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The Journal of Neuroscience, December 1, 1998, 18(23):10150-10156
Long-Term Antidepressant Treatments Result in a Tonic Activation
of Forebrain 5-HT1A Receptors
Nasser
Haddjeri,
Pierre
Blier, and
Claude
de Montigny
Neurobiological Psychiatry Unit, McGill University, Montréal,
Québec, Canada H3A 1A1
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ABSTRACT |
We report here the first direct functional evidence of an increase
in the tonic activation of postsynaptic 5-HT1A receptors by
antidepressant treatments. Because 5-HT1A receptor
activation hyperpolarizes and inhibits CA3 pyramidal
neurons in the dorsal hippocampus, we determined, using in
vivo extracellular recording, whether the selective
5-HT1A receptor antagonist WAY 100635 could disinhibit
these neurons. Unexpectedly, no disinhibition could be detected in
controls. However, after long-term treatment with the tricyclic
antidepressant imipramine, the selective 5-HT reuptake inhibitor
paroxetine, the reversible monoamine oxidase-A inhibitor befloxatone, the  2-adrenergic antagonist mirtazapine, or
the 5-HT1A receptor agonist gepirone or multiple
electroconvulsive shock (ECS) administration, WAY 100635 markedly
increased (60-200%) the firing activity of CA3 pyramidal
neurons. Such a disinhibition was absent in rats treated with the
nonantidepressant drug chlorpromazine, in rats receiving only one ECS,
or in rats receiving multiple ECSs in combination with an
intrahippocampal pertussis toxin treatment to inactivate
Gi/o-coupled 5-HT1A receptors. These data
indicate that such antidepressant treatments, acting on entirely
different primary targets, might alleviate depression by enhancing the
tonic activation of forebrain postsynaptic 5-HT1A receptors.
Key words:
antidepressants; serotonin (5-HT); 5-HT1A
receptors; WAY 100635; disinhibition; dorsal hippocampus
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INTRODUCTION |
With a prevalence of at least 4% of
the general population, major depression is one of the most common
psychiatric disorders. Although its physiopathology is not fully
defined, there is a growing body of evidence supporting the implication
of the serotonin (5-HT) system in the therapeutic effect of
antidepressant treatments (Heninger and Charney, 1987 ; Price et al.,
1990; Van Praag et al., 1990; Cummings, 1993; Blier and de Montigny,
1994; Maes and Meltzer, 1995). Accordingly, it has been shown that
long-term tricyclic antidepressant (TCA) and repeated electroconvulsive shock (ECS) administration lead to an enhanced 5-HT neurotransmission through a progressive sensitization of the postsynaptic
5-HT1A receptors in the dorsal hippocampus (de Montigny and
Aghajanian, 1978; de Montigny, 1984; Welner et al., 1989; Nowak and
Dulinski, 1991; Stockmeier et al., 1992; Burnet et al., 1994).
Long-term treatments with monoamine oxidase inhibitors (MAOIs) and
selective 5-HT reuptake inhibitors (SSRIs) desensitize the
somatodendritic 5-HT1A autoreceptors of 5-HT neurons in the
dorsal raphe nucleus, thereby allowing their firing rate to recover in
the presence of the drugs (Blier and Montigny, 1985; Chaput et al.,
1988). In addition, longterm SSRI treatment desensitizes terminal
5-HT1B/1D autoreceptors, whereas long-term MAOI treatment
desensitizes 2-adrenoceptors that are located on 5-HT
terminals and inhibit 5-HT release (Blier and Bouchard, 1994; Mongeau
et al., 1994). Long-term treatment with the antidepressant
mirtazapine, an 2-adrenoceptor antagonist, increases
5-HT neurotransmission as a result of a sustained increase in 5-HT
neuron firing activity in the presence of decreased function of
2-adrenoceptors located on 5-HT terminals in the dorsal
hippocampus (Haddjeri et al., 1997). Finally, a long-term treatment
with 5-HT1A receptor agonist, such as gepirone,
desensitizes the presynaptic 5-HT1A receptors on 5-HT
neuron somata but not the postsynaptic 5-HT1A receptors on
CA3 pyramidal neurons (Blier and de Montigny, 1987).
Consequently, it was hypothesized that in the presence of the exogenous
5-HT1A receptor agonist and a normalized release of
endogenous 5-HT, long-term treatment with a 5-HT1A receptor agonist also leads to an enhanced 5-HT neurotransmission. Together, these data indicate that adaptive changes in the 5-HT system may play a
pivotal role in the therapeutic effect of antidepressant treatments.
Although in vivo microdialysis studies have shown that
long-term antidepressant treatments increase extracellular 5-HT levels
in several brain structures including the hippocampus (Bel and Artigas,
1993; Yoshioka et al., 1995), direct functional evidence of an enhanced
tonic activation of postsynaptic 5-HT1A receptors induced
by long-term antidepressant treatments is not yet available.
In the present study, several classes of antidepressant treatments were
studied to determine whether their long-term administration could
indeed modify the degree of tonic activation of postsynaptic 5-HT1A receptors on dorsal hippocampus CA3
pyramidal neurons. Because the activation serotonin1A
receptors hyperpolarize CA3 pyramidal neurons, the degree
of disinhibition induced by intravenous administration of the potent
and selective 5-HT1A receptor antagonist WAY 100635 was
measured as an index of the tonic activation of postsynaptic
5-HT1A receptors.
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MATERIALS AND METHODS |
Treatments. The experiments were performed in
vivo in male Sprague Dawley rats. Six groups of rats were treated
for 21 d with imipramine (Ciba-Geigy, Montréal, Canada; 10 mg · kg 1 · d1),
chlorpromazine (Rhone-Poulenc, Montréal, Canada; 10 mg · kg1 · d1),
befloxatone (Synthelabo Recherche, Rueil-Malmaison, France; 0.75 mg · kg1 · d1),
mirtazapine (Organon, Oss, The Netherlands; 5 mg · kg1 · d1),
paroxetine (SmithKline Beecham, Harlow, England; 10 mg · kg1 · d1), or
vehicle (50% ethanol-water solution) delivered by osmotic minipumps
(Alza, Palo Alto, CA) inserted subcutaneously. One group of rats was
treated with gepirone (Bristol-Myers Squib, Wallingford, CT; 15 mg · kg1 · d1,
solubilized in water) for 2 weeks. One other group was administered one
ECS (150 V pulses of 10 msec duration delivered at a frequency of 50 Hz
for 1 sec), and another group was given a series of seven ECSs (7-ECS)
every other day for 14 d. Finally, one group of rats was treated
with pertussis toxin (Sigma, St. Louis, MO), which inactivates
Gi/o-proteins, and one last group was given both seven ECSs
and a pertussis treatment. Pertussis toxin, 1 µg in 2 µl, was
injected (at a rate of 0.4 µl/min) unilaterally in the dorsal hippocampus (anterior = 4.2, lateral = 4.2, ventral = 3.5) 10 d before the electrophysiological experiment (Blier et
al., 1993). The rats were tested after the long-term treatments with
the minipumps in place to mimic clinical conditions, because patients
undergo an improvement of their depressive condition while taking their medication and not after withdrawal. In fact, patients often rapidly relapse if their medication is stopped immediately after remission. The
animals were anesthetized with chloral hydrate (400 mg/kg, i.p.), with
supplemental doses given to maintain constant anesthesia and to prevent
any nociceptive reaction to a tail pinch.
Electrophysiological experiments. Recording and
microiontophoresis were performed with five-barreled glass
micropipettes prepared in a conventional manner (Haigler and
Aghajanian, 1974). The central barrel was filled with a 2 M
NaCl solution and used for extracellular unitary recordings. The
pyramidal neurons were identified by their large amplitude (0.5-1.2
mV) and long-duration (0.8-1.2 msec), simple spikes alternating with
complex spike discharges (Kandel and Spencer, 1961). The side barrels
contained the following solutions: 5-HT creatinine sulfate (Sigma; 2 and 20 mM in 200 mM NaCl, pH 4), quisqualate
(Sigma; 1.5 mM in 200 mM NaCl, pH 8), and 2 M NaCl used for automatic current balancing. The rats,
control or treated with the minipumps in place, were mounted on a
stereotaxic apparatus, and the microelectrodes were lowered at 4.2 mm
lateral and 4.2 anterior to lambda into the CA3 region of
the dorsal hippocampus. Because most hippocampus pyramidal neurons are
not spontaneously active under chloral hydrate anesthesia, a leak or a
small ejection current of quisqualate (+1 to  6 nA) was used to
activate them within their physiological firing range (Ranck, 1975).
Neuronal responsiveness to the microiontophoretic application of 5-HT
was assessed by determining the number of spikes suppressed for
applications of 5-HT (10 nA) and for a duration of 50 sec. This
corresponds to the number of spikes due minus the number of spikes
found with a baseline of firing recorded with a cumulative interval
frequency of a duration of 40 sec before the application of 5-HT. The
same current of ejection of 5-HT was always used before and after the intravenous injection of the selective 5-HT1A receptor
antagonist WAY 100635 (Wyeth Research, Berkshire, UK; 100 µg/kg). Two
minutes before the intravenous administration of WAY 100635, the firing activity of the quisqualate-activated CA3 pyramidal neurons
tested was decreased to ~5 Hz to allow the detection of possible
changes in firing activity after WAY 100635 administration in control and treated rats. On the basis of previous studies from our laboratory showing that WAY 100635 dose-dependently increases the firing activity
of quisqualate-activated CA3 pyramidal neurons in rats treated with the dual 5-HT/norepinephrine reuptake inhibitor
duloxetine, a dose of 100 µg/kg (i.v.) was chosen because it
corresponds to the maximum of effect of WAY 100635 (Rueter et al.,
1998).
To assess the effectiveness of the long-term treatment with paroxetine,
the recovery time 50 (RT50) method was
used. The RT50 value has been shown to be a
reliable index of the in vivo activity of the 5-HT reuptake
process in the rat hippocampus. This value is obtained by calculating
the time in seconds required for the neuron to recover 50% of its
initial firing rate at the end of the microiontophoretic application of
5-HT onto a CA3 pyramidal neuron. Thus, the blockade of the
5-HT transporter by an SSRI reveals a greater
RT50 value than in controls (Piñeyro et
al., 1994). The neuronal responsiveness to 5-HT was assessed using the
I·T50 method. It is the product of
the current (in nanoamperes) used to eject 5-HT from the
micropipette and the time (in seconds) required to obtain a 50%
decrease from the baseline of the firing rate of the recorded neuron.
The more sensitive a neuron is to 5-HT, the smaller will be the
I·T50 value because the number of molecules ejected is
proportional to the charge (de Montigny and Aghajanian, 1978).
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RESULTS |
Effects of long-term antidepressant treatments on the
responsiveness of dorsal hippocampus CA3 pyramidal neurons
to 5-HT
It has been demonstrated previously that the microiontophoretic
application of 5-HT onto rat dorsal hippocampus pyramidal neurons
produces a suppressant effect on their firing activity via activations
of postsynaptic 5-HT1A receptors (Blier and de Montigny,
1987; Chaput and de Montigny, 1988). For all CA3
hippocampus pyramidal neurons tested, 5-HT (10 nA) induced a reduction
of firing activity (Figs. 1,
2; and see 4A). This inhibitory
effect of 5-HT occurred without any alteration of the action potential shape and was abolished by pertussis toxin treatment (see Fig. 4C,D). Treatment with one ECS or long-term treatment with
chlorpromazine, befloxatone, mirtazapine, or gepirone did not modify
the suppressant effect of microiontophoretically applied 5-HT on the
firing activity of CA3 pyramidal neurons. On the other
hand, the treatment with seven ECSs and the long-term treatment with
imipramine markedly enhanced the responsivity of CA3
pyramidal neurons to microiontophoretically applied 5-HT: the mean
I·T50 value for 5-HT was
significantly lower in rats treated with seven ECS or with imipramine
than in controls and rats treated with one ECS or with chlorpromazine (Fig. 3B); the
I·T50 value for 5-HT (5 nA of a 2 mM solution) was 75 ± 13 (n = 16) in
control rats, 79 ± 12 (n = 14) in rats treated
with one ECS (t = 0.215, df = 28, p > 0.8), 72 ± 11 (n = 14) in
rats treated with chlorpromazine (t = 0.147, df = 28, p > 0.8), 37 ± 6 (n = 16) in rats treated with seven ECSs
(t = 2.57, df = 30, P < 0.015),
and 36 ± 6 (n = 17) in rats treated with
imipramine (t = 2.71, df = 31, p < 0.013). Moreover, the mean
RT50 value for 5-HT was increased by 344% in
paroxetine-treated rats because of the blockade of the 5-HT reuptake
process (Fig. 3A). The RT50 value for
5-HT (10 nA of a 20 mM solution) was 45 ± 6 sec in
control rats (n = 7) and 146 ± 7 sec in rats
treated with paroxetine (n = 7, t = 11.2, df = 12, p < 0.01). The
intravenous administration of the selective 5-HT1A receptor
antagonist WAY 100635 (100 µg/kg) significantly reduced the
suppressant effect of 5-HT on CA3 pyramidal neurons in all
groups. As illustrated in Figures 1 and 2, the intravenous
administration of WAY 100635 significantly reduced the suppressant
effect of 5-HT on the firing activity of CA3 pyramidal
neurons by 52% in controls (t = 3.18, df = 7, p <0.01), 59% in
mirtazapine-treated rats (t = 3.74, df = 6, p < 0.01), 62% in gepirone-treated rats
(t = 7.59, df = 6, p < 0.01), and 57% in befloxatone-treated rats (t = 3.99, df= 7, p < 0.01).
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Figure 1.
Integrated firing rate histogram of a dorsal
hippocampus CA3 pyramidal neuron, showing its
responsiveness to microiontophoretic application of 5-HT in control
(A) and rats treated with mirtazapine
(B). These neurons were activated with a
quisqualate ejection current of +1 and 1 nA. Horizontal
bars indicate the duration of the applications (current given
in nanoamperes). Note the altered effectiveness of 5-HT to suppress
firing activity after administration of WAY 100635 (0.1 mg/kg, i.v.) in
control (A) and treated rats
(B). At the bottom of
A and B, the responsiveness to 5-HT in
controls and rats treated with mirtazapine is expressed as the number
of spikes suppressed per 10 nA; the number in the
columns indicates the number of neurons and rats tested.
*p < 0.01 (paired Student's t
test).
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Figure 2.
Integrated firing rate histogram of a dorsal
hippocampus CA3 pyramidal neuron, showing its
responsiveness to microiontophoretic application of 5-HT before and
after the intravenous injection of WAY 100635 (0.1 mg/kg) in rats
treated with befloxatone (A) and with gepirone
(B). These neurons were activated with a
quisqualate ejection current of 1 and 3 nA. Horizontal
bars indicate the duration of the applications (current given
in nanoamperes). Note the altered effectiveness of 5-HT to suppress
firing activity after administration of WAY 100635 in treated rats. At
the bottom of A and B, the
responsiveness to 5-HT in rats treated with befloxatone or gepirone is
expressed as the number of spikes suppressed per 10 nA; the
number in the columns indicates the number of neurons
and rats tested. *p < 0.01 (paired Student's
t test).
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Figure 3.
A, Recovery time, expressed as
RT50 values (means ± SEM), of dorsal
hippocampus CA3 pyramidal neurons from the
microiontophoretic application of 5-HT in control rats and rats treated
with paroxetine for 21 d (10 mg · kg1 · d1, s.c.).
The numbers in the columns indicate the number of rats
tested. *p < 0.05 (unpaired Student's
t test). B, Mean (± SEM)
I·T50 values (see Materials and Methods)
in control (CTL) and rats treated with one ECS
(1-ECS), seven ECSs (7-ECS),
chlorpromazine (CPZ), and imipramine
(IMI). The numbers in the columns
indicate the number of neurons tested. *p < 0.05 (unpaired Student's t test).
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Effects of long-term antidepressant treatments on the disinhibition
induced by WAY 100635
As mentioned in Materials and Methods, the dorsal hippocampus
CA3 pyramidal neurons were activated by a leak or a small
current of quisqualate. In the present study, none of the treatments
used significantly modified the firing activity of dorsal hippocampus CA3 pyramidal neurons (in control rats, the application of
0.58 ± 0.47 nA of quisqualate resulted in a firing activity of
5.1 ± 04 Hz, n = 12). In controls, the
intravenous administration of WAY 100635 did not modify the firing
activity of dorsal hippocampus CA3 pyramidal neurons
(before: 5.1 ± 0.4 Hz; after WAY 100635: 4.7 ± 0.5 Hz,
n = 12) (Figs.
4A,
5). Similarly, in rats that received one
ECS or were treated with chlorpromazine or pertussis toxin, the
administration of WAY 100635 did not modify the firing activity of
CA3 pyramidal neurons (before: 4.6 ± 0.5 Hz; after
WAY 100635: 4.2 ± 1 Hz in rats treated with one ECS,
n = 8; before: 3.9 ± 0.5 Hz; after WAY 100635:
3.5 ± 0.6 Hz in rats treated with chlorpromazine, n = 7; before: 4.9 ± 0.5 Hz; after WAY 100635:
3.8 ± 0.3 Hz in rats treated with pertussis toxin,
n = 6) (Fig. 5). In contrast, in all other treated
groups, WAY 100635 significantly increased the firing activity of
dorsal hippocampus CA3 pyramidal neurons. In the groups
treated with seven ECSs, imipramine, and paroxetine, the firing
activity of the CA3 pyramidal neurons was markedly increased (7-ECS, before: 3.6 ± 0.6 Hz; after WAY 100635:
7.6 ± 1 Hz, n = 7; imipramine, before: 3.7 ± 0.6 Hz; after WAY 100635: 6.3 ± 1 Hz, n = 7;
paroxetine, before: 4.8 ± 0.6 Hz; after WAY 100635: 11.1 ± 1.4 Hz, n = 7) (Figs. 4, 5). The firing activity of
CA3 pyramidal neurons in groups treated with befloxatone
(before: 4.2 ± 0.5 Hz; after WAY 100635: 8.1 ± 0.8 Hz,
n = 8) (Figs. 4B, 5), mirtazapine
(before: 5.1 ± 0.5 Hz; after WAY 100635: 8.2 ± 0.8 Hz,
n = 12) (Figs. 4C, 5), and gepirone (before:
5 ± 0.8 Hz; after WAY 100635: 15.2 ± 2.5 Hz,
n = 7) (Fig. 4D, 5) was also significantly increased after the intravenous administration of WAY
100635. However, in rats treated with pertussis toxin, a 7-ECS administration failed to increase the disinhibition of CA3
pyramidal neurons induced by the intravenous administration of WAY
100635 (before: 4.8 ± 0.5 Hz; after WAY 100635: 3.7 ± 0.7 Hz, n = 7) (Fig. 5).
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Figure 4.
Integrated firing rate histograms of dorsal
hippocampus CA3 pyramidal neurons showing their
responsiveness to microiontophoretic application of 5-HT and to
intravenous injection of WAY 100635 (0.1 mg/kg) in rats receiving seven
ECSs (A), in sham-operated rats
(B), in rats treated with pertussis toxin
(PTX) (C), and in rats
receiving both 7-ECS and pertussis toxin treatments. These neurons were
activated with a quisqualate ejection current of 1 to 3 nA. Note
the altered firing activity after the administration of WAY 100635 only
in rats receiving seven ECSs (A), and the altered
suppressant effect of 5-HT in rats treated with pertussis toxin
(C, D).
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Figure 5.
Changes (% ± SEM) of the firing activity of
quisqualate-activated dorsal hippocampus CA3 pyramidal neurons after
intravenous injection of WAY 100635 (100 µg/kg) in control rats
(CTL) and in rats treated with imipramine
(IMI, t = 6.74,
df = 17, p < 0.01), paroxetine
(PRX, t = 4.71,
df = 17, p < 0.01),
mirtazapine (MIR, t = 5.86,
df = 22, p < 0.01),
befloxatone (BFX, t = 3.37,
df = 18, p < 0.01), gepirone
(GEP, t = 8.95,
df = 17, p < 0.01),
chlorpromazine (CPZ, t = 0.77,
df = 17, p > 0.4), or
pertussis toxin treatment (PTX, t = 0.44, df = 16, p > 0.6) and
receiving single (1-ECS, t = 0.34, df = 18, p > 0.3) or multiple
electroconvulsive shocks (7-ECS, t = 7.31, df = 17, p < 0.01), or
both multiple electroconvulsive shocks and pertussis toxin treatment
(7-ECS + PTX, t = 0.18, df = 17, p > 0.8). The
number for each column indicates the number of rats
tested.
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DISCUSSION |
Various classes of antidepressant treatments enhance 5-HT
neurotransmission with a time course consistent with their delayed therapeutic effect. Clinical evidence in support of the involvement of
5-HT is provided by the antidepressant activity of SSRIs, the long-term
administration of which increases extracellular 5-HT, and also by the
antidepressant activity of 5-HT1A receptor agonists. In
addition, the reduction of 5-HT levels, induced by either
parachlorophenylalanine (a 5-HT synthesis inhibitor) or the dietary
depletion of the 5-HT precursor L-tryptophan, reverses the
antidepressant effect of several drugs, including MAOIs, TCAs, SSRIs,
and mirtazapine (Shopsin et al., 1975; Delgado et al., 1990, 1997). As
mentioned in the introductory remarks, preclinical evidence suggests
that long-term antidepressant treatments enhance 5-HT neurotransmission
via different adaptive changes [see also Blier and de Montigny
(1994)]. The present electrophysiological studies show that only
treatments with drugs endowed with antidepressant activity increased
the tonic activation of postsynaptic 5-HT1A receptors in
the dorsal hippocampus, as evidenced by the enhancing effect of the
administration of the 5-HT1A receptor antagonist WAY
100635. These results provide the first direct functional evidence of a
sustained enhancement of 5-HT neurotransmission, which seems to be a
common and specific to antidepressant treatments.
Among the 5-HT1A receptor antagonists that are available,
WAY 100635 is by far the most potent and selective antagonist at both
presynaptic and postsynaptic 5-HT1A receptors (Khawaja et al., 1994; Fletcher et al., 1996). The present results indicate that
WAY 100635 is indeed an effective antagonist at postsynaptic 5-HT1A receptors, because WAY 100635 reduced the
suppressant effect of microiontophoretically applied 5-HT on the firing
activity of CA3 pyramidal neurons. The capacity of WAY
100635 to block the somatodendritic 5-HT1A autoreceptor is
not expected to alter its effectiveness in disinhibiting postsynaptic
neurons. Indeed, any interference would dampen this disinhibitory
effect of WAY 100635, because in the presence of an SSRI in freely
moving cats (Fornal et al., 1996) and of befloxatone in anesthetized
rats (Haddjeri et al., 1998), WAY 100635 increases the firing of 5-HT neurons.
Treatments with ECS and TCA, studied in vivo and ex
vivo, appear to sensitize postsynaptic (both intrasynaptic and
extrasynaptic) 5-HT1A receptors (de Montigny and
Aghajanian, 1978; Gallager and Bunney, 1979; de Montigny, 1984; Gravel
and de Montigny, 1987; Chaput et al., 1991; Blier and Bouchard, 1992;
Maj et al., 1996; Bijak et al., 1997), although negative results have
been reported (Olpe and Schellenberg, 1981; Rowan and Anwyl, 1985; Beck
and Halloran, 1989). Perhaps these negative results are attributable in
part to the use of 5-HT as an agonist, which can also increase neuronal
excitability via non-5-HT1A receptors such as
5-HT2/5-HT4 receptors (Beck, 1992;
Torres et al., 1996). In the present study, long-term treatment with
imipramine and seven ECSs, but not with chlorpromazine, pertussis
toxin, or one ECS, significantly increased the disinhibition produced
by the 5-HT1A receptor antagonist WAY 100635, unveiling an
enhancement of the tonic activation postsynaptic 5-HT1A
receptors. That this subtype of 5-HT receptor is mediating this
phenomenon is supported by the observation that in rats treated with
seven ECSs the inactivation of the Gi/o-proteins by
pertussis toxin prevented it. Indeed, other hippocampal 5-HT receptors
(i.e., 5-HT2, 5-HT3,
5-HT4, 5-HT6, and
5-HT7 receptors) are not coupled with
Gi/o-proteins.
The classes of antidepressant treatments, other than TCA and ECS, used
in the present study have been shown to alter only the presynaptic
component of 5-HT neurotransmission. In fact, in rats treated with
paroxetine, the enhancement of the tonic activation postsynaptic
5-HT1A receptors would be caused by an increased synaptic
5-HT concentration in the dorsal hippocampus after desensitization of
somatodendritic and terminal 5-HT autoreceptors and by blockade of the
neuronal 5-HT carrier (Piñeyro et al., 1994). After a 21 d
treatment with befloxatone, the enhancement of the tonic activation of
postsynaptic 5-HT1A receptors would be caused by the
increased synaptic 5-HT concentration resulting from both monoamine
oxidase-A (MAO-A) inhibition and desensitization of
2-adrenoceptors on 5-HT nerve terminals (Blier and
Bouchard, 1994; Mongeau et al., 1994). A similar enhancement of tonic
5-HT1A receptor activation would result from repeated
administration of mirtazapine, in this case as a result of a sustained
increase in the activity of 5-HT neurons accompanied by a
desensitization of 2-adrenoceptor (Haddjeri et al.,
1997). Finally, it has been shown that gepirone treatment desensitized
the presynaptic 5-HT1A autoreceptors on 5-HT neurons, but
not the postsynaptic 5-HT1A receptors on CA3
pyramidal neurons (Blier and de Montigny, 1987). Therefore, it was
hypothesized that such a treatment might result in an increase of 5-HT
neurotransmission, but it must be noted that, at the time, selective
5-HT1A receptor antagonists were not available to test this
hypothesis. In the present study, the intravenous administration of WAY
100635 significantly increased the firing activity of CA3
pyramidal neurons in rats treated with gepirone, whose 5-HT neurons
have regained their normal firing activity, thus showing that the
blockade of the postsynaptic 5-HT1A receptors by WAY 100635 unveils an enhancement of their tonic activation.
Serotonin receptors other than those of the 5-HT1A subtype
may also be involved in the antidepressant response. Indeed, it has
been demonstrated that some postsynaptic 5-HT receptors, other than the
5-HT1A subtype, become sensitized after long-term
antidepressant treatments. For instance, repeated TCA administration
sensitizes postsynaptic 5-HT2 receptors in the facial motor
nucleus and a yet uncharacterized 5-HT receptor subtype in the amygdala
(Menkes et al., 1980; Wang and Aghajanian, 1980).
In conclusion, the present electrophysiological studies show that
chronic treatment with the TCA imipramine, the SSRI paroxetine, the
selective and reversible MAO-A befloxatone, the
2-adrenergic antagonist mirtazapine, or the
5-HT1A receptor agonist gepirone, as well as repeated ECS
therapy, enhanced the tonic activation of postsynaptic
5-HT1A receptors in the dorsal hippocampus, as shown by the
disinhibition produced by the selective 5-HT1A receptor antagonist WAY 100635. These results constitute novel direct evidence that an enhanced 5-HT neurotransmission may underlie the antidepressant response in humans.
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FOOTNOTES |
Received Aug. 3, 1998; revised Sept. 2, 1998; accepted Sept. 15, 1998.
This work was supported in part by Medical Research Council of Canada
(MRC) Grants (MT-11014 and MA-6444 to P.B. and C.dM., respectively), a
fellowship from the Fonds de la Recherche en Santé du
Québec and the Royal Victoria Hospital Research Institute to
N.H., and an MRC Scientist Award to P.B. We thank J.-C.
Béïque for friendly advice throughout this work.
Correspondence should be addressed to Dr. Nasser Haddjeri,
Neurobiological Psychiatry Unit, McGill University, 1033 Pine Avenue West, Montréal, Québec, Canada H3A 1A1.
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Top
Abstract
Introduction
