5-HT1A receptor ligands in animal models of anxiety, impulsivity and depression: Multiple mechanisms of action?

Prcg. New-o-Psychopharmncd dl3bL Psychfat 1993. Vol. 17. pp. 87-104 0278 - 5845/93 $15.00

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5-HT RECEPTOR LIGANDS IN ANIMAL MOD& OF ANXIETY, IMPULSMTYAND DEPRESSION: MULTIPLE MECHANISMS

OF ACTION?

RUDY SCHREIBER and JEAN DE VRY

Institute for Neurobiology, Department of Psychopharmacology, Troponwerke, Cologne, Germany

(Final form, February 1992)

1. 2. 2.1 2.2 2.3 2.4 3.

4.

5.

6.

Abstract Introduction

Contents

5-HT,,, Receptor Ligands in Anxiety, Impulsivity and Depression S-HT,,, Receptors: Selective Ligands and Distribution 5-HT, Receptor Ligands and Anxiety S-HT, Receptor Ligands and Impulsivity 5-HT, Receptor Ligands and Depression Are 5-HT,, Receptors dysfunctional in Anxiety, Impulsivity and Depression? Are 5-HT, Receptors Involved in the Mechanism of Action of Classical Anxiolytics and Antidepressants? Are 5-HT,/5-HT, Receptor Interactions Involved in the Therapeutic Effects of 5-HT,, Receptor Ligands ? Conclusions References

87 88 89 89 89 91 92

94

96

97 99 99

Abstract

Schreiber, Rudy and De Vry, Jean: 5-HT,, Receptor Ligands in Animal Models of Anxiety, Impulsivity and Depression: Multiple Mechanisms of Action? Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1993 17( 1): 87-104.

1. Preclinical and clinical studies suggest that 5-HT, receptor agonists are a new class of mixed axiolytics/antidepressants with, possibly, impulsivity reducing properties.

2. The anxiolytic effects of 5-HT, receptor agonists result predominantly from an interaction with presynaptic 5-HT, receptors (resulting in a decrease of serotonergic transmission), whereas the antidepressive and, possibly, the impulse control enhancing effects, result predominantly from an interaction with postsynaptic 5-HT,, receptors.

87

88 R. Schreiber and J. De Vry

3. These proposed mechanism(s) of action fit well with the generally held view that anxiety is the result of a hypersensitive S-HT system; whereas impulsivity and depression is the result of a hyposensitive 5-HT system.

4. However, it appears very likely that activation of pre- and postsynaptic S-HT, receptors is additionally involved in the antidepressive and impulse control enhancing effects, on the one hand, and in the anxiolytic effects of these compounds, on the other hand.

5. These latter, seemingly paradoxical, findings can be explained by assuming that (1) the presynaptic mechanism reflects an anxiolytic component in the animal models of impulsivity and depression, (2) antagonism of postsynaptic 5-HT,, receptors by these compounds contributes to their anxiolytic effects, (3) postsynaptic 5-HT,,and 5-HT, receptors have functionally opposing effects or, alternatively, that (4) downregulation of postsynaptic 5-HT, receptors contributes to the therapeutic effects of these compounds.

Keywords: animal models, anxiety, depression, 5-HT, 5-HT, receptors, 5-HT, receptors, impulsivity.

Abbreviations: 5,7_dihydroxytryptamine (5,7-DHT), Shydroxy-2-(di-n-propylamino)tetralin (&OH-DPAT), ethanol (EtOH), para-chlorophenylalanine (pCPA), serotonin (5-HT).

1. Introduction

Both, from clinical and preclinical studies, evidence is accumulating that serotonergic (5-HT)

neurotransmission may be involved in the etiology, expression and treatment of anxiety, impulsivity

and depression (Brown and van Praag 1991). However, many contradictory findings concerning

the dysfunction of 5-HT in these disorders have been reported. The discovery of multiple 5-HT

receptor subtypes in recent years and the development of selective ligands for these receptors, may

offer an opportunity to clarify the ambiguous role of 5-HT in these mental disorders and to treat

them more effectively (Cowen 1991, Marsden 1989). Currently, 5-HT receptors are classified into

seven subtypes, called 5-HT,.5-HT,,5-HT,,S-HT,,, 5-HT,, 5-HT, and 5-HT, receptors, each of

them having a particular brain distribution (Glennon 1990). 5-HT, receptors have been of

particular interest because they are involved in the regulation of emotional and behavioral

processes and possibly in the mechanism of action of a number of currently used treatments of

anxiety, impulsivity and depression (Dourish et al 1987, De Vry et al 1992, Lesch 1991). Therefore,

5-HT, receptor ligands may consist of a new class of psychotherapeutic agents with improved

efficacy and/or side-effect profile (Traber and Glaser 1987, De Vry et al 1991a, 1992). Concerning

the other 5-HT receptor subtypes, some evidence has been reported which suggests an

involvement of 5-HT, receptors and, possibly, 5-HT, and 5-HT,, receptors in (some of) these

5-I-IT,, ligands - anxiolytics/antidepressants 89

disorders (Cowen 1991). The present paper will briefly review preclinical studies on the

mechanism of action of SHT, receptor ligands in anxiety, impulsivity and depression and discuss

the possibility that an interaction between SHT,, and 5-HT, receptors may contribute to the

therapeutic effects of SHT,,, receptor ligands.

2. 5_HT,.,Receptor Ligands in Animal Models of Anxiety. Impulsivity and Depression

2.1. 5_HT,, Recemors: Selective Lipands and Distribution

The most widely used high affinity ligands for the 5-HT,, receptor are the pyrimidinylpiperazine

partial agonists buspirone (which has additional affinity for dopamine D, receptors), ipsapirone

and gepirone, and the aminotetralin full agonist 8-OH-DPAT. 5-HT,receptors are located both

presynaptically (somatodendritic autoreceptors) on the 5-HT cell bodies in the dorsal and median

raphe nuclei of the brainstem which innervate the forebrain; and postsynaptically, predominantly

in limbic structures like the hippocampus and the septum. Activation of presynaptic 5-HT,

receptors results in an inhibition of cell firing activity and a consequent decrease in 5-HT

neurotransmission. Therefore the physiological function of these receptors is to provide the brain

with an autoinhibitory feedback system controlling 5-HT neurotransmission. Activation of

postsynaptic 5-HT,, receptors results in neuronal inhibition of particular parts of the limbic system.

Due to their particular distribution, 5-HT,, receptors offer the possibility to control 5-HT

neurotransmission in a general manner (mediated by the presynaptic receptors) and neuronal

activity in the limbic system in a selective manner (mediated by the postsynaptic receptor). For

a review and further references on the localization, biochemistry, electrophysiology, and selective

ligands of 5-HT,, receptors; see: Glaser and De Vry 1992.

2.2. 5-HT, Receotor Lieands and Anxiety

Anxiolytic properties of 5-HT,, receptor ligands have been shown in a number of animal models

of anxiety (including models based on unconditioned and conditioned anxiety, conflict, novelty,

exploration and social behavior), as well as in man (for reviews; see: De Vry et al 1991a, 1992,

Schweizer and Rickels 1991). Although it is not firmly established whether 5-HT,, receptor ligands

are equally effective in all anxiety disorders (e.g., general anxiety disorder, panic disorder,

obsessive-compulsive disorder); until now, the majority of clinical studies supports a role for these


ligands in the treatment of general anxiety disorder and, possibly, obsessive-compulsive disorder.

Most preclinical studies on the mechanism of action of these compounds in animal models of

anxiety have focussed on the relative contribution of pre- and postsynaptic S-HT, receptors after

acute administration. E.g., in a rat model of conditioned anxiety, local application of ipsapirone

and 8-OH-DPAT into the dorsal raphe nucleus (Fig 1, upper panel), as well as, lesioning of the

5-HT system by means of the neurotoxin 5,7-DHT or the 5-HT synthesis inhibitor pCPA

(Schreiber and De Vry 1990a, 1991a) resulted in robust reductions of anxiety levels. These

findings, and the finding that after systemic application of ipsapirone, the time-effect curves

reflecting the anxiolytic effects, those reflecting the 5-HT cell firing inhibitory effects (as measured

in the dorsal raphe nucleus) and those reflecting the release inhibitory effects (as measured in the

dorsal hippocampus) correlate well with each other (Sommermeyer et al 1991), suggest that the

anxiolytic effects of ipsapirone result, at least partially and upon acute administration, from a

presynaptically mediated decrease in serotonergic neurotransmission.

1”“.

,P HIP DRN

DOSE 300 40 1 ug/RAT

DOSE 2000 30 60 ug/RAl

Fig 1: Upper panel: anxiolytic effects of ipsapirone in the ultrasonic vocalization test after systemic (IP) and local application into the hippocampus (HIP) and the dorsal raphe nucleus (DRN). Lower panel: antidepressive effects of ipsapirone in the rat forced swimming test after systemic and local application into the lateral septum (LS) and the dorsal raphe nucleus (DRN).

533~~~ ligands - anxiolytics/ant.tdepressants 91

However, an additional involvement of postsynaptic S-HT, receptors is very likely, because

microinjection of 8-OH-DPAT and ipsapirone into the hippocampus leads to a similar, although

less potent, anxiolytic response as compared to dorsal raphe application (Fig 1, upper panel;

Schreiber and De Vry 1990a, 199la).Therefore it appears that both presynaptic and (possible to

a lesser extent) postsynaptic S-HT,receptors are involved in the acute anxiolytic effects of 5-HT,

receptor ligands (De Vry et al 1992, Marsden 1989). This dual contribution of pre- and

postsynaptic receptor systems can, however, lead to an apparent paradox. Indeed, how can it be

understood that a (presynaptically mediated) reduction of S-HT neurotransmission has a similar

functional effect as a (postsynaptically mediated) increase in S-HT neurotransmission?

A possible explanation is based on the assumption that the intrinsic activity of these S-HT,

receptor ligands is different at pre- and postsynaptic receptors (i.e., that these compounds have

ago&tic properties at presynaptic receptors and antagonistic (or partial agonistic) properties at

postsynaptic receptors (Glaser and De Vry 1992)). According to this view, the anxiolytic activity

is the additive result from a reduction of S-HT neurotransmission (mediated by an agonistic

activity at presynaptic receptors) and an antagonistic activity at postsynaptic receptors.

Alternatively, anxiolytic activity is explained by assuming that activation of different postsynaptic

5-HT receptor subtypes has functionally opposite effects. According to this hypothesis, activation

of S-HT, receptors, which results in hyoeroolarisation of the postsynaptic neuron (neuronal

inhibition) is anxiolytic; whereas activation of non-5-HT,, receptors (5HT,, S-HT,, or 5-HT,?)

which results in deoolarisation of the postsynaptic neuron (neuronal excitation) is “anxiogenic” (see

further). A common feature of both hypotheses, however, is that overactivity of the 5-HT system

in particular brain areas is involved in pathological anxiety and that reduction of this overactivity

is anxiolytic. In line with this suggestion is the recent finding that rats in an aversive environment

(elevated X-maze) have increased 5-HT levels in the ventral hippocampus and that systemic

application of ipsapirone attenuates the elevated 5-HT activity (Wright et al 1991a).

2.3. 5-HT2.y

Preclinical studies have supported the concept that 5-m dysfunction may be involved in

impulsivity and impulse control disorders and have suggested that 5-HT, receptor ligands may

affect impulsivity (for reviews; see: Soubrie 1986, De Vry et al 1991a, 1992). E.g., anti-aggressive


effects of these compounds have been reported in animal models for territorial aggression

(Schuurman et al 1991), shock-induced aggression (De Vry et al 1991a), maternal aggression

(Olivier et al 1989) and isolation-induced aggression (White et al 1991). Reductions in the intake

of (and possible craving for) alcohol and nicotine have been obtained in preclinical and some

clinical studies (for reviews; see: De Vry et al 1992, Tollefson 1991).

The finding that local application of 8-OH-DPAT into the dorsal raphe nucleus has

anti-aggressive effects (Mos and Olivier 1991) suggests that a reduction in 5-HT neurotransmission

is involved in the anti-aggressive effects of 5-HT, receptor ligands. Evidence for a similar

mechanism of action for the ethanol (EtOH) preference reducing activity of 8-OH-DPAT and

ipsapirone has been found in selectively inbred Wistar rats with high preference for EtOH over

water in a two bottle free choice situation (Schreiber et al 1991). However, because anxiety may

play a role in these animal models of impulsivity, it remains unclear to what extent the suggested

presynaptic mechanism does not merely reflect such an anxiolytic component (see above).

Moreover, it has been suggested that a reduction in 5-HT neurotransmission may actually increase

impulsivity (Soubrie 1986, Roy et al 1987). Such a dysfunction of 5-HT could possibly explain the

observed supersensitivity of postsynaptic 5-HT,, receptors in isolated rats and alcohol preferring

rats (Wright et al 1991b, Wong and Murphy 1989). However, it remains to be shown that local

application of 5-HT,, receptor ligands in brain regions rich in postsynaptic 5-HT, receptors leads

to efficacy in animal models of impulsivity.

2.4. 5-HT,. Receotor Lieands and Depression

Antidepressive activity has been reported for several 5-HT,, receptor ligands, both at the

preclinical and clinical level (for reviews; see: De Vry et al 1991a, 1992). In general, antidepressive

effects have been obtained in a variety of animal models based on stress induced behavioral

deficits (i.e., forced swimming test, learned helplessness and restraint stress).

Studies on the mechanism of action for the antidepressive effects of 5-HT, receptor ligands

have, as in case of the anxiolytic effects, focussed on the relative contribution of pre- and

postsynaptic receptors. Similar to the effects observed in an animal model of anxiety,

antidepressive effects were obtained after microinjection of ipsapirone and 8-OH-DPAT into the

dorsal raphe nucleus in the forced swimming depression test (Fig 1, lower panel; Schreiber and

5-HT,, ligands - anxiolytks/antidepressants 93

De Vry 199Ob). However, as compared to the anxiolytic effects, considerably higher doses were

needed after local application of ipsapirone (and 8-OH-DPAT) in the dorsal raphe; suggesting that

the contribution of presynaptic 5-HT, receptors is relatively less important in the case of the

antidepressive effects. Additionally, lesioning of the brain 5-HT system by means of either

5,7-DHT or pCPA had only small antidepressive effects on its own (Schreiber and De Vry 1991b),

again suggesting that presynaptic 5-HT, receptors are only weakly involved in the antidepressive

effects of these compounds. Moreover, as in the case of the animal models of impulsivity, it cannot

be ruled out that the apparent contribution of presynaptic 5-HT, receptors reflects an anxiolytic

component of the test. Alternatively, it has been suggested that activation of presynaptic 5-HT,

receptors leads to disinhibition of dopaminergic activity, which, in turn, would be responsible for

the effects of 5-HT, receptor agonists in this animal model of depression (Cervo et al 1988).

Because the antidepressive effects of 5-HT,, receptor ligands appear to correlate with their

intrinsic activity at postsynaptic 5-HT,, receptors (De Vry et al 1991a, 1992) and because these

compounds appear to be more potent after local application into the lateral septum (Fig 1, lower

panel) than after local application into the dorsal raphe, it is suggested that postsynaptic 5-HT,

receptors are strongly involved in the antidepressive effects. This suggestion is supported by the

finding that in the learned helplessness model of depression, local application of buspirone and

8-OH-DPAT in the septum, but not in the raphe nuclei, shows antidepressive effects (Martin et

al 1991). As in the case of impulsivity, a major contribution of postsynaptic 5-HT, receptors

appears to be in accordance with the hypothesis which states that 5-HT neurotransmission is

reduced in depression and that an increase in 5-HT neurotransmission results in antidepressive

effects (Coppen 1967).

Taken together, it is concluded that 5-HT,, receptor ligands exert their anxiolytic effects

predominantly by activation of presynaptic 5-HT,, receptors (resulting in a general decrease of

serotonergic activity, Fig 2) and their antidepressive, and possibly impulse control enhancing

effects, predominantly by activation of postsynaptic 5-HT, receptors (resulting in-a selective

increase of serotonergic activity in particular brain structures, Fig 2). Because ample evidence

suggests that serotonergic activity is enhanced in anxiety and reduced in impulsivity and

depression, the proposed mechanism of action of 5-HT,, receptor ligands in anxiety, impulsivity

and depression is in line with currently accepted hypotheses concerning the role of 5-HT in these

disorders.

94 R. Schreiber and J. De Vxy

However, some data which apparently do not fit into these hypotheses have also been obtained.

First, activation of presynaptic S-HT,, receptors leads to some efficacy in several animal models

of impulsivity and depression (Fig 1, lower panel). A possible explanation for these findings is that

an anxiety component is present in these animal models and that the presynaptic component

indentified in these models represents the anxiolytic activity of S-HT,, receptor ligands. Second,

activation of postsynaptic 5-HT, receptors leads to some efficacy in several animal models of

anxiety. In order to explain these findings, it has been suggested that antagonistic activity of these

compounds at postsynaptic 5-HT, receptors contributes to their anxiolytic effects. Alternatively,

activation of postsynaptic 5-HT,, and non-5HT,, receptors (5-HT,, 5-HT,, or 5-HT,?) may have

functionally opposite effects (i.e., activation of postsynaptic 5-HT, receptors and non-5-HT,

receptors leads to anxiolytic and anxiogenic effects, respectively; see Fig 2 and further).

3. Are 5-HT,. Receptors Dysfunctional in Anxiety. Imnulsivity and Depression?

The 5-HT, receptors which are involved in the hypothermic and ACTH/cortisol increase

induced by ipsapirone appear to be subsensitive in patients with panic disorder, but not in those

with obsessive-compulsive disorder (Lesch 1991). Although it may be premature to draw firm

conclusions about the pre- and postsynaptic location of the dysfunctional 5-HT,receptors in panic

disorder (because the synaptic localization of the 5-HT,, receptors involved in these responses is

not unequivocally established in human), subsensitivity of 5-HT,, receptors could tentatively be

interpretated as an adaptive response to increased 5-HT levels. It remains to be determined to

what extent dysfunctional 5-HT,, receptors are involved in other anxiety disorders (e.g., general

anxiety disorder) and to what extent challenge tests with 5-HT,,receptor ligands may become ”

diagnostic tools ” for these disorders.

Post-mortem studies revealed increased postsynaptic 5-HT, receptor densities in the frontal

cortex and hippocampus of suicides and smokers, respectively (Arango et al 1991, Benwell et al

1990). On the other hand, in patients with impulsive aggressive behaviour, buspirone-induced

prolactin release was attenuated compared to healthy controls (Coccaro et al 1990). In animal

models of impulsivity, increased densities of postsynaptic 5-HT,, receptors were found in the

cortex and hippocampus of alcohol preferring rats; whereas presynaptic 5-HT, receptor densities

in the brain stem were decreased (Wong and Murphy 1989).

95

S-HT, receptor (partial) agonists

m WIT, receptors

non-s-HT, receptors a (e.g., 5-ST, S-HT&

Fig 2: Schematic drawing summar~zin~ the relative ~ntribut~o~ of pre- and postsynaptic S-HI;, receptors to the anxiolytic, antidepressive and anti-impulsivity effects of 5-HT, receptor ligands.

96 R. Schrelber and J. De Yry

Similar MI’T.,receptor changes were found in isolation-reared rats (Wright et al 1989, 1991b).

These S-HT, receptor changes can tentatively be explained as adaptive responses to a

dysfunctional 5-HT system in impulsivity and impulse control disorders (for review; see: Coccaro

1989).

In depressed suicides, it has been suggested that postsynaptic 5-HT, receptor densities are

increased in the frontal cortex (Lowther et al 1990). In addition, postsynaptic 5-I-IT1, receptors

were found to be supersensitive in an animal model of depression (Kennett et al. 1985). As in the

case of the impulse control disorders, these preliminary data can be interpretated as supportive

evidence of a dysfunctional serotonergic system in depression (Coppen 1967). However, in patients

with unipolar depression, ipsapirone-induced hypothermia and ACTH/cortisol increase was also

blunted; suggesting that pre- and/or postsynaptic 5-HT,, receptors were subsensitive in this

disorder (Lesch 1991). Therefore it may be that upregulated and/or supersensitive 5-HT,

receptors are not a common feature of all types of depression. Clearly, as in the case of anxiety

disorders, further clinical and preclinical studies are needed to clarify this issue and the complex

relationship between adaptation of the 5-HT,, receptor system and apparent hyper- or

hyposensitivity of the 5-HT system.

4. Are 5-HT,, R ce r Inv Iv 1

Antidemessants?

Because 5-HT, receptor agonists and benzodiazepines reduce serotonergic activity, it has been

suggested that this effect may be involved in the anxiety reducing properties of these compounds

(Section 2, Stein et al 1975, Thiebot et al 1982; but see also: Thiebot 1986). Accordingly, the

anxiolytic activity of diazepam in the elevated X-maze coincides with a decrease of 5-HT release

in the ventral hippocampus, as measured by in vivo microdialysis (Wright et al 1991a) and, as

mentioned before, it was found in a test of conditioned anxiety that the time-effect curves

reflecting the anxiolytic effects of ipsapirone correlated well with those reflecting the release

inhibitory effects in the dorsal hippocampus (Sommermeyer et al 1991). However, the effects of

benzodiazepines in animal models of anxiety cannot be antagonized with 5-HT, receptor

antagonists; suggesting that 5-HT,, receptors are not involved in the anxiolytic effects of

benzodiazepines (Glaser et al 1992). Because benzodiazepines and 5-HT, receptor agonists induce

a desynchronization of hippocampal rhythmical slow activity, a phenomenon which possible results

from reduced 5-HT activity in the hippocampus and which is thought to reflect anxiolysis (Hirose

5-HTIA ligands - anxiolytics/antidepressants 97

et al 1990, MC Naughton and Coop 1991); it is concluded that the mechanism of action for the

anxiolytic effects of benzodiazepines and S-HT,,, receptor ligands may, at least partially, overlap

and share a common final pathway.

With respect to antidepressants, it has been reported that repeated administration of tricyclics,

MAO-inhibitors, 5-I-IT reuptake inhibitors and electroconvulsive shock affect pre- and/or

postsynaptic S-HT,, receptor function, suggesting that S-HT, receptors may be involved in the

mechanism of action of currently used antidepressants (for review; see: De Vry et al 1992).

However, although the evidence for such an involvement appears stronger in the case of the

antidepressants than in the case of the anxiolytics, the issue remains controversial and needs to

be clarified further.

5. Are 5-HT,.!5-HT, Receptor Interactions Involved in the Therapeutic Effects of

5_HT,, Receptor Ligands?

Chronic treatment with most antidepressants results in a downregulation of 5-HT, receptors

(Kendall and Nahorski 1985, Peroutka and Snyder 1980). In addition, it is well established that

many currently used antidepressants are effective in the treatment of panic disorder and obsessive-

compulsive disorder. Therefore, it has been proposed that 5-HT, receptor mechanisms may be

involved in anxiety disorders (Deakin 1989). Moreover, because (1) both repeated and acute

administration of 5-HT, receptor agonists (De Vry et al 1991b, Fig 3) and chronic application of

the 5-HT,,, antagonist ritanserin (Wright et al 1991~) reduces anxiety and (2) chronic application

of these compounds results in downregulation of 5-HT, receptors (Benjamin et al 1990, Leysen

et a1.1986, Schechter et al 1990, Frazer et al 1991), it is suggested that downregulation of 5-HT,

receptors may be a common mechanism of action for the anxiolytic effects of 5-HT, receptor

agonists and 5-HT, receptor antagonists. Therefore, 5-HT, receptor downregulation induced by

repeated administration of 5-HT,,, receptor ligands may add to, or substitute for, the anxiolytic

effects induced by 5-HT, receptor activation. It is tempting to suggest that such a mechanism is

related to the clinical observation that the anxiolytic effects of 5-HT, receptor ligands require at

least 2 weeks to fully develop.

If downregulation of 5-I-IT, receptors by 5-HT, receptor agonists contributes to the mechanism

of action of these compounds in anxiety and, possibly, impulsivity and depression, it is expected


that S-I-IT, receptors are upregulated and/or supersensitive in (animal models of) these psychiatric

disorders. Indeed, some studies found increased .5-HT, receptor densities in impulse control

disorders (e.g., Mann et al 1989) and depression (e.g., Arora and Meltzer 1989, Barone et al

1990).

*

60

PRETREATMENT - 18 x _ 18 x

TREATMENT 0.5 0.5 3 3 mdb i.p

Fig 3: Anxiolytic effects of ipsapirone after acute and repeated administration, as measured in the ultrasonic vocalization test.

However, some controversy exists about the presumed increased S-HT, receptor densities in

depressed suicides (e.g., Cheetham et al 1988). Unfortunately, not much is known about S-I-IT,

receptor regulation in anxiety disorders.

These findings suggest the existence of mutual inhibitory S-HT,/S-HT, receptor interactions.

Indeed, rapidly growing evidence suggests that such receptor interactions do exist (for review; see:

Glennon et al 1991); although the nature of these interactions is not always the same across

different experimental procedures used in these studies. Recently, indirect evidence has been

obtained for a synergistic effect of S-HT,, agonism and S-HT, antagonism in an animal model of

anxiety (Barrett and Zhang 1991).

It should be mentioned that formulation of firm conclusions about the involvement of these

receptor interactions in the therapeutic effects of SHT, receptor agonists is hampered by the fact

that most evidence is provided by studies using ritanserin as ‘selective’ 5-HT, antagonist. Indeed,

5-HT,, ligands - anxiolytics/antidepressants 99

because of the additional 5HT,,receptor blocking properties of this compound, it cannot be ruled

out that S-I-IT,&HT,,interactions were studied. The possible relevance of such a receptor

interaction is emphasized by the observation that activation of 5-I-IT,, receptors by the 5-

I-IT,&HT,, receptor agonist mCPP appears to he anxiogenic in the rat (for review; see: Curzon

et al 1991). Mutual inhibitory interactions between S-HT,, and 5-HT,, receptors have already been

proposed for some components of the S-OH-DPAT-induced 5-HT behavioural syndrome

(Berendsen 1991). Nevertheless, the receptor downregulation obtained after repeated treatment

with ipsapirone is observed for the 5-HT,, but not the 5-HT,,. receptor (Gozlan and Hamon,

personal communication).

6. Conclusions

It is suggested that - in line with current hypotheses about the role of 5-HT in anxiety on the

one hand (serotonergic hyperactivity) and impulsivity and depression on the other hand

(serotonergic hypoactivity) - the anxiolytic activity of 5-HT, receptor agonists is induced by a

reduction of serotonergic activity (predominantly mediated by activation of presynaptic 5-HT,

receptors, and probably also by inactivation of 5-HT, receptors, achieved either by mutual

inhibitory postsynaptic 5-HT,/5-HT, receptor interactions, or by downregulation of 5-HT,

receptors upon repeated administration); whereas the antidepressive activity and, possibly, the

impulse control enhancing activity, is predominantly induced by activation of postsynaptic 5-HT,,

receptors (either directly or by attenuation of the inhibitory effect of 5-HT, receptors). According

to this hypothesis a careful analysis of the interaction between 5-HT receptor subtypes may add

to a better understanding of the therapeutical effects of 5-HT,, receptor ligands and possibly lead

to the development of more efficient and safer drugs.

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5-HT1A receptor ligands in animal models of anxiety, impulsivity and depression: Multiple mechanisms of action?