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NEUROPHARMACOLOGY
Neurobiology (M.H., W.E.H.) and Research Biostatistics (R.J.W.), Pharmacia Corporation, Kalamazoo, Michigan
Received March 4, 2003; accepted May 5, 2003.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)-ethyl]-4-piperidinemethanol
(MDL-100907)] reversed the action of 5-HT2C receptor agonists.
Furthermore, in control rats 5-HT2C receptor antagonists [SB-242084
and 5-methyl-1-(3-pyridil-carbamoyl)-1,2,3,5-tetrahydropyr-rolo[2,3-f]indole
hydrochloride (SB-206553)] induced or enhanced theta oscillation in MS/DBv and
hippocampal neurons and theta wave activity of the hippocampus. These findings
provide evidence for a tonic regulation of the activity and theta oscillation
of the septo-hippocampal system via 5-HT2C receptors in the
anesthetized rat, indicating that pharmacological interactions with these
receptors could modulate various physiological and pathological processes
associated with limbic theta activity.
;
Hasselmo et al., 2002;
Seager et al., 2002). Most
recently, theta activity recorded from epileptic patients showed correlation
between working memory task and an increase in amplitude of theta oscillation
(Raghavachari et al., 2001).
The medial septum/diagonal band of Broca (MS/DB) plays an important role in
regulation of hippocampal activity, particularly in generation of hippocampal
theta wave activity (Vertes and Kocsis,
1997; Buzsaki,
2002). Septal cholinergic and GABAergic neurons innervating the
hippocampus have been shown to contribute to hippocampal theta activity and
phase-lock the activity of hippocampal neurons
(Bland et al., 1999;
Dragoi et al., 1999;
Buzsaki, 2002). Due to
intrinsic membrane properties, MS/DB GABA neurons oscillate at theta frequency
(Buzsaki, 2002), and it is
argued that brain stem control of hippocampal theta activity is mediated, at
least in part, via septo-hippocampal neurons
(Vertes and Kocsis, 1997;
Dragoi et al., 1999).
It has been demonstrated that activity of the septo-hippocampal system is
under a tonic 5-HT regulation (Vertes and
Kocsis, 1997). The medial septum and diagonal band receives dense
5-HT innervation from the median raphe nucleus and 5-HT-containing axons form
perisomatic and peridendritic baskets and asymmetric synaptic contacts on
parvalbumin GABAergic neurons (Leranth and
Vertes, 1999). Interestingly, the median raphe also innervates the
hippocampus, and very frequently both the medial septum and the hippocampus
receive input from the same individual 5-HT neuron
(Acsady et al., 1996). In
anesthetized rats, inhibition of activity of median raphe neurons evokes theta
oscillation of septal neurons (Kinney et
al., 1996) and theta wave activity in hippocampus
(Vertes et al., 1994).
Similarly, inhibition of 5-HT neurons by the selective 5-HT1A
receptor agonist 8-hydroxy-2-dipropylaminotetralin induces hippocampal theta
activity in freely moving cats (Marrosu et
al., 1996). These findings indicate that 5-HT neurons play an
inhibitory role in regulation of hippocampal theta activity, although the
postsynaptic 5-HT receptors mediating this tonic inhibition have not been
identified. Both the medial septum-diagonal band and hippocampus express a
variety of 5-HT receptors, including 5-HT2C receptors
(Pompeiano et al., 1994;
Clemett et al., 2000).
Interestingly, mice lacking 5-HT2C receptors are prone to
spontaneous seizures and display lowered seizure threshold, suggesting that
5-HT2C receptors mediate tonic inhibition of neuronal network
excitability (Tecott et al.,
1995; Heisler et al.,
1998). Given the fact that serotonin system influences various
hippocampal functions, including hippocampal-dependent behaviors and synaptic
plasticity, in the present study we investigated the role of 5-HT2C
receptors in regulation of activity of the septohippocampal system.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Electrophysiological Recordings
Single Unit Recordings. Single units were recorded from the medial
septum and vertical limb of the diagonal band of Broca (MS/DBv; coordinates:
0.2 mm anterior to bregma, lateral 0 mm, and 5–7 mm below the dura;
Paxinos and Watson, 1986) and
hippocampal CA1 neurons (coordinates: 3.3 mm posterior to bregma, lateral
1–2 mm, and 2.8 mm below the dura) and dentate gyrus neurons
(coordinates: 4.2 mm posterior to bregma, lateral 1–2 mm, and
3.4–4.2 mm below the dura) using glass microelectrodes filled with 2 M
NaCl (impedance 10–20 MOhms). Extracellularly recorded potentials were
amplified, filtered, displayed, discriminated, and recorded for off-line
analysis using conventional electrophysiological methods
(Hajós et al., 1998).
Neuronal activity was followed by constructing firing rate, frequency, and
interspike interval histograms using Spike3 program (Cambridge Electronic
Design, Cambridge, UK). Oscillation of neuronal activity was analyzed by
autocorrelation; power of oscillation was calculated by Fast Fourier
transformation analysis of autocorrelation. Location of the recording
electrode was marked with iontophoretic ejection of Pontamine Sky Blue and
revealed by routine histological procedure.
EEG Recording. Unilateral hippocampal field potential (EEG) was
recorded by a metal monopolar macroelectrode placed into the CA1 region
(coordinates: 3.8 mm posterior from the bregma, 2.2 mm lateral, and 3.6 mm
ventral; Paxinos and Watson,
1986). Field potentials were amplified, filtered (0.1–100
Hz), displayed, and recorded for on-line and off-line analysis (Spike3
program). Rhythmic synchronized (theta) and large-amplitude irregular
hippocampal activities were distinguished in the EEG; quantitative EEG
analysis was performed by means of Fast Fourier transformation
(Hajós et al., 2003).
Power spectrum density of EEG was calculated between 0 and 12 Hz.
Cross-correlation between hippocampal EEG activity and discharge of MS/DBv
neurons was processed by using Spike3 wave-form average program. Location of
the recording electrode was verified histologically.
Drugs
Drugs solutions were made up based upon their salt weights in
H2O with concentrations adjusted so that injection volumes equaled
1 ml/kg body weight. After establishing baseline recordings (10–20 min),
drugs were injected i.v. Drug structures, salts, and sources were as follows.
5-HT2C receptor agonists
(Kennett et al., 1997;
Martin et al., 1998;
Heisler and Tecott, 2000)
1-(3-chlorophenyl)piperazine dihydrochloride (m-CPP; Sigma/RBI,
Natick, MA) and
[S]-2-(chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine fumarate (Ro
60-0175; synthesized at Pharmacia Corporation, Kalamazoo, MI);
5-HT2C receptor antagonists (Kennett et al.,
1996,
1997)
6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbomyl] indoline
(SB-242084; Sigma/RBI) and 5
methyl-1-(3-pyridil-carbamoyl)-1,2,3,5-tetrahydropyr-rolo[2,3-f]indole
hydrochloride (SB-206553; Sigma/RBI); 5-HT2B receptor antagonist
(Bonhaus et al., 1999)
2-amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (RS-127445; synthesized
at Pharmacia Corporation); and 5-HT2A receptor antagonist
(Kehne et al., 1996)
R-(+)--(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
(MDL-100,907; synthesized at Pharmacia Corporation).
Data Analysis and Statistics
Mean firing rates were determined in periods of 120 to 300 s before and
after drug treatment. Interspike interval histograms, autocorrelograms, and
hippocampal EEG power spectra were determined in periods of 300 s preceding
and after drug treatment. Cumulative dose-response curves and
agonist/antagonist interaction studies were obtained from one neuron per
animal; cumulative doses of agonists and subsequent administration of
antagonist(s) were administered at approximately 5-min intervals. The
percentage of inhibition or increase quoted represents the difference between
the postdrug firing rate and the predrug firing rate, as a percentage of the
predrug firing rate. Dose-response relationships were analyzed by one-way
ANOVA. Total and relative power at low (1–3), theta (3–5), and
high (5–12) Hertz frequencies were calculated from quantitative EEG
analysis, together with power and frequency of maximal peak. Power and
frequency of maximal peak of neuronal oscillatory activity were also
determined. Differences between treatment periods within groups were assessed
by paired Student's t test. Data are presented as mean ±
S.E.M. (n) values throughout. Statistical significance at the
p < 0.05 level is reported.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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; Vertes and Kocsis,
1997; Bland et al.,
1999), theta-on and theta-off MS/DBv neurons were distinguished,
displaying an increased or decreased firing rate during hippocampal theta
activity, respectively (data not shown). Systemic administration of the
5-HT2C receptor agonist m-CPP (0.01 to 0.3 mg/kg i.v.;
n = 12) dose dependently inhibited firing activity in most (11/12) of
the recorded MS/DBv neurons (p < 0.0001, ANOVA;
Fig. 1a). Although there was
some variation in the inhibitory response between individual neurons, no
correlation was found between the basal firing rate and the degree of
m-CPP-induced inhibition of MS/DBv neurons (n = 11; Spearman
rank correlation, p = 0.1). Furthermore, the selective
5-HT2C receptor agonist Ro 60-0175 (1 mg/kg i.v.; n = 6)
also inhibited firing activity most of the recorded MS/DBv neurons (4/6).
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The selective 5-HT2C receptor antagonist SB-242084 (1 mg/kg i.v.) reversed the m-CPP-induced inhibition of firing rate in all tested neurons (n = 9/9) and significantly increased firing activity over the basal firing rate (Fig. 1b). Changes in firing activity induced by the 5-HT2C receptor agonists Ro 60-0175 (1 mg/kg i.v.) (either inhibition or excitation) were also reversed by systemic administration of the 5-HT2C receptor antagonist SB-242084 (1 mg/kg i.v.) in all tested neurons (firing rate, 103% of control; n = 6).
Constructing autocorrelation histograms, an oscillation in firing activity
of MS/DBv neurons was revealed (Figs.
2 and
3). As it has been established
before (Dragoi et al., 1999),
this oscillation was time locked to hippocampal theta wave activity
(Fig. 4; see below). Systemic
administration of m-CPP (0.03–0.1 mg/kg i.v.; n = 12)
or the 5-HT2C receptor agonist Ro 60-0175 (1 mg/kg; n = 6)
abolished theta oscillation in all tested neurons (Figs.
2 and
3). Furthermore, the selective
5-HT2C receptor antagonist SB-242084 (1 mg/kg i.v.) reversed theta
oscillation of MS/DBv neurons induced by either m-CPP (n =
12/12) or the 5-HT2C receptor agonists Ro 60-0175 (n =
6/6; Figs. 2 and
3). In addition, the
5-HT2C agonist-induced elimination of phase-locked activity between
MS/DBv neurons and hippocampal theta wave activity was also restored by the
5-HT2C receptor antagonist SB-242084
(Fig. 4). In contrast, the
selective 5-HT2B antagonist RS-127445 (3 mg/kg i.v.; n =
4) failed to reverse the m-CPP-induced inhibition of firing rate or
oscillation of MS/DBv neurons (Figs.
3 and
4).
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In a separate set of experiments, a possible role of 5-HT2A receptors in the pharmacological effects of m-CPP on MS/DBv neuronal activity was evaluated (Fig. 5). The selective 5-HT2A receptor antagonist MDL-100907 (0. 1–1 mg/kg i.v.; n = 6) did not reverse the m-CPP-induced decrease in firing activity of MS/DBv neurons (13.6 ± 6 and 13.4 ± 4 spikes/s before and after administration of the antagonist, respectively). Oscillation of MS/DBv neurons was quantified by Fast Fourier transformation of autocorrelograms (see Materials and Methods) during control period, and after administration of m-CPP and the 5-HT2 receptor antagonists. Thus, the m-CPP-induced (0.1 mg/kg i.v.) reduction in power of MS/DBv neuronal oscillation at theta frequency (3–5 Hz) was not reversed by MDL-100907 (1 mg/kg i.v.) but the selective 5-HT2C receptor antagonist SB-242084 (1 mg/kg i.v.; n = 5; Fig. 6). Similar results were revealed, if power of maximum peak of oscillation was compared after administration of 5-HT2A or 5-HT2C antagonist. Thus, the 5-HT2C receptor antagonist SB-242084 (but not the 5-HT2A antagonist MDL-100907) reversed the effect of m-CPP and significantly increased power of maximum peak of oscillation (control, 2.8 ± 1.1; m-CPP + MDL-100907, 0.88 ± 0.29; p < 0.001; m-CPP + SB-242084, 4.1 ± 0.6; p < 0.05 versus control).
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Effects of 5-HT2C Agonists on Hippocampal EEG Activity.
Simultaneously with MS/DBv single unit activity, hippocampal EEG was recorded
and its power spectrum monitored with on-line Fast Fourier transformation.
During control recordings, spontaneous alterations in hippocampal EEG were
observed, displaying shifts between large-amplitude irregular activity and
rhythmic, synchronized (theta) activity, as it has been described previously
either in urethane (Bland et al.,
1999; Varga et al.,
2002), halothane (Bland et al.,
2003), or chloral hydrate anesthesia
(Hajós et al., 2003).
Systemic administration of m-CPP (0.01–0.3 mg/kg i.v.;
n = 12/12) or the 5-HT2C receptor agonist Ro 60-0175 (1
mg/kg i.v.; n = 6/6) desynchronized hippocampal theta activity in
anesthetized rats, parallel to inhibition of theta oscillation of MS/DBv
neurons (Figs. 2 and
3). Both m-CPP
(n = 12) and Ro 60-0175 (n = 6) reduced EEG absolute power,
specifically in 3 to 5 Hz, theta range, which was reversed by the selective
5-HT2C receptor antagonist SB-242084 (1 mg/kg i.v.) in all tested
rats (Figs. 2 and
3). Thus, the mean power of
hippocampal EEG (V2/2 Hz) at theta frequency range (3–5 Hz)
was significantly reduced by m-CPP (0.1 mg/kg i.v.): mean powers were
0.37 ± 0.08 and 0.11 ± 0.04 during control period and after
m-CPP, respectively (n = 12; p < 0.001). The
m-CPP induced reduction of theta power was reversed by the
5-HT2C receptor antagonist SB-242084 (1 mg/kg i.v.; power: 0.67
± 0.15 V2/2 Hz; p < 0.001 versus
m-CPP). In addition, the mean peak frequency of theta activity was
shifted to higher frequency after administration of SB-242084 [frequencies:
3.7 ± 0.11 Hz and 4.0 ± 0.13 Hz during control period and after
SB-242084, respectively (n = 12, p < 0.01)].
Large-amplitude irregular hippocampal activity was not altered by
m-CPP (n = 3; data not shown). In contrast, the selective
5-HT2B antagonist RS-127445 (3 mg/kg i.v.; n = 4) failed
to reverse the desynchronizing effect of m-CPP on hippocampal EEG
(n = 4, Fig. 3).
However, a subsequent administration of SB-242084 (1 mg/kg i.v.) antagonized
the EEG effect of m-CPP also in these rats (n = 4; Figs.
3 and
4). Furthermore, the
m-CPP-induced hippocampal EEG desynchronization was not reversed by
MDL-100907 (0.1–1 mg/kg i.v.), a selective 5-HT2A receptor
antagonist but the selective 5-HT2C receptor antagonist SB-242084
(1 mg/kg i.v.; Figs. 5 and
6). These findings mirrored
changes in oscillation of MS/DBv neurons observed simultaneously (see
above).
Effects of the Selective 5-HT2 Receptor Antagonists on the Septo-Hippocampal Activity. Systemic administration of the selective 5-HT2C receptor antagonists SB-242084 (1 mg/kg i.v.,; n = 8) had no consistent effect on firing rate of MS/DBv neurons (baseline firing rate: 8.0 ± 2.4 and 8.9 ± 2.8 spikes/s after the antagonist; p = 0.8). However, firing activity was significantly increased by the 5-HT2C receptor antagonist in a subset of MS/DBv neurons (n = 3/8), which showed strong theta oscillation and relatively high firing rate (baseline firing rate: 9.8 ± 4.3 and 15.1 ± 4.8 spikes/s after the antagonist; p < 0.01).
Regardless the firing rate response of the recorded MS/DBv neurons, SB-242084 (1 mg/kg i.v.) induced or enhanced theta oscillation in the majority of MS/DBv neurons parallel with hippocampal theta activity (n = 6/8; Fig. 7). Similarly, SB-206553 (1 mg/kg i.v.), a 5-HT2C receptor antagonist and an analog of SB-242084-induced or -enhanced theta oscillation of MS/DBv neurons and hippocampal theta activity (n = 8/10). In line with hippocampal theta wave activity, theta oscillation of hippocampal CA1 (n = 6/6) or dentate (n = 2/2) neurons were recorded after administration of the 5-HT2C receptor antagonist SB-206553 (1 mg/kg i.v.; data not shown).
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Although the selective 5-HT2A receptor antagonist MDL-100907 (1 mg/kg i.v.) failed to reverse the desynchronizing action of m-CPP on either MS/DBv neuronal oscillation or hippocampal theta wave activity (see above) its ability to induce theta activity was tested in control rats. Thus, MDL-100907 (0.1–1 mg/kg i.v.; n = 8) showed a moderate activity in inducing or enhancing theta activity, particularly at a higher dose (1 mg/kg i.v.; Fig. 8). However, subsequent administration of the selective 5-HT2C receptor antagonist SB-242084 (1 mg/kg i.v.) further increased theta oscillation of MS/DBv neurons because it significantly increased power of oscillation at peak frequency, parallel to an augmented hippocampal EEG power at theta (3–5 Hz) frequency (Fig. 9).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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5-HT2C Receptor Activation Inhibits Theta Activity. The
5-HT2C receptor agonists m-CPP and Ro 60-0175
(Kennett et al., 1997;
Martin et al., 1998;
Heisler and Tecott, 2000) dose
dependently inhibited firing activity and theta oscillation of MS/DBv neurons.
In parallel to changes in septal neuronal activity, 5-HT2C agonists
desynchronized hippocampal EEG by inducing large-amplitude irregular activity.
In line with previous observations (Bland
et al., 1999; Dragoi et al.,
1999; Buzsaki,
2002), peak frequency of theta oscillation of MS/DBv neurons and
hippocampal theta wave activity overlapped and were phase-locked during
control recordings. Although theta activity in anesthetized rats shows similar
contributes to theta activity recorded in non-anesthetized rats
(Buzsaki, 2002), the frequency
of theta activity is lower (
4 Hz) in urethane-anesthetized
(Bland et al., 1999;
Varga et al., 2002) or chloral
hydrate-anesthetized (Hajós et al.,
2003; present study) rats than in nonanesthetized rats. The
5-HT2C receptor agonists significantly reduced power of EEG at
theta frequency and abolished phase-locked relationship between activity of
MS/DBv neurons and hippocampal EEG.
The 5-HT2C receptor agonist-induced desynchronization of the
septo-hippocampal system was associated with a reduced firing activity of the
majority of MS/DBv neurons. This finding is in line with the observation that
the majority of septal neurons show an increased firing rate during theta
activity, i.e., theta-on cells (Ford et
al., 1989). Interestingly, in some theta-off cells, inhibition of
theta oscillation by the 5-HT2C receptor agonist Ro 60-0175 was
coupled to an increased firing rate. Thus, it is a possibility that changes in
firing activity of the majority of MS/DBv neurons in response to
5-HT2C receptor agonists are partly due to inhibition of theta
oscillation of the septo-hippocampal system.
The inhibitory effect of the presently used agonists on theta activity was
revered by the selective 5-HT2C receptor antagonist SB-242084
(Kennett et al., 1997),
indicating that inhibition was most likely mediated via 5-HT2C
receptors. This assumption is further supported by the facts that neither a
selective 5-HT2B nor a 5-HT2A receptor antagonist
reversed the action of m-CPP or Ro 60-0175 on septo-hippocampal theta
activity. Although no highly selective 5-HT2C receptor agonists are
currently available, the selectivity of 5-HT2C, 5-HT2B,
and 5-HT2A receptor antagonists used in the present study provides
support to our conclusion of critical role of 5-HT2C receptors in
regulation of septo-hippocampal theta activity by 5-HT neurons.
Theta Activity Induced by Inhibition of 5-HT2C Receptors.
Interestingly, inhibition of 5-HT2C receptors by systemic
administration of SB-242084 (Kennett et
al., 1997) had a profound synchronizing effect on the activity of
the septohippocampal system resulting in theta wave activity of hippocampal
EEG and theta oscillation of MS/DBv neurons. Because all of these responses
can be evoked by inhibition of 5-HT neurons
(Vertes and Kocsis, 1997), the
present findings indicate that postsynaptic 5-HT2C receptors are
under a tonic influence in anesthetized rats. To our best knowledge, this is
the first report demonstrating that 5-HT2C receptors, at least in
part, mediate the tonic regulatory action of 5-HT system on the
septo-hippocampal theta activity. Inhibition of 5-HT2A receptors by
MDL-100907 (Kehne et al.,
1996) also enhanced theta activity, although it was significantly
less effective that the 5-HT2C receptor antagonist. These findings
indicate that 5-HT2A and 5-HT2C receptors might have
similar role in regulation of activity of the septo-hippocampal system. Our
results support the previous finding demonstrating that activation of
serotonin neurons blocks and inhibition of serotonin neurons activates both
septal and hippocampal theta activity either in anesthetized or
unanesthetized, behaving animals (Kinney
et al., 1996; Marrosu et al.,
1996; Vertes and Kocsis,
1997; Varga et al.,
2002). Moreover, we have shown recently that enhanced hippocampal
norepinephrine, but not 5-HT neurotransmission, induces theta and gamma
oscillatory activity of the septo-hippocampal system in anesthetized rats
(Hajós et al.,
2003).
Our findings are in line with the presumed role of 5-HT2C
receptors in neuronal excitability. Mutant mice lacking 5-HT2C
receptors are prone to spontaneous seizures and display lowered seizure
threshold, suggesting that 5-HT2C receptors mediate tonic
inhibition of neuronal network excitability
(Tecott et al., 1995;
Heisler et al., 1998).
Furthermore, activation of cortical neurons by iontophoretically applied
quisqualate is significantly enhanced in 5-HT2C receptor mutant
mice, suggesting that 5-HT2C receptors serve a tonic inhibitory
role in membrane excitability (Rueter et
al., 2000). Our present findings show that activation of
5-HT2C receptors inhibits synchronous activity of the
septo-hippocampal system. Moreover, blockade of 5-HT2C receptors by
a selective antagonist induces synchronous activity in the hippocampus and
time-locked theta oscillation of MS/DBv neurons. Although the exact mechanisms
underlying synchronous theta activity are not fully revealed, recent findings
suggest a critical role for a two-way, feedback inhibitory (GABA) interaction
between the medial septum and hippocampus
(Dragoi et al., 1999). It has
been shown that functional inhibitory networks alone can produce synchronized
activity, and synchrony could occur in mutually inhibitory networks
(Skinner et al., 1999).
Termination pattern of 5-HT fibers in the hippocampus show high target
selectivity, forming direct synapses distinctively of certain classes of GABA
interneurons (Gulyas et al.,
1999). Because 5-HT2C receptors are exclusively located
on GABA neurons in the septo-hippocampal system, including GABA-containing
projecting neurons in the medial septum
(Leranth and Vertes, 1999),
their activation is expected to modulate the system oscillatory behavior. Our
findings on 5-HT2C receptor agonists support this concept and
demonstrate that 5-HT2C receptors regulate neuronal network
excitability.
Functional Aspects. Theta rhythm is a characteristic activity of the
entire limbic system (Bland and Colom,
1993; Vertes and Kocsis,
1997; Collins et al.,
1999; Pare and Collins,
2000), showing correlation with various behavior stages
(Vinogradova, 1995;
Buzsaki, 2002). Although
presently it is not clear whether theta oscillation is associated with a
specific limbic function within a discrete limbic area, generally theta
oscillation is presumed to play a role in cognition and memory formation
(Winson, 1978;
Hasselmo et al., 2002;
Seager et al., 2002), and
emotion processing (McNaughton,
1997; Anagnostaras et al.,
1999). Based on experimental observations in rats, theta
oscillation of the hippocampal formation is considered as a physiological
encoding frequency in memory formation
(Kahana et al., 2001;
Buzsaki, 2002;
Hasselmo et al., 2002). In
addition, recent observation of human theta has strengthened the connection
between theta oscillation and cognitive processes. Intracranial recordings
from human cortex have revealed evidence of high-amplitude theta oscillations
throughout the brain, including the neocortex, and its occurrence during
working memory tasks (Raghavachari et al.,
2001). In regard to emotions, it has been shown that in anxiogenic
situations amygdaloid neurons became synchronized through a modulation at the
theta frequency (Pare and Collins,
2000), and the propensity of hippocampal areas to generate theta
activity increases during EEG activated states, arousal, and anxiety
(Green and Arduini, 1954;
Collins et al., 1999). Our data
indicate that brain 5-HT neurons regulate theta activity of the
septo-hippocampal system via 5-HT2C receptors, and pharmacological
interactions with these receptors could modulate various physiological and
pathological processes associated with limbic oscillatory activity.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: MS/DB, medial septum/diagonal band of Broca; 5-HT,
5-hydroxytryptamine, serotonin; MS/DBv, vertical limb of the diagonal band of
Broca; m-CPP, 1-(3-chlorophenyl)piperidine; ANOVA, analysis of
variance; MDL 100,907,
R-(+)--(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol;
Ro 60-0175,
(S)-2-(chloro-5-fluoro-indol-l-yl)-1-methylethylamine
fumarate; R,S-127445,
2-amino-4-(4-fluoronaphth-1-yl)6-isopropyl-pyrimidine; SB-206553,
5-methyl-1-(3-pyridil-carbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole
hydrochloride; SB-242084,
6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbomyl]
indoline.
Address correspondence to: Dr. Mihály Hajós, Principal Research Scientist, Neurobiology, Pharmacia Corporation, 301 Henrietta St., Kalamazoo, MI 49007. E-mail: mihaly.hajos{at}pharmacia.com
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References |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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