Effects of chronic antidepressants and electroconvulsive shock on serotonergic neurotransmission in...

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Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 729–739

Review article

Effects of chronic antidepressants and electroconvulsive shock on

serotonergic neurotransmission in the rat hippocampus

Eliyahu Dremencova,*, Eitan Gurb, Bernard Lererb, Michael E. Newmanb

aLife Sciences Faculty, Bar-Ilan University, Ramat-Gan 52900, IsraelbBiological Psychiatry Laboratory, Department of Psychiatry, Hebrew University Hadassah Medical Center, Jerusalem, Israel

Accepted 22 April 2003

Abstract

The hippocampus may play a critical role in the pathophysiology and treatment of depression. There are two main lines of evidence for

this: firstly, many of its functions correspond to those altered in depression, and secondly, many hippocampal functions are regulated by the

serotonergic (5-HT) system, which is a common target of antidepressant treatments. Chronic effects of antidepressants and electroconvulsive

shock (ECS) have been studied by various methods using electrophysiology, in vivo microdialysis or ex vivo neurochemical measurements.

The aim of the current review is to point out possible correlations between these studies based on different methods and to suggest

neurochemical mechanisms that result in the observed changes in hippocampal physiology and neurogenesis. These changes in hippocampal

neurochemistry are reviewed and compared with the abnormalities associated with stress, corticosterone or depression.

D 2003 Elsevier Science Inc. All rights reserved.

Keywords: Antidepressants; Electroconvulsive shock; Hippocampus; 5-HT1A autoreceptor; 5-HT1B autoreceptor; Postsynaptic 5-HT1A receptor; cAMP

1. Introduction

Major depression is a severe disorder that involves

disturbances of emotional, cognitive, autonomic and endo-

crine functions. The pathophysiology of the disease is still

unknown and may include functional abnormalities of

different brain regions and circuits. The hippocampal forma-

tion is one of those brain systems that was suggested to play

a critical role in depressive disorder. There are two reasons

for interest in the hippocampus. First, this region controls

0278-5846/03/$ – see front matter D 2003 Elsevier Science Inc. All rights reserv

doi:10.1016/S0278-5846(03)00123-4

Abbreviations: AC, adenylate cyclase; BDNF, brain-derived neuro-

trophic factor; CA, cornu ammonis; cAMP, cyclic adenosine mono-

phosphate; CREB, cAMP response element binding protein; DG, dentate

gyrus; HPA axis, hypothalamo–pituitary–adrenal axis; IP3, inositol

triphosphate; PLC, phospholipase C; ECS, electroconvulsive shock; LTP,

long-term potentiation; MAOI, monoamine oxidase inhibitor; PKA, protein

kinase A; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and

noradrenaline reuptake inhibitor; TMS, transcranial magnetic stimulation;

TCA, tricyclic antidepressant; GR 127935, N-[4-methoxy-3-(4-methyl-1-

piperizinyl)phenyl]-20-methyl-40-(5-methyl-1,2,4-oxadiazole-3-yl)[1,10-bi-

phenyl]-carboxamide; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetra-

lin; 5-HT, 5-hydroxytryptamine, serotonin.

* Corresponding author. Tel.: +972-3-531-8123; fax: +972-3-535-

1824.

E-mail address: [email protected] (E. Dremencov).

many of the brain functions that are disturbed in depressed

patients, such as altered regulation of neuroendocrine and

autonomic functions, mood and cognition difficulties,

adverse responses to stressful stimuli and others. Second,

hippocampal functions are highly regulated by serotonergic

(5-HT) systems, the involvement of which in the pathology

and treatment of depression has been shown in many studies

(Hjorth et al., 2000). The effects of chronic antidepressant

and electroconvulsive shock (ECS) administration on the

hippocampal 5-HT system, measured using electrophysio-

logical methods, have been described by Blier and de

Montigny (1998, 1999), Blier et al. (1998) and Mongeau

et al. (1997). These authors postulated that different classes

of antidepressants and ECS facilitate 5-HT neurotransmis-

sion in the hippocampus using different mechanisms. Thus,

chronic administration of tricyclic antidepressants (TCA)

and ECS causes sensitization of postsynaptic 5-HT1A recep-

tors, monoamine oxidase inhibitors (MAOIs) desensitize

presynaptic 5-HT1A receptors within the raphe nuclei and

selective serotonin reuptake inhibitors (SSRIs) desensitize

both nerve terminal 5-HT1B autoreceptors within the hip-

pocampus and somatodendritic 5-HT1A autoreceptors. Thus,

in the presence of 5-HT reuptake or monoamine oxidase

inhibition, desensitization of 5-HT autoreceptors results in

increased 5-HT input to the hippocampus.

ed.

Fig. 1. Human hippocampal formation. Cortical input to the hippocampus,

named perforant fiber pathway, innervates the neurons of the DG. The

axons of dentate neurons, mossy fibers pathway, innervate CA3 area

pyramidal cells. These pyramidal neurons innervate, via the Schaffer

collateral fiber pathway, the CA1 region, the output area of the

hippocampus.

E. Dremencov et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 729–739730

The 5-HT-mediated effects of antidepressants on the

neurochemistry of the hippocampus have been studied by

D’Sa and Duman (2002), Duman (2002), Duman and

Vaidya (1998), Duman et al. (1999, 2001) and Vaidya and

Duman (2001). These authors postulated that antidepres-

sants activate 5-HT neurotransmission by stimulation of

receptors positively coupled to adenylate cyclase (AC). This

activation results in an increase in the synthesis of neuro-

tropic factors, which prevent or reverse glucocorticoid

mediated neurodegenerative processes in the hippocampus

caused by chronic stress or depression.

Another method used to measure in vivo activity of 5-HT

presynaptic receptors is microdialysis (Auerbach and

Hjorth, 1995; Bosker et al., 1995a,b; Cremers et al., 2000;

Dremencov et al., 2000; Hjorth and Auerbach, 1994, 1999;

Hjorth et al., 2000; Gur et al., 1997, 1999a,b, 2000, 2001,

2002a,b; Invernizzi et al., 1995; Kreiss and Lucki, 1995).

The present work will discuss microdialysis findings within

the rat hippocampus and their correlation with electro-

physiological studies. In other studies, we used the micro-

dialysis technique to determine the activity at postsynaptic

5-HT1A receptors in the rat hippocampus (Dremencov et al.,

2000; Gur et al., 2001, 2002b; Newman et al., 2000) using

in vivo monitoring of cyclic adenosine monophosphate

(cAMP) levels. The results of these studies will be discussed

in the current work. The authors suggest that monitoring of

hippocampal cAMP levels is a unique method that enables

determination of possible correlations between electrophysi-

ology and neurochemistry of the hippocampus after anti-

depressant treatment. These correlations will be discussed in

the current work.

2. Hippocampus

Embryologically, hippocampus is formed as a folding of

temporal cortex of mammalian brain. Histologically, the

hippocampus is described as a paleocortical formation. In

contrast to the neocortex, the hippocampal formation con-

sists of three layers of neurons only: two layers of granular

cells and a layer of pyramidal neurons between them. The

hippocampal formation (Fig. 1) is divided into four regions:

dentate gyrus (DG) and the three regions of the cornu

ammonis CA1, CA2 and CA3. The DG is an input area of

the hippocampus, which receives afferent connections from

the entorhinal cortex. DG efferents, called mossy fibers,

project to the pyramidal cells of CA3 and CA2. CA2/3

efferents, called Schaffer collaterals, project to the output

area of hippocampal formation, CA1. The main hippocampal

outputs project from CA1 to the subiculum. The function of

the hippocampal formation is complex and poorly under-

stood. However, three central properties of the hippocampal

formation, which are all modified in depressed patients, may

be pointed out. The main function of the hippocampus relates

to memory and cognition. It has been described that lesion of

the hippocampal formation causes severe anterograde amne-

sia called Korsakoff syndrome. Secondly, the hippocampus

is part of a brain network that controls emotional behavior,

called the Papez emotional circuit (Chronister and Hardy,

1997). Thirdly, the hippocampus plays a central role in the

regulation of neuroendocrine functions related to stress.

Hippocampal neurons express both glucocorticoid and min-

eralocorticoid receptors. Lesion of the hippocampus or its

efferents projecting to the hypothalamus causes loss of

corticosterone-induced inhibition of ACTH release (Jacob-

son and Sapolsky, 1991; Lathe, 2001). Additionally, hippo-

campal activity itself may have an inhibitory action on stress-

induced corticosterone release (Feldman and Weidenfeld,

2001). Major depressive disorder, despite its classification as

an affective disorder, includes cognitive abnormalities

(Seligman, 1975). Indeed, the function of the hippocampus

may be described as cognitive recognition of the emotional

meaning of environmental stimuli. It has been suggested that

the hippocampus compares between predicted results of the

behavior and real output from the environment (Buzsaki,

1989; Lorincz and Buzsaki, 2000; Foster et al., 2000). The

mistake in the prediction mechanism is translated into

frustration. Detected mismatch must be repaired within a

portion of time. Failure to do this results in anxiety and

stress. Chronic anxiety and stress may result in a patho-

logical process within the hippocampus, which results in

depressive mind and behavior (Mongeau et al., 1997).

Indeed, human brain imaging studies found that stress (Czeh

et al., 2001) and depression (Sheline et al., 1996; Bremner et

al., 2000) cause hippocampal atrophy. Laboratory animal

studies found destructive effects of stress on hippocampal

synaptic plasticity (Duman, 2002; Duman et al., 1999;

Shakesby et al., 2002). Chronic hypercorticosolemia, which

has been postulated to be a biochemical model of depression

(Gur et al., 2001; Dremencov et al., 2002), results in hippo-

campal atrophy (Sapolsky, 2000), dendritic reorganization

(Wellman, 2001), a reduction in synthesis of brain-derived

E. Dremencov et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (2003) 729–739 731

neurotrophic factor (BDNF) and memory difficulties (Schaaf

et al., 2000).

3. 5-HT system of the hippocampus

The hippocampus is innervated by 5-HT terminals ori-

ginating from the dorsal and median raphe nuclei (Bruinvels

et al., 1993). Hippocampal cells express postsynaptic

5-HT1A (Banerjee et al., 1993; el Mestikawy et al., 1989),

5-HT2A (Vaidya et al., 1997), 5-HT2B (Sanden et al., 2000),

5-HT2C (Clemett et al., 2000; Abramowski et al., 1995),

5-HT3 (Hewlett et al., 1998; Mitchell and Pratt, 1991; Tecott

et al., 1993), 5-HT4 (Vilaro et al., 1996), 5-HT5A, 5-HT5B,

5-HT6 and 5-HT7 (Kinsey et al., 2001; Neumaier et al., 2001)

receptors. 5-HT3 receptors are coupled to Na+ ion channels;

their activation results in membrane depolarization (Barnes

and Sharp, 1999). In the hippocampus, 5-HT3 receptors

activate cholinergic (Consolo et al., 1994) and glutamatergic

(Ohno and Watanabe, 1997) neurotransmission; blocking of

hippocampal 5-HT3 receptors decreases the efficiency of

working memory (Ohno and Watanabe, 1997). Postsynaptic

5-HT1A receptors and presynaptic 5-HT1A and 5-HT1B

autoreceptors are Gi protein-coupled receptors. Their activa-

tion induces dissociation of Gi, which results in inhibition of

AC (a subunit action), opening of K + channels (bg subunits

action) and cell membrane hyperpolarization (Raymond et

al., 2001). Indeed, activation of 5-HT1B autoreceptors

expressed on the 5-HT nerve terminals within the hippocam-

pus and presynaptic 5-HT1A autoreceptors expressed on the

5-HT cell bodies within the dorsal raphe nuclei inhibits 5-HT

neuronal activity and 5-HT release (Kikvadze and Foster,

1995; Hervas et al., 2000; Adell et al., 2001). However, no

effect of presynaptic 5-HT1A autoreceptors on cAMP con-

centration was observed (Clarke et al., 1996). In in vivo

studies, postsynatic 5-HT1A receptor activation was found to

activate cAMP formation (Cadogan et al., 1994). The para-

doxical activation of cAMP synthesis by Gi/Go-coupled

postsynaptic 5-HT1A receptors may be explained by the type

of AC expressed in the hippocampal cells. Thus, hippo-

campal neurons express type II of AC, which is not inhibited

by G protein ai or ao units but is stimulated by bg units

(Tang and Gilman, 1991; Federman et al., 1992). In the

hippocampus, postsynaptic 5-HT1A receptor activation

increases local cholinergic (Wilkinson et al., 1994; Fujii et

al., 2000) and dopaminergic (Sakaue et al., 2000) neuro-

transmission. Hippocampal application of a 5-HT1A receptor

agonist was found to attenuate cognitive deficits caused by

brain injury (Kline et al., 2001). On the other hand, antagon-

ist application ameliorates traumatic cognitive impairment

(Harder et al., 1996).

5-HT2 receptors constitute a family of Gq-coupled recep-

tors. Their activation results in phospholipase C (PLC)-

mediated inositol triphosphate (IP3) formation and in cell

membrane depolarization by opening of Ca2 + channels

(Raymond et al., 2001). However, activation of 5-HT2A

receptors in the hippocampus was found to inhibit synthesis

of BDNF, in contrast to the cortex where 5-HT2A receptor

activation stimulates BDNF formation (Vaidya et al., 1997).

Hippocampal 5-HT2 receptors also regulate activity of the

hypothalamo–pituitary–adrenal axis (HPA axis). Thus,

local administration of a 5-HT2A receptor antagonist

decreases the hypothalamic hormonal response to sexual

stimuli, while a 5-HT2C receptor antagonist increases it

(Popova and Amstislavskaya, 2002). Hippocampal 5-HT2A

receptor activation was found to increase working memory

efficiency (Williams et al., 2002).

5-HT4, 5-HT6 and 5-HT7 receptors are Gs coupled. Their

activation enhances cAMP formation (Raymond et al.,

2001). Hippocampal 5-HT4 receptors positively autoregu-

late 5-HT neurotransmission (Ge and Barnes, 1996) and

increase acetylcholine outflow (Siniscalchi et al., 1999). A

correspondence between 5-HT4 receptor-induced increase in

hippocampal cholinergic neurotransmission and cognitive

functions was established (Matsumoto et al., 2001). 5-HT4

receptors were found to modulate long-term potentiation

(LTP) formation within the hippocampus (Kulla and Man-

ahan-Vaughan, 2002). Hippocampal 5-HT6 receptor antag-

onists were found to enhance excitatory neurotransmission

(Dawson et al., 2001). Activation of 5-HT7 receptors was

found to synchronize neuronal activity within the hippocam-

pus (Gill et al., 2002). Despite initial uncertainty, the

5-HT5A receptor is now known to be negatively coupled

to AC together with the members of the 5-HT1 family

(Thomas et al., 2000). The hippocampal 5-HT system is

affected by stress, depression or hypercorticosolemia. Rosel

et al. (2000) demonstrated altered 5-HT2A receptor density

and IP3 levels within the hippocampus of depressive suicide

victims. Neumaier et al. (2002) found that stress alters

dorsal raphe 5-HT1B mRNA levels, while hypercorticosole-

mia affects hippocampal 5-HT1A mRNA levels. Stress-

induced desensitization of hippocampal 5-HT1A receptors

and sensitization of 5-HT4 receptors was found using ex

vivo electrophysiology (Bijak et al., 2001).

A recent electrophysiological study (Matsumoto et al.,

2002) has shown that three of the above-mentioned receptors

are involved in endogenous 5-HT-mediated synaptic trans-

mission in the CA1 field of the hippocampus. 5-HT1A

receptor activation was found to mediate by 5-HT-induced

inhibition, while 5-HT4 and 5-HT7 receptor activation was

associated with facilitation. In the CA3 field, however,

facilitatory effects of endogenous 5-HT were mediated by

both 5-HT1A and 5-HT7 receptors. The variety of 5-HT

receptors thus plays an important region-specific role in

modulating hippocampal responses to incoming stimuli.

4. Chronic effects of antidepressants and ECS on

hippocampal 5-HT neurotransmission

The chronic effects of different antidepressant drugs and

treatments on presynaptic regulation of hippocampal 5-HT


release have been determined in various laboratories using

in vivo electrophysiological or microdialysis techniques

(Hjorth et al., 2000). Kreiss and Lucki (1995) demonstrated

a reduction of 5-HT1A autoreceptor-mediated inhibition of

hippocampal 5-HT release after chronic administration of

fluoxetine (15 mg/kg/day for 14 days), while our study

(Dremencov et al., 2000) showed that 7 days of fluoxetine

administration at 10 mg/kg/day reduced hippocampal

5-HT1B autoreceptor activity (Fig. 2). Cremers et al.

(2000), using in vivo microdialysis, showed that chronic

14-day administration of the SSRI, citalopram (20 mg/kg),

caused a significant decrease in 5-HT1A autoreceptor-medi-

ated inhibition of hippocampal 5-HT release. These findings

correlate with previous electrophysiological findings (Mon-

geau et al., 1997). However, other investigators (Bosker et

al., 1995a,b; Hjorth and Auerbach, 1994, 1999; Invernizzi et

al., 1995; Auerbach and Hjorth, 1995) were unable to show

any change in autoreceptor sensitivity in the hippocampus

after chronic administration of the SSRIs citalopram or

fluvoxamine. SSRI-mediated desensitization of 5-HT autor-

eceptors cannot be explained by alteration of receptor

density, which is normally unchanged by the treatment

(Hensler et al., 1991; Li et al., 1997; Gobbi et al., 1997;

LePoul et al., 2000), although in one study (Welner et al.,

1989) a decrease in 5-HT1A receptor number in the dorsal

raphe was found after chronic fluoxetine. However, the

decrease in 5-HT autoreceptor activity could be explained

Fig. 2. Effect of systemic N-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-

20-methyl-40-(5-methyl-1,2,4-oxadiazole-3-yl)[1,10-biphenyl]-carboxamide

(GR 127935) (5 mg/kg sc) on 5-HT levels in hippocampus of saline- and

fluoxetine-treated rats. Results are means ± S.E.M. of observations from

seven animals treated with saline and five animals treated subchronically

with fluoxetine (10 mg/kg/day ip for 6 days). Measurements were made 72

h after the last fluoxetine injection. Two-way analysis of variance on the

data from fractions 4 – 10 showed a significant effect of time

[ F(df = 6,60) = 3.62, P=.0039], an almost significant effect of treatment

[ F(df = 1,10) = 4.21, P=.067] and a significant interaction between time and

treatment [ F(df = 6,60) = 2.76, P=.019]. Post hoc Newman–Keuls tests

showed a significant difference ( *P < .006) between saline- and fluoxetine-

treated rats at fraction 6, i.e., 1 h after injection of GR 127935.

by chronic fluoxetine-induced Gi/Go protein down-regu-

lation within raphe nuclei, as shown by Li et al. (1996).

Alternatively, a reduction in 5-HT1A receptor–G protein

coupling in the raphe nuclei after chronic administration of

fluoxetine has been shown by several groups using 5-HT1A

receptor agonist-stimulated [35S]GTPgS binding (Castro et

al., 2003; Pejchal et al., 2002; Shen et al., 2002; Hensler,

2002).

Concerning other drugs, an effect of the reversible MAOI

befloxatone (0.75 mg/kg/day) to reduce 5-HT1A autorecep-

tor-mediated inhibition of firing activity of 5-HT neurons

was shown in the electrophysiological study of Haddjeri et

al. (1998b). A 3-week administration of the serotonin and

noradrenaline reuptake inhibitor (SNRI) venlafaxine was

shown in both in vivo electrophysiological studies and in

vitro [3H]5-HT release studies using hippocampal slices to

reduce 5-HT1A autoreceptor activity at a dose of 10 mg/kg/

day but to affect 5-HT1B autoreceptor activity only at the

much higher dose of 40 mg/kg/day (Beique et al., 2000a,b).

A recent study with the SNRI milnacipran (Mochizuki et al.,

2002) indicated that this drug given per os at 30 mg/kg b.i.d.

for 7 or 14 days also desensitized 5-HT1A autoreceptors, as

shown by a reduction in the potency of 5-HT to inhibit

firing of 5-HT neurons in slices of dorsal raphe, although no

such effect was observed in an earlier in vivo study by

Mongeau et al. (1998). On the other hand, microdialysis

studies from our laboratory (Gur et al., 1999a, 2002a)

showed no effect of chronic venlafaxine at a dose of 5

mg/kg/day for 4 weeks on either 5-HT1A or 5-HT1B auto-

receptor activity. Similarly, the tricyclic drugs clomipramine

(Newman et al., 2000), desipramine and mianserin (Kreiss

and Lucki, 1995) and ECS (Gur et al., 1997) did not alter

autoreceptor-mediated changes in 5-HT release in the hip-

pocampus. The absence of the effect of clomipramine and

desipramine on presynaptic regulation of 5-HT release may

be explained by the pharmacological properties of these

drugs. Desipramine acts mainly as a noradrenaline reuptake

inhibitor, and clomipramine dissociates rapidly to a metab-

olite that is inactive at the 5-HT reuptake site (Fujita et al.,

1991).

The chronic effects of antidepressants on postsynaptic

hippocampal 5-HT receptors have principally been deter-

mined in electrophysiological studies. An increase in post-

synaptic 5-HT1A receptor sensitivity was originally shown

by de Montigny and Aghajanian (1978) after chronic

administration of a variety of tricyclic drugs and by Chaput

et al. (1991) after chronic ECS. These effects may be due to

an increase in the 5-HT1A receptor number. Such an increase

has been found in the hippocampus after chronic imipr-

amine (Klimek et al., 1994; Burnet et al., 1994; Papp et al.,

1994; Moreau et al., 2001) and after chronic ECS (Hay-

akawa et al., 1994; Burnet et al., 1995) although other

studies have not confirmed these reports. The in vivo studies

of de Montigny’s group have been confirmed by ex vivo

studies performed with hippocampal slices (Bijak et al.,

1996, 2001). In these experiments, both chronic imipramine


and ECS enhanced the effects of 5-HT1A receptor activation

to inhibit the firing of pyramidal CA1 neurons, although

imipramine did not affect 5-HT1A receptor number. Interest-

ingly, 7-day administration of corticosterone, which as

mentioned above can be considered as a biochemical model

of depression, had an opposite action and attenuated the

inhibitory effect of 5-HT1A receptor activation. An altern-

ative mechanism, which could explain the increased func-

tional sensitivity of postsynaptic 5-HT1A receptors in the

hippocampus after chronic imipramine administration, is the

increase in receptor–G protein coupling recently demon-

strated by Shen et al. (2002) using the [35S]GTPgS binding

technique. It is of interest that although two studies (Welner

et al., 1989; Hensler, 2002) have shown increased hippo-

campal 5-HT1A receptor number after chronic administra-

tion of the tricyclic drug amitriptyline, there was no change

in 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)-

stimulated [35S]GTPgS binding after this treatment, sug-

gesting that the extra receptors were uncoupled from G

proteins (Hensler, 2002). Electrophysiological studies have

also shown that the SNRIs venlafaxine and milnacipran

(Beique et al., 2000a; Mochizuki et al., 2002) as well as the

5-HT and specific noradrenergic antidepressant mirtazapine

(Haddjeri et al., 1998c) did not modify the sensitivity of

postsynaptic 5-HT1A receptors in the hippocampus. Regard-

ing the MAOIs, Blier et al. (1986) showed that the sens-

itivity of hippocampal pyramidal neurons to microiontopho-

retic applications of 5-HT was decreased after long-term

treatment with clorgyline but not with phenelzine. However,

these authors concluded that the increased effectiveness of

stimulation of firing of 5-HT neurons induced by chronic

MAOI administration overcomes the desensitization at the

postsynaptic level, so that the net effect is an increase in

5-HT transmission.

The TCA imipramine and ECS increase 5-HT4 receptor

activity (Bijak et al., 2001). On the other hand, antidepres-

sants and ECS showed opposite effects on 5-HT3 receptor

activity. 5-HT3 receptor activity was increased by ECS

(Ishihara and Sasa, 2001) but reduced by paroxetine (Mon-

geau et al., 1997). Regarding 5-HT2 receptor number,

although opposite effects are seen in cortex, with chronic

ECS up-regulate 5-HT2 receptors while antidepressants

reduce their density (Mongeau et al., 1997), there have

been few studies in hippocampus and only in the autoradio-

graphic study of Biegon and Israeli (1987) was a highly

localized increase in 5-HT2 receptor binding in the CA1

region seen in male rats only.

5. Chronic effects of antidepressants and ECS on

hippocampal cAMP formation

As mentioned above, activation of hippocampal 5-HT4,

5-HT6 and 5-HT7 receptors increases local cAMP synthesis.

Although the 5-HT1A receptor when cloned and transfected

induces inhibition of cAMP formation, in vivo studies as

described above have shown 8-OH-DPAT-induced stimu-

lation of cAMP formation. In addition, in vitro studies

(Markstein et al., 1999; Thomas et al., 1999) indicate that

the effect of 5-HT to stimulate AC activity in rat hippo-

campal homogenates and guinea pig hippocampal mem-

branes is mediated at least in part by activation of 5-HT1A

receptors. cAMP activates protein kinase A (PKA), which

may phoshorylate a cytosolic protein named cAMP

response element binding protein (CREB) (Duman et al.,

1997). CREB phosphorylation results in expression of

BDNF, which prevents or restores destructive morpho-

logical processes caused by corticosteroids, stress or depres-

sion (Duman et al., 1999). Indeed, cAMP-induced neuro-

genesis was demonstrated by Nakagawa et al. (2002), and

the regulation of neurogenesis by antidepressants (Duman et

al., 2001; Malberg et al., 2000) and ECS (Duman and

Vaidya, 1998; Vaidya et al., 1999) is an established phe-

nomenon. Shirayama et al. (2002) demonstrated antidepres-

sant effects of BDNF in a behavioral animal model of

depression. Additionally to alteration of gene expression,

cAMP may increase synaptic plasticity via PKA-mediated

channel phosphorylation, resulting in changes in ion con-

ductivity (Kandel et al., 1983) or cytoskeleton reorganiza-

tion, resulting in alterations in properties of dendritic spines

(Murphy and Segal, 1997; Segal and Murphy, 1998).

Indeed, chronic ECS and fluoxetine (Stewart and Reid,

2000) as well as chronic desipramine, mianserin and trans-

cranial magnetic stimulation (TMS) (Levkovitz et al., 2001)

showed positive effects on hippocampal LTP formation. Our

studies (Dremencov et al., 2000; Gur et al., 2001, 2002b;

Newman et al., 2000) determined hippocampal 5-HT1A

receptor-mediated cAMP formation using in vivo micro-

dialysis in freely moving rats. Postsynaptic 5-HT1A receptor

activation was found to increase hippocampal cAMP levels,

as previously described (Cadogan et al., 1994). Addition-

ally, we found that chronic treatment with clomipramine (10

mg/kg/day for 28 days) sensitized 5-HT1A-mediated cAMP

formation (Fig. 3) (Newman et al., 2000). Thus, the pro-

posed cAMP-related therapeutic effect of antidepressants

may be mediated via postsynaptic 5-HT1A receptors in the

hippocampus. These results correlate with the sensitization

of postsynaptic 5-HT1A receptor activity by TCAs previ-

ously described in electrophysiological studies (Mongeau et

al., 1997; Bijak et al., 2001). Sensitization of 5-HT1A-

mediated cAMP synthesis cannot be explained by alteration

of AC, because forskolin-induced cAMP formation was not

altered by clomipramine (Fig. 3). It is also unlikely that the

clomipramine-induced activation of 5-HT1A-mediated

cAMP formation is due to elevation of the 5-HT1A receptor

number, since Srinivas et al. (2001) found no effect of

clomipramine (10 mg/kg/day for 40 days) on 5-HT1A

receptor density in the hippocampus, although Lesch et al.

(1992) did show an increase in 5-HT1A receptor mRNA

levels after administration of clomipramine at 5 mg/kg/day

for 3 weeks. However, chronic administration of the tricy-

clics imipramine and clomipramine resulted in an increase

Fig. 3. Effect of systemic 8-OH-DPAT (0.2 mg/kg sc) and forskolin (50

mM) on cAMP levels in hippocampus of saline- and clomipramine-treated

rats. Results are means ± S.E.M. of observations from five animals treated

with saline and seven animals treated chronically with clomipramine (10

mg/kg/day for 28 days, administered by osmotic minipump). Measurements

were performed 24 h after the last day of clomipramine administration.

Two-way analysis of variance of cAMP levels over fractions 3–9, the

period from injection of 8-OH-DPAT until cAMP levels returned to

baseline, showed a significant effect of treatment [ F(df = 1,10) = 5.712,

P=.037], a significant effect of time (fraction number) [ F(df = 6,60) = 2.32,

P=.044] but no interaction between time and treatment [ F(df = 6,60) = 1.06,

P=.39]. Two-way analysis of variance of cAMP levels over fractions 9–14,

from the end of the period during which forskolin was infused until cAMP

levels returned to baseline, showed a significant effect of time

[ F(df = 5,40) = 3.398, P=.011] but no effect of treatment [ F(df = 1,8) =

0.005, P=.98] or interaction [ F(df = 5,40) = 0.918, P=.479].

Fig. 4. Effect of 8-OH-DPAT (0.2 mg/kg sc) and forskolin (50 mM) on

cAMP levels in hippocampus of sham- and ECS-treated rats. Results are

means ± S.E.M. of observations from 9 sham-treated rats and 14 ECS-

treated rats. Two-way analysis of variance of cAMP levels over fractions

4–10, the period from injection of 8-OH-DPAT until cAMP levels returned

to baseline, showed a significant effect of time (fraction number)

[ F(df = 6,144) = 3.96, P=.001] but no significant effect of treatment

[ F(df = 1,24) = 2.84, P=.104] or interaction between time and treatment

[ F(df = 6,144) = 1.69, P=.13]. Two-way analysis of variance of cAMP

levels over fractions 10–16, from the period during which forskolin was

infused until cAMP levels returned to baseline, showed a significant effect

of time [ F(df = 6,144) = 3.29, P=.004], a significant effect of treatment

[ F(df = 1,24) = 5.27, P=.03] and a significant interaction between time and

treatment [ F(df = 6,144) = 3.22, P=.005].


in the level of the a subunit of Go (Lesch et al., 1991), while

imipramine also decreased the level of the a subunit of the

G protein Gi. Since Go dissociation releases bg units, the

changes in Gi/Go expression could provide an explanation

for clomipramine-induced activation of 8-OH-DPAT-medi-

ated cAMP synthesis, according to the mechanism proposed

above (Section 2).

In contrast to clomipramine, the majority of studies

indicate that repetitive administration of SSRIs does not

change postsynaptic 5-HT1A receptor activity in the hip-

pocampus, as determined by electrophysiological analysis

(Mongeau et al., 1997; LePoul et al., 2000). Beck et al.

(1997), however, found that fluoxetine (6.7 mg/kg/day for 3

weeks) increased the potency of 5-HT for the 5-HT1A

receptor-mediated hyperpolarization in area CA1 but not

in area CA3 of the hippocampus. Similarly, Castro et al.

(2003) and Shen et al. (2002) both found an increase in 5-

HT1A receptor agonist-mediated [35S]-GTPgS binding in

both DG and CA1 areas of the hippocampus after chronic

administration of fluoxetine (10 mg/kg/day for 2 or 3

weeks), indicative of an increase in receptor–G protein

coupling, although two other studies (Hensler, 2002; Pejchal

et al., 2002) did not find such an effect. It is of interest that

studies performed in rat hippocampal membranes (Newman

et al., 1992; Valdizan et al., 2002) showed that chronic

fluoxetine (10 mg/kg/day for 2 weeks or 15 mg/kg/day for 3

weeks) resulted in a decrease in the degree of 5-HT- or 8-

OH-DPAT-induced inhibition of forskolin-stimulated AC.

This would be expected to raise intracellular cAMP levels

and thus stimulate expression of CREB and BDNF. How-

ever, no such increase in cAMP levels was observed in

microdialysis studies after administration of fluoxetine at 10

mg/kg/day for 7 days (Dremencov et al., 2000). Further-

more, recent work (Miro et al., 2002) has shown that 14

days of treatment with 3 mg/kg fluoxetine down-regulated

expression of BDNF in hippocampus, in contrast to the

results of Duman et al. (1997, 1999).

Chronic ECS, on the other hand, reduced hippocampal

AC activity in response to local administration of forskolin,

as measured by cAMP monitoring using microdialysis (Fig.

4) (Gur et al., 2002b). This effect may be explained by ECS-

induced Gs down-regulation (McGowan et al., 1996). How-

ever, chronic ECS did not change the cAMP response to

8-OH-DPAT administration. Because the 5-HT1A-induced

cAMP response is mediated via AC, we postulated that

repetitive ECS actually increases postsynaptic 5-HT1A

receptor activity in the hippocampus, and the unchanged

response to 8-OH-DPAT is due to canceling out of the

increased receptor activity and decreased AC activity (Gur

et al., 2002b). This correlates with previous findings of in

vivo electrophysiological (Mongeau et al., 1997) and ex

vivo receptor density studies (for review, see Newman et al.,


1998). Direct effects on 5-HT1A receptor-mediated cAMP

formation of other antidepressant drugs and treatments, e.g.,

SNRIs, reversible MAOIs, noradrenergic and specific 5-HT

antidepressants, TMS, etc., have not according to our

knowledge been demonstrated. Antidepressant-induced

sensitization of hippocampal 5-HT1A receptors is an oppos-

ite process to the antidepressant-induced receptor desens-

itization observed in hypothalamus (Dremencov et al.,

2002) or raphe nuclei (Hjorth et al., 2000; Mongeau et al.,

1997). A possible reason for the difference is the subtype of

Gi/Go protein expressed in the hippocampus. Indeed, hippo-

campal neurons express only Go protein, while raphe nuclei

cells express only Gi3 and hypothalamus Gi1, Gi3 and Gz

proteins (Hensler, 2003).

6. Conclusions

In conclusion, it has been established that the pathophysi-

ology of depression includes processes in the hippocampus

such as a decrease in neurogenesis and synaptic plasticity.

Antidepressant treatment or ECT reverses these changes by

activation of 5-HT neurotransmission in the hippocampus

(Table 1). Hippocampal 5-HT neurotransmission may be

increased using different mechanisms. Thus, MAOIs and

SSRIs increase intensivity of 5-HT input into the hippocam-

Table 1

Postulated mechanism of action of chronic antidepressants and ECS on 5-HT n

synaptic plasticity

5-HT1A autoreceptor activity, electrophysiological measurements

(Beique et al., 2000a; Haddjeri et al., 1998a,c; Mongeau et al., 1997)

5-HT1A autoreceptor activity, microdialysis measurements

(Hjorth et al., 2000; Kreiss and Lucki, 1995)

5-HT1B autoreceptor activity, electrophysiological measurements

(Beique et al., 2000a; Haddjeri et al., 1998a,c; Mongeau et al., 1997)

5-HT1B autoreceptor activity, microdialysis measurements

(Hjorth et al., 2000)

5-HT1A heteroreceptor activity, electrophysiological measurements

(Beique et al., 2000a; Haddjeri et al., 1998a,c; Mongeau et al., 1997;

Beck et al., 1997)

5-HT1A-mediated cAMP synthesis, microdialysis measurements

(Dremencov et al., 2000; Gur et al., 2002b; Newman et al., 2000)

5-HT1A agonist-mediated increase in GTPgS binding to autoreceptors

(Castro et al., 2003; Hensler, 2002; Pejchal et al., 2002;

Shen et al., 2002)

5-HT1A agonist- mediated increase in GTPgS binding to postsynaptic

receptors (Castro et al., 2003; Hensler, 2002; Pejchal et al., 2002;

Shen et al., 2002)

Hippocampal neurogenesis (Duman and Vaidya, 1998; Duman et al., 2001;

Malberg et al., 2000; Vaidya et al., 1999)

Synaptic plasticity and LTP formation

(Levkovitz et al., 2001; Stewart and Reid, 2000)

Noradrenergic and specific 5-HT antidepressants, NaSSAs; no effect, 0; positive e

symbols indicates that both effects have been observed, with approximately equal n

that only a minority of papers observed such an effect, with the majority of paper

possible, the references cited are to comprehensive reviews; if no such reviews exi

5-HT1A autoreceptors are situated in the dorsal raphe and not in the hippocampus,

overall 5-HT transmission in the hippocampus.

pus by desensitization of presynaptic autoreceptors, while

tricyclic drugs and ECS sensitize postsynaptic 5-HT hetero-

receptors in the hippocampus. Antidepressant-induced alter-

ations in 5-HT auto- and heteroreceptor activity are probably

mediated via changes in Gi/Go protein expression in the

raphe nuclei or in the hippocampus, respectively. Among the

hippocampal 5-HT heteroreceptors altered in the hippocam-

pus, we would like to point out 5-HT1A and 5-HT4 receptors,

for two reasons. Firstly, both antidepressants and ECS

sensitize 5-HT1A and desensitize 5-HT4 heteroreceptors,

while their actions on 5-HT2 and 5-HT3 receptors are

different. Secondly, hypercorticosolemia has an action on

5-HT1A and 5-HT4 receptors, opposite from the effect of

antidepressants and ECS. The neurotrophic action of anti-

depressants is probably mediated via activation of cAMP

formation. However, chronic ECS was found to decrease AC

activity and may not activate cAMP synthesis. Thus, the

neurotrophic action of ECS may be explained by a different

pathway, which may be mediated via other subtypes of 5-HT

receptors.

Acknowledgements

We acknowledge support from the United States–Israel

Binational Science Foundation (grant 96-8), the Israel

eurotransmission in the rat hippocampus, hippocampal neurogenesis and

TCAs SSRIs MAOIs SNRIs NaSSAs ECS

0 # # # 0 0

0 #0 – 0 – 0

0 # 0 # 0 0

0 #0 – 0 – 0

" 0(") 0# 0 0 "

" 0 – – – 0

0 # # – – –

"0 "0 0 – – –

" " – – – "

" " – – – "

ffect, "; negative effect, #; was not directly studied, – . The presence of two

umbers of papers finding each of the effects. A symbol in brackets indicates

s observing the effect indicated by the symbol outside the brackets. Where

st, the references are to individual representative studies. Note that although

their activity determines the firing rate of 5-HT neurons and thus influences


Science Foundation (grant 692/0) and the National Institutes

of Health, USA (grant MH 60580).

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