Buspirone And Anxiety Disorders: A Review With

Pharmacological And Clinical Perspectives

Farhat Batool Ph.D.

Neurochemistry and Biocmeical Neuropharmacology Research Laboratory
Department of Biochemistry, University of Karachi Email address Physical Address

Address:
Karachi
Pakistan

Citation: F. Batool : Buspirone And Anxiety Disorders: A Review With Pharmacological And
Clinical Perspectives . The Internet Journal of Pharmacology. 2008 Volume 5 Number 2

Keywords: Buspirone | Anxiety | Serotonin | 5-HT-1A Receptor Agonists

Table of Contents

* Introduction
* Anxiety
* Serotonin Receptors In The Modul...
* Pre-Synaptic And Post-Synaptic 5...
* Clinical Implications

Abstract

The treatment of anxiety is one of the leading problems in medicine today. Buspirone, an
azpirone derivative and a 5-HT-1A (5-hydroxytryptamine-1A) partial agonist, is the first
nonbenzodiazepine anxiolytic introduced into medicine for the treatment of generalized anxiety
disorder (GAD). It has a strong affinity for the 5-HT-1A receptor and does not appear to interact at
the benzodiazepine receptor complex. Buspirone's distinctive mechanism of action helps to avoid
pharmacological properties ancillary to the treatment of anxiety and contributes towards an
apparently superior safety profile with generally fewer and more tolerable adverse effects than
benzodiazepines.
This article provides a brief overview on the results of animals and clinical studies in which the
potential for buspirone dependence or abuse and the effects of its withdrawal were assessed.
The pharmacology of serotonin systems and its role in the management of anxiety, along with the
review of the contemporary literature is also discussed.

Introduction

A role of central serotonin (5-hydroxytryptamine; 5-HT) in the pathogenesis of anxiety has been
the subject of intensive research. Experimental evidence based primarily on drug therapy
suggests that anxiolytic effects of benzodiazepines (BZs), the conventional anxiolytics, are
manifested by the stimulation of BZ-GABA (Gamma amino butyric acid) receptor complex and a
concomitant decrease in serotonergic neuronal activity 1,2 . Despite a trend of reduced
prescribing the BZs remain the most widely used psychotropic drugs and this is due to their
considerable effectiveness as anxiolytic 3 , hypnotic 4 and anticonvulsant 5 . Although a large
number of different BZs exist, they share a common property of binding with a high affinity to
specific recognition sites in brain 6 . Drugs that tend to increase 5-HT functions are anxiogenic
while blockade of serotonergic neurotransmission produced anti-anxiety effects. Serotonergic
hypothesis of anxiety is complicated by recent awareness of heterogeneity of 5-HT receptors in
the central nervous system 7 . The advent of selective agonists and antagonists for 5-HT receptor
subtypes has rekindled investigation of the role of 5-HT in anxiety mechanisms 8 .
Serotonin agonists with selectivity towards 5-HT-1A sites have been shown to release
suppression of behaviour in models of anxiety 9,10 . These drugs decreased 5-HT turnover in rat
brain 11,12,13 . Serotonergic cell groups of the median raphe nucleus innervating the
hippocampus have an important role in the anxiety mechanisms. Brain hippocampus, an
important site of BZ action, possessing high density of 5-HT-1A binding sites 14,15 .
Pharmacological studies show that decreasing the availability of 5-HT at postsynaptic 5-HT-2A or
5-HT-2C sites is anxiolytic 16,17,18 . 5-HT-1A agonists such as buspirone, ipsapirone and 8-
hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) showed anxiolytic profile 19,20 . This may be
due to their potent agonistic activity towards cell body autoreceptors 21 . Since they reduce
serotonin neural function by suppressing neuronal firing. It has been proposed that this is the
basis of their anxiolytic action 22 . Unlike the BZs, 5-HT-1A agonists have been reported to
produce little sedation, do not potentiate the effects of ethanol, and do not show potential for
dependence or abuse 19,23 . They do not seem to interact with the GABA-benzodiazepine-Cl
ionophore complex 24 . Depression of 5-HT neuron function is, therefore, critically important for
therapeutic effects of both 5-HT-1A 25,26 and BZ anxiolytics 27 . Taken together, these
observations lead to the conclusion that different 5-HT mechanisms, mediated by different
receptor subtypes, are involved in the genesis of anxiety. <I>
Anxiety

Anxiety is a normal reaction but when it is severe and disabling it becomes pathological 28 .
Anxiety is an almost ubiquitous component of mental illnesses. It is present in its purest form in
the so-called anxiety disorders 29 , but also found in depression, schizophrenia and personality
disorders. Anxiety disorders are common psychiatric manifestations of the modern world. The
phenomenon as a &#8220;disorder&#8221; has travelled through medical history under various
labels such as &#8220;<I>anxiety neurosis&#8221; and &#8220;<I>agoraphobia&#8221; 30 .
Advances in clinical understanding of anxiety have led to the characterization of several
diagnostic entities as now described in DSM IV 31 . In this classification system <I>generalized
anxiety disorder (GAD), <I>agoraphobia with panic attacks (APA), <I>panic disorder (PD) and
<I>obsessive-compulsive disorder (OCD) are discrete diagnostic entities 32,33 (see Table 1).

Thumbnail: Table 1: Treatments for Anxiety Disorders

Table 1: Treatments for Anxiety Disorders

Buspirone (BuSpar) is an azapirone, a class of drugs showing promise for generalized anxiety
disorder 34,35,36,37,38,39,40 . Unfortunately, it usually takes several days to weeks for the drug
to be fully effective, and it is not useful against panic attacks. Unlike the benzodiazepines,
buspirone is not addictive, even with long-term use, and it seems to have less pronounced side
effects and no withdrawal effects, even when the drug is discontinued quickly. The drug does not
produce any immediate euphoria or change in sensation, so some people believe, erroneously,
that the drug doesn't work. Because it has a low potential for abuse, buspirone is useful in
persons whose anxiety disorder coexists with alcoholism 40 . Some experts also think it may
useful for adolescents and children. Common side effects include dizziness, drowsiness, and
nausea. Patients who have recently been taking benzodiazepines may respond less well to
buspirone than others. BuSpar should not be used with monoamine oxidase inhibitors (MAOIs)
41,42,43,44 .

Evidence supporting the involvement of central serotonin in the anxiety-related behaviour and in
the mechanisms of action of anxiolytics is well documented 45,46,47,48,49,50,51 . With the
introduction of several new and more specific drugs that act on serotonin receptors there has
been a resurgence of interest in the possible role of these pathways in the control of anxiety. The
hypothesis that serotonin may be involved in the anti-anxiety originated from the early work by
Geller and Blum 52 . It was shown that administration of para-chlorophenylalanine (PCPA), a
tryptophan hydroxylase inhibitor, produced anxiolytic effects in animal tests of anxiety. This study
was confirmed by Stein and Colleagues 53 in 1973. The anxiolytic effect of PCPA was reversed
by the administration of 5-hydroxytryptophan (5-HTP; an immediate precursor of 5-HT).
Neurochemical studies on the effects of BZs on brain 5-HT metabolism also support the
hypothesis because systemic administration of BZs has been reported to decrease synthesis and
release of 5-HT in many regions of rat brain 54,55,56,57 .

Lesions of serotonergic pathways, resulting from the injection of neurotoxins 5,6 or 5,7-
dihydroxytryptamine (5,7-DHT) have been reported to produce anxiolytic profiles in conflict
paradigms 47 . The dorsal raphe ascending pathways seems to be of particular importance.
Small 5,7-DHT lesions of this nucleus produced anxiolytic effects in the social interaction test 58
and a similar effect was also produced by injecting the toxin into the lateral septum 59 . Thiebot et
al 60 also found that 5,7-DHT lesions of the dorsal raphe resulted in an anti-conflict effect in
animal models.

Microiontophoretic injections of 5-HT into the dorsal raphe were found by Thiebot et al 61 to
release punished responding. Because of evidence that these 5-HT injections may depress the
firing rate of dorsal raphe neurons, probably through an action of autoreceptors, the results were
interpreted as support for the hypothesis that decreased 5-HT activity results in an attenuation of
behavioural suppression.

The 5-HT agonist, -methyltryptamine suppressed punished responding in both the pigeon and the
rat, but since unpunished responding was also decreased, the results may simply reflect a non-
specific depressant effect of the drug 62 . Another 5-HT agonist, 5-methoxy, N, N-
dimethyltryptamine (5-MeODMT) had no effect on punished response rates in a conflict
procedure and reduced unpunished rates 63 . However, in this study 5-MeODMT was unable to
reverse the anti-conflict effects of chronic administration of PCPA. The effects of quipazine, a
non-selective 5-HT agonist have been studied in the social interaction test 56 (Nutt and Cowen
1987). The compound did not appear to be anxiogenic in this test but an anxiogenic action was
shown by decreased social interaction without a concomitant drop in motor activity 64 .
Fenfluramine, which releases 5-HT, had no effect on punished responding, whereas the 5-HT
precursor, 5-HTP did have pro-conflict effect 65 . However, this effect was blocked by the addition
of carbidopa, which blocks peripheral decarboxylation, indicating that a peripheral action of 5-
HTP was responsible for the behavioural effect. It has been shown that administration of
carbidopa, a 5-HTP decarboxylase inhibitor, did accumulate 5-HTP in the rat brain and
contributes to the reduced 5-HT synthesis. The data, however, strongly supported the hypothesis
that central serotonin may be involved in the anti-anxiety effects of BZs.
Serotonin Receptors In The Modulation Of Anxiety

A substantial body of work in animals and some exciting recent findings in humans warrant a
closer examination of the 5-HT/ anxiety relationship. Figure 1 gives a schematic overview of the
localizations of the 5-HT receptor types and subtypes on a hypothetical 5-HT neuron. The present
contribution focuses on the possible role of different 5-HT receptors in the modulation of anxiety.
For example, anxiolytic behavioural effects (like exploratory behaviour, elevated plus maze etc.)
of 5-HT-1A receptor agonists such as buspirone 100 appear to be produced by the stimulation of
presynaptic 5-HT-1A autoreceptors that inhibit the synthesis and secretion of serotonin.
Alternatively, antagonists of 5-HT-1A, 5-HT-2, or 5-HT-3 receptors may exhibit anxiolytic effects
by blocking postsynaptic serotonin receptors 18 (Fig 1).

Thumbnail: Figure 1: Schematic overview of the localization of 5-HT receptors on a hypothetical

serotonergic neuron showing pos...
Figure 1: Schematic overview of the localization of 5-HT receptors on a hypothetical serotonergic
neuron showing possible involvement of various receptors types in the mediation of anxiety and
depression.

The 5-HT-2A receptors are also involved in anxiety. For example, animal studies have
demonstrated that 5-HT-2 receptors can independently modulate the function of the
hypothalamo-pituitary adrenocrtical (H-PA) axis 101 , although the respective role of 5-HT-2A
receptors in the management of anxiety is highly complex. A number of commonly used
antidepressants, such as amitriptyline, clomipramine and trazodone are potent antagonists of 5-
HT-2A receptors and demonstrate anxiolytic effects in some animal models 102,103 . Early
evidence from clinical trials indicated that ritanserin, a slective 5-HT-2 receptor antagonist, may
be an effective anxiolytic agent 104 and is being tested in a variety of psychiatric syndromes,
including anxiety disorders. Peroutka and Snyder 105 have reported that cortical 5-HT-2A
receptors are down-regulated by the long-term administration to rats a variety of tricyclic
antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Behavioural studies with the
X-maze anxiety model and punished responding suggest that 5-HT-2A receptor antagonists
demonstrate anxiolytic effects in animal models 102,103 .

One psychoactive drug, meta-chlorophenylpiperazine (m-CPP), has attracted considerable recent

attention because it is a metabolite of the antidepressants trazodone and nefazodone and has a
high affinity as an agonist for a number of 5-HT receptors. In a variety of animal models, m-CPP
produces diverse behavioral changes (such as hypolocomotion, hypophagia, hypothermia etc.).
Hypolocomotion, an axiogenic behaviour has been shown to be mediated by the stimulation of 5-
HT-2C receptors 103,106 . Blockade of 5-HT-2C receptors with selective 5-HT-2C receptor
antagonists can prevent anxiogenic effects of m-CPP 106 . In addition, 5-HT-2C receptor
antagonists given alone may produce anxiolytic effects 107,108 . The functional effects of 5-HT-
2C receptor activation are desensitized by the long-term administration of selective serotonin
reuptake inhibitors (SSRIs) and MAOIs 109 . It is possible that some of the effects produced by
long-term administration of SSRIs and MAOIs on anxiety-related behaviours 110 are involve in
this common mechanism. Clinical studies have demonstrated that m-CPP can produce symptoms
of anxiety in normal volunteers 111 . This drug also augments symptoms of panic anxiety and
OCD 112 .

Ondansetrone (Zofran), a 5-HT-3 receptor antagonist, currently marketed as an antiemetic agent

for the treatment of chemotherapy-induced nausea and vomiting. Recent studies suggest that it
might be an effective anxiolytic in a variety of animal models 18 . A variety of other 5-HT probes
have been also utilized in the patients with anxiety disorders like OCD. These include tryptophan
113 (5-HT precursor), fenfluramine 114 (5-HT releaser) and metergoline 115 (5-HT antagonist).

The very recent development of compounds that interact in a specific manner with part of the 5-
HT system and that possess anxiolytic properties in animals and human, has offered the
possibility to elucidate the role of 5-HT in anxiety in more detail. The 5-HT receptors in the
hippocampus and also other parts of the limbic systems are primarily of the 5-HT-1A type 9 . It is
therefore tempting to speculate that the drug which displays a high degree of selectivity towards
5-HT-1A receptor sites may selectively affects anxiety states. It has been suggested by Dourish
116 that 5-HT-1A receptor agonists elicit their anxiolytic effects through stimulation of 5-HT-1A
receptors located on the cell bodies and/ or dendrites of 5-HT neurons in the raphe nuclei 15 . A
breakthrough in that direction was the finding that, buspirone, a drug with anxiolytic activity in
animals and humans 117 , could displace [ 3 H]-5-HT with relatively high potency from its
hippocampal binding sites 10 . Later discovery that buspirone and other 5-HT-1A receptor
agonists produce anxiolytic and antidepressant activity directed attention to the 5-HT-1A receptor
as the possible site of all the anxiolytic and antidepressant effects 118 .

In the central nervous system (CNS), the 5-HT-1A receptors are broadly distributed, occurring as
a somatodendritic autoreceptor on 5-HT cell bodies located in the raphe nuclei, and
postsynaptically in other areas such as the hippocampus 10,26,119 (see Fig 3). The distribution
of 5-HT-1A receptor sites in the brain and pattern of buspirone binding to different brain structures
has been established using radiolabelled 5-HT and buspirone. This evidence confirms that in
regions of the brain implicated in the mediation of mood and emotion, buspirone acts in a similar
fashion to 5-HT. Buspirone appears to exert its beneficial effects by binding specifically, and with
a high affinity, to the 5-HT-1A receptor in the brain and thus altering serotonergic transmission 7 .
Pre-Synaptic And Post-Synaptic 5-Ht-1a Receptor Interaction In Anxiety

Buspirone, a nonbenzodiazepine anxiolytic, belongs to the azapirone family of drugs and differs
from the BZs both chemically and pharmacologically 130 . It was originally suggested that the
proposed anxiolytic activity of buspirone involved action on dopamine systems in the brain 131 .
Buspirone was found to displace binding to 5-HT-1 sites in hippocampal membranes from the calf
11 . Displacement of binding to a 5-HT-1 site in rat hippocampus was subsequently reported
132 . Buspirone and related compounds (gepirone, ipsapirone and tandospirone) that are
effective for the treatment of generalized anxiety disorder demonstrate a high affinity for 5-HT-1A
receptors. The important pharmacologic

actions of buspirone are (1) stimulating presynaptic 5-HT-1A receptors 133,134 , (2) blocking
postsynaptic 5-HT-1A receptors 135,136 and (3) reducing the density of 5-HT-2 receptors during
long-term or chronic administration 137,138 . These effects act in concert to diminish serotonin
neurotransmission and might underlie the actions of buspirone in anxiety and depression. The
hypothesis is further supported by the reported observations that the complex behavioural
syndrome observed following administration of serotonin agonists reflects activation of central
serotonin receptors 139 , particularly the 5-HT-1A receptors 140 .

Thumbnail: Figure 2: Functional anatomy of 5-HT-1A receptors.

Figure 2: Functional anatomy of 5-HT-1A receptors.

Various reported studies have shown that BZs and buspirone 141 reduce the activity of
serotonergic neurons in the dorsal raphe nucleus. The 5-HT-1A receptors in the dorsal raphe are
considered presynaptic, while those located in the hippocampal formation and cortex are
considered postsynaptic 142 . Buspirone demostrates varying agonistic activity at these
regionally distinct receptors (Fig 2).

Electrophysical studies of events in the dorsal raphe nucleus show that spontaneous firing of
serotonergic neurons is attenuated or abolished by buspirone in a way similar to that of a
serotonin agonist 26 . Binding of buspirone to presynaptic 5-HT-1A receptors inhibits the activity
of serotonergic neurons via a negative feedback mechanism. Thus, buspirone acts as a full
agonist at presynaptic receptors. Studies in rat hippocampal membranes of the binding of
buspirone to postsynaptic 5-HT-1A receptors showed it to have approximately half the intrinsic
activity of 5-HT i.e. implying partial agonist activity of postsynaptic receptors 142 . As a partial
agonist, buspirone competes for the binding sites and displaces the more active full agonist from
such sites. This allows buspirone to function like an antagonist in the presence of high
concentrations of 5-HT. Thus, buspirone acts as a 5-HT agonist at presynaptic receptors and a
partial agonist at postsynaptic receptors 18 .
Clinical Implications

This article provides a brief overview of the pharmacology of serotonin systems and
developments in research so that the relationship between serotonin compounds and anxiety can
be better understood. There is convincing evidence that 5-HT brain pathways are involved in the
mechanisms of action responsible for the alleviation of anxiety. Hence, the role of 5-HT in anxiety
and other affective disorders is fundamental to the pharmacology of 5-HT-1A agonist buspirone.
Evidence suggests that pre-synaptic 5-HT-1A receptors located on cell body dendrites are
involved in the anti-anxiety effects of azapirones while post-synaptic 5-HT-1A receptors
stimulated by serotonergics produce antidepressant effects. Because anxiety and depression
often coexist, drugs of azapirone type may have clinical implications in the treatment of both
anxiety and depression. The fact that anxiety can be treated with the novel serotonergic drugs
buspirone, gepirone and ipsapirone sheds new light on the old hypothesis that BZ anxiolytics act
in part via modulation of 5-HT neurotransmission. A common effect of the BZs and 5-HT-1A
receptor-related anxiolytics is their inhibition of serotonergic impulse flow.

In conclusion, the study supports the suggestion that activation of somatodendritic 5-HT-
1A autoreceptors play a critical role in the mechanisms underlying the anxiolytic effects of
selective 5-HT-1A receptor agonists 130 . Further clinical studies with more selective
pharmacological agents are required to identify the specific contribution of the serotonergic
systems in the pathophysiology of anxiety disorders and therapeutic strategies to combat the
undesirable stressful situations in anxiety and depression. Unravelling the role of serotonin in
anxiety and related disorders and parallel studies on animal models could hopefully provide better
therapy and is likely to lead to new insights in our understandings of anxiety and depression.
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