounts of
hippocampal involvement in learning
behavior[2].
Considerable evidence shows that the dorsal
hippocampus plays an important role in spatial
memory[4-6]. Ablation of the dorsal hippocampus, in which between 20% and 37%
of the total hippocampal volume is removed, results in
profound impairment of spatial location of a submerged
platform in the Morris water maze[5]. Bannerman
et al also found that performance in the water maze and elevated
T maze was impaired by selective dorsal but not ventral
hippocampal lesions[4]. On the other hand, ventral hippocampal lesions
are considered to affect anxiety but not spatial
learning[7,8]. However, Ferbinteanu et
al demonstrated that the ventral hippocampus might also be involved in acquisition of
spatial memory in Long-Evans rats[9]. So far, little is known
about the functions performed by the ventral hippocampus
in spatial memory.
Both histamine and its precursor histidine facilitate
memory retrieval deficits induced by aging, dorsal
hippocampal lesions and scopolamine, as determined by passive
and active avoidance tasks and an 8-arm radial maze test for
rats[10-12]. a-Fluoromethylhistidine (FMH), a selective
histidine decarboxylase (HDC) inhibitor, produces significant
memory deficits in an active avoidance task and the 8-arm
radial maze in rats[13,14]. Furthermore,
N-methyl-d-aspartate (NMDA) receptors play an important role in learning and
memory[15,16]. Bekkers[15] and Vorobjev
et al[17] found that histamine could dramatically enhance NMDA
receptor-mediated synaptic transmission and facilitate the induction of
long-term potentiation in cultured hippocampal pyramidal
cells. Our previous studies indicate that histamine in the
dorsal hippocampus ameliorates spatial working memory and
reference memory deficits induced by MK-801, and the
action is mediated by postsynaptic histamine
H1 receptors[18,19]. However, whether histamine in the ventral hippocampus is
involved in spatial memory deficits induced by MK-801 remains unclear.
Therefore, the objectives of this investigation were to
use the radial maze task with 4-arms baited to further clarify
the effects of the histaminergic system in the ventral hippocampus on the regulation of spatial memory in rats.
Materials and methods
Animals All experiments were carried out in accordance
with the National Institutes of Health Guide for the Care and
Use of Laboratory Animals. Male Sprague-Dawley rats
(220-270 g, grade II, certificate No 22-9601018, Experimental
Animal Center, Zhejiang University) were maintained in an
air-conditioned room at 22-26 ºC and 40%-70% humidity, and
housed in individual cages with a 12-h light-dark cycle (lights
on from 8:00 AM to 20:00 PM ). Animals were given free
access to water and kept at 80%-85% of their free-feeding
body weight throughout the experiments. Experiments were
carried out between 10:00 AM and 17:00 PM.
Surgical procedures The rats were anesthetized with
sodium pentobarbital (35 mg/kg, ip), and fixed in a
stereotaxic apparatus (Narishige, SR-5, Tokyo, Japan). Two guide
cannulas made of stainless steel tubing (700 μm in outer
diameter), were implanted bilaterally into the ventral
hippocampus according to the following coordinates measured from
the bregma: antero-posterior: -4.52 mm; medio-lateral: ±5.0
mm; dorso-ventral: 8.0 mm from the skull surface. The
cannula was fixed to the skull with three screws and dental acrylic.
A stylet was inserted into the cannula to keep it patent prior
to injections. At least 10 d were allowed for recovery from
the surgery. After the behavioral tests, Evans blue (1 μL)
was injected bilaterally into the ventral hippocampus and
the rats were killed by decapitation. The accuracy of the
injection site was carefully determined (Figure 1). Based on
histological examination, data from nine rats with incorrect
injections were excluded from the results.
Intracerebral microinfusion Rats were manually
restrained and the stylets were carefully removed from the
guide tubes. Infusion cannulae, connected via flexible
polyetheretherketone tubing to 5 μL Hamilton microsyringes
mounted on a microinfusion pump (KN-201, Natsume, Tokyo,
Japan), were then inserted into the guide tubes. Drugs in
1 μL vehicle (0.9% saline) or 1 mL vehicle per side were
infused into the ventral hippocampus at a rate of 1 μL/min. To
allow absorption of the infusion bolus, infusion cannulae
were left in the brain for 60 s after infusion before being
replaced by the stylets.
Radial-arm maze training The apparatus used is
described in our previous
reports[18,19]. The rats were familiarized with the radial maze once per day for 2 d prior to training.
Food pellets (45 mg each, Bio-Serv, Frenchtown, NJ, USA)
were scattered over the entire maze surface, and three or four
rats were simultaneously placed in the maze and allowed to
explore and take food freely for 10 min. After adaptation, all
rats were trained with one trial per day. In each trial, only 4
arms (3, 5, 6, and 8) were baited, and the sequence was never
changed throughout the experiment. The rat was placed on
the center platform that was closed off by a door. After 15 s,
the door was opened and the rat was allowed to make an arm
choice to obtain food pellets until all 4 pellets had been eaten
or 5 min had elapsed. The number of entries into
never-baited arms was regarded as reference memory error (RME),
whereas re-entry into arms where the pellet had already been
eaten was considered as working memory error (WME). Rats
continued training until reaching a criterion of less than 1
error per trial for 5 consecutive trials. Once a rat reached
criterion, training for that rat was reduced to 2 trials per week
until all rats reached criterion (range 35-50 d). After each
trial, the maze was wiped clean using paper towels that were
dampened with 10% ethanol and rotated 180º.
Drugs During the drug test, (+) MK-801 hydrogen
maleate (Sigma, St Louis, MO, USA), histamine dihydrochloride
(Sigma), cimetidine dimaleate (Sigma), or pyrilamine
dihydrochloride (Sigma) were dissolved in saline and injected
bilaterally into the ventral hippocampus. Histidine
monohydrochloride (Sigma) was dissolved in saline and
injected ip. Studies for drug effects were carried out once a
week, on Tuesday or Friday.
Statistics All results are expressed as mean±SEM.
Statistical significance was assessed by one-factor analyses of
variance (ANOVA) or the Kruskal-Wallis non-parametric
ANOVA test (when the data were not normally distributed or
the variances of the groups differed significantly), followed
by DunnettĄ¯s test or the Mann-Whitney U test as
a post hoc analysis. The software SPSS 11.5 (SPSS, Chicago, IL, USA)
was used. P<0.05 was considered statistically significant.
Results
Effect of MK-801 on memory retrieval as evaluated by 4-arm baited radial maze performance
Non-parametric ANOVA (Kruskal-Wallis) showed that bilateral ih injection
of MK-801 caused a significant impairment of working
memory and reference memory {WME: H[3]=13.873,
P=0.003; RME: H[3]=25.161, P<0.01}. MK-801 at a dose of 0.1
mg/site slightly increased the memory error, but this was not
significant (Mann-Whitney U test; WME:
P=0.335; RME: P=0.145). At a dose of 0.3 μg/site it significantly increased the number
of both WME and RME (Mann-Whitney U test;
P<0.01; Figure 2). However, at a dose of 0.5 μg/site MK-801 did not
significantly impair spatial working or reference memory
(Mann-Whitney U test; WME: P=0.338; RME:
P=0.061).
Effects of histamine and histidine on MK-801-induced
memory deficits Intrahippocampal injection of histamine
antagonized the effects of MK-801 {WME: H[3]=8.846,
P=0.031; RME: H[3]=8.004, P=0.044}. At doses of 25 or 50
ng/site it significantly decreased the number of RME
(Mann-Whitney U test; P<0.05; Figure 3), whereas histamine at a
dose of 50 ng/site significantly decreased the number of
WME(Mann-Whitney U test; P<0.05; Figure
3). Intraperitoneal injection of histidine produced an effect similar to
histamine (WME: H[3]=11.314, P=0.010; RME:
H[3]=20.415, P<0.01). At doses of 25, 50 or 100 mg/kg, histidine
significantly inhibited MK-801-induced spatial reference memory
deficits (Mann-Whitney U test; P<0.01; Figure 4). It
significantly reversed the spatial working memory deficit induced
by MK-801 only at the dose of 100 mg/kg (Mann-Whitney
U test; P<0.01; Figure 4).
Effects of pyrilamine and cimetidine on memory
amelioration of histidine on MK-801-induced memory deficits
Intrahippocampal injection of pyrilamine, a representative
central histamine H1 antagonist, significantly antagonized
the ameliorating action of histidine on RME
(H[3]=7.811, P=0.04) at doses of 0.5 and 1.0 μg/site (Mann-Whitney
U test; P<0.05; Figure 5), but not on WME. In addition, cimetidine,
a histamine H2 antagonist, at the high dose of 2.5
mg/site, also significantly antagonized the ameliorating action of
histidine on RME (Mann-Whitney U test;
P<0.05; Figure 5), but not on WME (Mann-Whitney
U test; P=0.974).
Discussion
Previously, we observed that bilateral injection of
MK-801, an NMDA receptor antagonist, into the dorsal
hippocampus impaired both working and reference
memory[18]. Our present results are consistent with previous studies as
assessed by performance in the 8-arm (4-arm baited) radial maze.
We found that blockade of NMDA receptors in the ventral
hippocampus impaired the retrieval of spatial working and
reference memory, which suggested that the ventral
hippocampus might be involved in the spatial memory process in
rats[9,20], although a chemical lesion study demonstrated that
the ventral hippocampus was less involved in spatial memory
modulation[5,7]. The different findings may arise from the
different experimental procedures (eg using the Morris
water maze, the T-maze, and the 8-arm maze). In addition, the
lesion method is less specific than local delivery of
com-pounds.
Intrahippocampal application of MK-801 (0.3 μg/site) did
not lead to obvious changes in running time per choice
(locomotor activity) or other behaviors, such as ataxia (data
not shown), which usually occurs after systemic or
intracerebroventricular (icv) treatment with
MK-801[16]. However, we found that MK-801 at a dose of 0.5 μg/site did
not impair spatial memory. A few rats exhibited epileptic
symptoms or even died when given a dose of 0.5 μg/site,
phenomena resembling those following systemic or icv
treatment with MK-801[16]. Therefore, we used MK-801 (0.3
μg/site) to induce the spatial memory deficits in the
following experiments.
Both histamine and histidine ameliorated the memory
retrieval deficits induced by MK-801, including working
memory and reference memory. Intraperitoneal injection of
histidine significantly increased histamine levels in the
cortex and hippocampus (data not shown). This was
consistent with previous studies showing that ip or icv injection of
histidine increased hippocampal histamine
levels[11,12]. Our results were consistent with previous findings in which
MK-801 was delivered to the dorsal
hippocampus[18]. In addition, Chen et
al reported that histidine at higher doses of 200, 500,
and 1 000 mg/kg improved the impairment of radial maze
performance induced by MK-801 (0.1
mg/kg)[14]. Our results indicate that histidine at lower doses (25, 50 and 100 mg/kg)
can ameliorate the impairment induced by MK-801. The
difference can be attributed to the different injection routes,
different species, and different learning models. But these
present results at least suggest that ventral hippocampal
histamine may participate in the amelioration of both
short-term and long-term spatial memory deficits.
In the present study, the amelioration of reference memory
elicited by histidine was completely reversed by pyrilamine,
a central histamine H1 antagonist. However, this result is
different from those for the dorsal hippocampus in that
pyrilamine infused into the ventral hippocampus produced no
appreciable inhibition of the amelioration of working memory
by histamine. This result suggests that the ameliorating
effect of histidine on the working memory deficit induced by
MK-801 is independent of histamine. Histamine can act
directly on the NMDA receptor, as suggested by
Bekkers[15] and Vorobjev et
al[17]. Because the polyamine site of
the NMDA receptor may be a binding site for
histamine[21], the facilitating effect of histidine on MK-801-induced working
memory deficit may be attributed to histamine acting directly
on this site. So far, we have no explanation of why histamine
H1 receptors in the dorsal and ventral hippocampus have
different actions. We previously reported that the
improvement of both working and reference memory induced by
dorsal hippocampal histamine were antagonized by
pyrilamine[18]. Our present data, at least in part, suggest that the
histamine H1 receptors in the dorsal and ventral hippocampus participate in different components of memory.
Histamine H1 receptors in the dorsal hippocampus are involved in
both working and reference memory, but those in the ventral
hippocampus are mainly related to reference memory.
Moreover, we were surprised to find that cimetidine, a
histamine H2 antagonist, also blocked histamine-induced
amelioration of reference memory. So far, most reports show
that histamine H2 receptors are less involved in the learning
and memory process[18,19,21,22]. For example, the ameliorating
effect of histamine on scopolamine-induced learning deficit
is antagonized by pyrilamine but not by the selective
histamine H2 antagonists cimetidine and
zolantidine[10,11]. Intra-cerebroventricular injection of the histamine
H1 agonist, 2-thiazolylethylamine, but not the histamine
H2 agonist, 4-methylhistamine, reverses the working memory deficits
induced by MK-801 as evaluated by the 8-arm baited radial
maze in rats[14]. However, Flood et
al have recently reported that increased histamine
H1 and H2 receptor activity in the
septum facilitated memory retention, whereas decreased
histamine receptor activity resulted in impaired memory
processes as evaluated by T-maze
behavior[23]. Giovannini et al also provided evidence that bilateral post-training injection
of the histamine H2 agonist amthamine into the dorsal
hippocampus improved memory
consolidation[24]. These findings combined with our present data suggest that the
histamine H2 receptor in certain brain regions may be involved in
learning behavior. Further experiments are needed to
elucidate the function of the histamine
H2 receptor.
In conclusion, histamine in the ventral hippocampus is
involved in spatial memory, and histamine ameliorates the
memory deficits of both working memory and reference
memory induced by MK-801. The ameliorating action on
reference memory is mediated by postsynaptic histamine
H1 and H2 receptors, whereas the effect of histamine on working
memory may be mediated by other neuronal pathways.
Acknowledgement
We are very grateful to Dr Iain C BRUCE (University of
Hong Kong) for reading the manuscript.
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