Clinical Neuroscience Research 3 (2003) 253262

www.elsevier.com/locate/clires

A review of the relevance and validity of olfactory

bulbectomy as a model of depression
Andrew Harkin*, John P. Kelly, Brian E. Leonard
Department of Pharmacology, National University of Ireland, Galway, Ireland

Abstract
Development of valid animal models for human affective disorder. Attempts have involved numerous approaches such as the exploitation
of vulnerability factors for depression including maternal deprivation, exposure to psychophysiological stress or by pharmacological
depletion of monoamines. However, no approach is perhaps so radical as the removal of a part of the brain as occurs in the olfactory
bulbectomy (OB) model of depression. The ensuing behavioural symptoms also distinguish the OB model from other animal models of
depression, in that it possesses significant face validity as a model of agitated depression. OB in rodents provokes behavioural changes that
respond to chronic but not acute treatment with antidepressants thus mimicking the time-course of antidepressant action in the clinic. The
persistent use and popularity of the model over the past 25 years is a testament to its utility in exploring the neurobiological mechanisms of
antidepressant action, as well as the pathophysiology of major depression. In this review, the present status of the model is presented.
q 2003 Elsevier B.V. All rights reserved.
Keywords: Olfactory bulbectomy; Animal model; Depression; Antidepressant; Rat

1. Introduction
The olfactory bulbectomised (OB) rat model of
depression has been the subject of a number of published
review articles to date [1 5]. The purpose of the present
review was to assess the evidence reported in more recent
times that propose olfactory bulbectomy as an animal model
of depression. Some proponents of the OB model suggest
that there is good face validity with human depressive
disorder, especially agitated depression [5]. Others argue
that the behavioural normalisation of OB rats following
chronic antidepressant drug administration is more of a
predictive screen for antidepressant efficacy rather than a
model of depressive pathophysiology. In this regard the
model is likely to remain controversial.

2. Reported findings and analysis by topics

Removal of the olfactory bulbs provokes behavioural
changes in rats, which are independent of the loss of ability
to smell.
* Corresponding author. Tel.: 353-91-524411x3826; fax: 353-91525700.
E-mail address: andrew.harkin@nuigalway.ie (A. Harkin).
1566-2772/$ - see front matter q 2003 Elsevier B.V. All rights reserved.
doi:10.1016/S1566-2772(03)00087-2

Reviewed here are some recent reports contributing to

our understanding of the behavioural changes associated
with olfactory bulbectomy which can be attenuated
following antidepressant treatments.
2.1.1. Increased locomotor activity in a novel open field
environment
Upon placement in a novel open field environment,
OB rats will exhibit behavioural hyperactivity. This effect
does not appear to be related to the loss of smell as
peripherally induced anosmia does not affect open field
behaviour in a similar fashion [1,3]. Precipitation of the
hyperactive response is generally dependent upon high
illumination and reflective walls in the open field and is
associated with stress-induced behaviours including thigmotaxis and defecation. The nature of the test suggests that
open field exposure is associated with increased stress
and/or anxiety, which is a crucial determinant of OB
related hyperactivity [5].
OB animals appear to be incapable of inhibiting their
behaviour to the same extent as their sham-operated
counterparts under these aversive conditions [6]. Such
behavioural dysinhibition is a feature of bulbectomy that is
reported to appear in behavioural tests other than the open
field. OB rats exhibit an anxiolytic-like behavioural
response in the elevated plus maze, Vogels conflict and

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passive avoidance tests [7]. Others have suggested that the

behavioural changes associated with bulbectomy including
increased open field activity are related to a decrement in
the animals defensive responding rather than a general
increase in activity levels [8]. Olfactory bulbecomy has
been reported to decrease defensive responding during
exposure to a novel environment [9].
Methodological issues such as allowing an appropriate
time for the OB syndrome to develop are reviewed in detail
by Kelly et al. [5]. Whatever the test conditions, the
increased activity associated with this model differs from
other stress-based models of depression in modelling
agitated rather than retarded behavioural output. Thus the
OB model has been proposed to model a subgroup of
depressed patients with psychomotor agitation [2].
2.1.2. Deficits in avoidance behaviour
Deficits in avoidance behaviour following olfactory
bulbectomy have been discussed in detail previously [3].
There is new evidence, however, to support a hypothesis
that the OB syndrome may be useful in research as an
experimental model of Alzhemier type senile dementia.
Cholinergic neurons are degenerated with delay (14 days)
following olfactory bulbecomy, correlating with the appearance of a memory deficit in the step through passive
avoidance task. This deficit is improved by administration
of the M1 receptor agonists oxotremorine and McN-A-343,
suggesting that muscarinic M1 receptors play an important
role in the improvement process [10].
OB rats show deficits in other learning and memory tasks
including the eight-arm radial maze, Morris maze, three
panel runway apparatus, a three-lever operant task. Deficits
in the three-way runway apparatus appear with delay after
removal of the bulbs and are reported to be reduced following
administration of the cholinesterase inhibitor physostigmine
[11]. More recently, De Prato Primeaux and Holmes [12]
reported bulbectomy-induced deficits in footshock-induced
immobility, an aversively motivated behaviour. Studies have
also shown that rats do not require olfactory cues for effective
performance in these learning tasks. Since OB rats show
impairment of memory with some emotional changes, it has
been proposed that the OB syndrome may be a useful model
of dementia [13].
2.1.3. Hyper-responsivity to stressors
Air puff and restraint stress cause greater increases in
accumbal 5-HIAA in OB rats than in their sham-operated
counterparts [14], indicating increased serotonergic responsiveness to acute stress in OB rats. OB rats also exhibit a
higher plasma concentration of corticosterone but not
adrenocorticotrophic hormone (ACTH) in basal conditions
and higher ACTH and corticosterone concentrations after
stress when compared to sham operated controls. Daily
administration with fluoxetine had no effect on basal but
reduces stress-induced levels of ACTH in response to
immobilisation stress [15]. Other types of stress such as

startle, which may not be sufficiently stressful to obtain

differences between OB and sham-operated rats, when
tested against a background of increased stress evoke
differential responding in OB animals [16,17].
Integrity of the olfactory bulbs in rats appears to be
important for the elicitation of normal cardiovascular and
autonomic responses to a number of evocative stimuli. In a
recent report by Moffitt et al. [18] bulbectomy was shown to
attenuate cardiovascular sympathoexcitatory responses to
hypotension, air jet stress and smoke exposure, as well as
elevated basal blood pressure when compared to sham
operated controls.
2.1.4. Other associated behavioural changes
Olfactory bulbecomy is associated with deficits in the
expression of cocaine-induced conditioned place preference [19], daily intake of saccharin and sucrose solutions,
mating, maze running to obtain food pellets and
spontaneous wheel running when compared to sham
operated controls [5]. Such changes in behaviour are
proposed to reflect anhedonic features of the OB
syndrome. In contrast, acquisition and stable self-administration of amphetamine are increased in OB animals
when compared to sham-operated controls. Thus bulbectomy appears to increase the reinforcing effects of
amphetamine [20]. These findings may have particular
relevance to clinical depression as affective disorder and
substance abuse frequently co-exist.
Other behavioural changes including muricidal behaviour [3] and abnormalities in circadian rhythm [21]
following bulbectomy have been reviewed elsewhere.
2.2. OB-induced hyperactivity in a novel open field is
attenuated following chronic antidepressant treatment
In order to qualify as a model of depression, it is
imperative that OB rats respond selectively to antidepressant intervention. In this regard, a variety of behavioural
changes vary with regard to the specificity of the response.
Some parameters like irritability and hormonal changes
respond to neuroleptics and anxiolytics [3]. Some behavioural changes are not altered following chronic antidepressant treatment, e.g. effects of chronic desipramine on
waiting behaviour for a food reward in OB rats [22].
More recently, Mar et al. [6] reported that subchronic
lorazepam reduced OB-related hyperactivity in the open
field. This reduction was not related to increasing the rate
of habituation but alternatively by decreasing the residual
activity that occurs toward the end of the trial. Antidepressants and anxiolytics can therefore be differentiated on the
basis of the times at which they exert their effects.
Reduction in residual activity may also be attributable to
the sedative as opposed to the anxiolytic effects of
lorazepam.
Of the behavioural changes that occur following bulbectomy, two emerge that respond to antidepressant compounds

A. Harkin et al. / Clinical Neuroscience Research 3 (2003) 253262

in a selective fashion, namely the deficit in passive avoidance

and the hyperactivity in the open field. In this regard, the
passive avoidance deficit, whilst reversed specifically by
antidepressants, responds to acute antidepressant administration. By contrast, hyperactivity in the open field is a
behavioural change that is responsive selectively to chronic
antidepressant treatment thus mimicking the clinical timecourse of antidepressant action [3,5]. To date, no study has
reported the actions of any antidepressive agent, including
putative candidates, which will attenuate the hyperactivity of
OB rats in the open field following acute administration
[23 25]. The slow onset of action of antidepressants
distinguish the OB model from other simulations of
depression and tests of antidepressant action.
A higher initial reactivity upon introduction to the open
field (due to anosmia which is not responsive to
antidepressants) and a slow habituation to the test are
features which characterise hyperactivity in the open field
test [16]. Antidepressants (fluoxetine, amitryptyline and
buspirone) rectify the hyperactivity by increasing the rate of
habituation, permitting more effective adaptation or by
promoting the restoration of response inhibition mechanisms normally activated by aversive conditions [6,16].
In contrast to the view that stress is an essential factor in
precipitating OB-related hyperactivity, OB rats are also
more active than sham operated controls under certain
conditions in a home cage setting. This hyperactivity may
also respond to antidepressant treatments [5,26].
In recent times, the model has been used to detect
potentially novel antidepressant compounds and new
pharmacological strategies that demonstrate improved
efficacy or a faster onset of antidepressant action. Such
approaches have included an assessment of the antidepressant potential of serotonin (5-HT) receptor agonists. The
5-HT2C receptor agonist (s0-2-(4,4,7-trimethyl-1,4-dihydroindeno[1,2-b]pyrrol-1-yl)-1-memthylethylamine) reduces
olfactory bulbectomy-induced passive avoidance impairment in rats [27]. The 5-HT1A receptor agonist ( ) S-20499
attenuates OB-related hyperactivity following 2 weeks of
treatment [28]. The selective and brain penetrable mGLUr 5
receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine
restores the learning deficit of OB rats after 14 days of
treatment [29]. Other approaches have assessed dual action
on both noradrenergic and serotonergic synapses [23] and
targeting pre-synaptic receptor dysinhibition [25,30]. These
studies demonstrate that reversal of this aspect of the OB
induced behavioural syndrome is insensitive to the potential
faster onset of antidepressant action induced by 5-HT1A
receptor antagonists [25,30]. Currently no pharmacological
strategy tested has yielded a faster onset of action in
the model.
2.3. Does olfactory bulbectomy provoke a similar
syndrome in mice?
The OB model has most often been examined in rats,

255

whilst there are few studies on the effects of bulbectomy in

mice. In the context of testing antidepressant compounds,
mice are often preferable to rats on the grounds of cost, space
and amount of compound required. Furthermore, with the
advent of transgenic mice, there is a need for animal models
of depression and tests of antidepressant activity to extend to
the mouse where possible [31]. OB in C57B1/6j mice
produces an increase in activity in the open field test and
deterioration of active and passive avoidance learning
[32,33]. The development of these behaviours is most
expressed 4 weeks following the surgery. Repeated administration of amitriptyline, trazodone and imipramine have been
reported to normalise the behaviour of these animals. Some
strain differences have been reported following bulbectomy
in mice. DBA/2j mice also display elevated locomotion in the
open field, which is corrected by antidepressant treatment
but these mice do not show a significant passive or active
avoidance deficit [32].
OB mice display reduced aggression and social behaviour in a group housed semi-natural setting [34]. It is
thought that the mechanisms underlying the decrease in
aggression following bulbectomy is a direct consequence of
the olfactory sensory loss. The central role of olfaction in
aggressive behaviour of mice as well as other species is
reviewed elsewhere [35].
Transgenic/knockout technology has only been applied
to OB mice in recent times. Mice with a targeted deletion of
the tac1 gene, which encodes the neuropeptides substance P
and neurokinin A do not become hyperactive after
bulbectomy [36]. Substance P and its receptor neurokinin
1 have been implicated in the regulation of many
physiological and pathological processes including the
control of emotional behaviours [36].
2.4. What is known about the nature of the neurobiological
processes underlying the OB syndrome and its attenuation
by antidepressants?
As there is a lack of correlation to anosmia, changes
induced following bulbectomy are believed to relate to a
progressive degenerative process in the brain resulting in
dysfunction in limbic areas involving a variety of neurobiological changes and affecting many neurotransmitter
systems.
The olfactory bulbs in the rat form an important part of the
limbic circuit. Connections of the olfactory bulbs to the rest
of the brain have been reviewed in detail elsewhere [4,5].
Olfactory bulbectomy causes retrograde degeneration of
neurons in various regions projecting to the bulbs as well as
anterograde degeneration of neurons normally receiving
projections from the bulbs. Neuronal degeneration and
remodelling from OB to brain areas such as cortex,
hippocampus, amygdala, locus coeruleus (LC), medial and
dorsal raphe (MR and DR, respectively) are frequently
implicated in the behavioural syndrome and are reviewed
below.

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2.5. Olfactory bulbecomy initiates neuronal degeneration

and remodelling
Removal of the olfactory bulbs initiates a sequence of
secondary structural and functional alterations in brain areas
remote from the bulbs. Macroscopic changes in OB brain
include a pronounced enlargement of the lateral and 3rd
ventricle [37]. Magnetic resonance imaging also reveals
alterations in signal intensities in cortical, hippocampal,
caudate and amygdaloid regions [37]. Such changes parallel
those reported in depressed patients including increased
ventricular size, decreased frontal lobe, caudate and
amygdaloid volumes as well as lesions in the frontal lobes
and basal ganglia [38].
There are reports of neuronal degeneration and remodelling following bulbectomy in rats. Hall and Macrides [39]
reported reductions in dendritic branching, in the number of
dendritic spines and in the number of synapses on both
spines and shafts of dendrites within the piriform cortex
following bulbectomy. Bulbectomy was later reported to
reduce dendritic spine density in CA1, CA3 and dentate
gyrus of the hippocampus. Chronic treatment with amitryptyline reversed the reduction in dendritic spine density
in these regions [40]. Similar types of cellular adaptations
are associated with depression and in response to antidepressant treatments [41].
Olfactory bulbectomy induces neuronal cell death
manifested as an increased number of pyknotic neurons,
predominantly in the DR nucleus but also in the LC.
Treatment with antidepressants following bulbectomy
counteracts the degenerative process and improves the
functional condition of surviving neurons in both structures
[42].
2.6. Olfactory bulbectomy triggers an array of
neurochemical changes
Associated changes in the biogenic amine content and
their receptors in cortical and limbic regions have been the
focus of intense investigation in the past 25 years. Whilst
bulbectomy causes numerous neurochemical changes only
some of these have been consistently reported and are
therefore useful in formulating hypotheses on the aetiological basis of the OB syndrome. These changes are outlined
in turn below.
2.6.1. 5-HT hyperinnervation in the frontal cortex
Serotonergic hyper-innervation of the frontal cortex
occurs following OB in rats consistent with many reports
of the OB rat being a model of hypo-serotonergic depression
[43 46]. This hypothesis is supported by a number of recent
reports. Cell death and degeneration following bulbectomy
occurs in the DR nucleus, the point of origin for serotonin
projections to limbic and forebrain regions [42]. 5,7
Dihydroxytryptamine (5-HT neurotoxin) injections directly
into the DR nucleus produces a syndrome similar to that

reported following bulbectomy [47]. There is an increase in

the density of 5-HT transporters and tryptophan hydroxylase
concentrations in the frontal cortex of OB rats [44].
Moreover, 5-HT2 receptors are reported to up-regulate
following bulbectomy [33,48]. Such changes may well
reflect an up-regulation of serotonergic transmission in
response to neuronal degeneration.
These changes have also lead to speculation on the
association between changes to serotonergic transmission
and the behavioural changes associated with the OB rodent.
Interestingly up-regulation of cortical 5-HT2 receptors in
OB C57 mice is reported to be correlated with the deficit in
active avoidance learning rather than OB-induced hyperactivity [48]. Moreover, the deficit in passive avoidance
corrected following chronic imipramine administration
parallels with a reduction in tryptophan hydroxylase levels
in the frontal cortex supporting the view that the behavioural
normalisation is related to a restoration of 5-HT function in
the frontal cortex [45]. It therefore seems likely that
disruption of central 5-HT connections results following
OB leading to disturbances in serotonergic transmission in
the raphe and other regions connected to it. It is further
proposed that lasting changes in the levels of tryptophan
hydroxylase, 5-HT transporter and in the density of
serotonergic nerve terminals in projection fields that occur
following long term antidepressant treatments may serve to
address the imbalance [43,45]. Depression has been
associated with 5-HT2 receptor supersensitivity probably
resulting from a serotonin deficiency. Antidepressantinduced down-regulation of central 5-HT2 receptors might
be involved in their therapeutic activity.
Changes to the serotonergic system following bulbectomy may be dependent upon the age of the animals. 5-HT
transporter sites are reported to be increased in the cortex
and hippocampus of young OB but were decreased in aged
OB subjects indicating that there are biological distinctions
in effects of bulbectomy in young and aged animals [49].
Such studies provide important insights into the underlying
biological differences related to ageing of the brain.
2.6.2. Dysinhibition of the amygdala
The amygdala is linked to the control of emotion and is
therefore of relevance in clinical depression. Changes
induced in the amygdala following bulbectomy include an
increase in electrical activity, increased 2-deoxyglucose
uptake [50] and faciliatated kindling [51]. The amygdala is
also known to be critical in mediating footshock-induced
sensitisation of the acoustic startle response. Bulbectomy
enhances sensitisation of the acoustic startle reflex
produced by acute or repeated stress [17] consistent with
the hypothesis that OB mediates its effects by dysinhibition of the amygdala. The induction of a dysinhibited
amygdala following OB was originally proposed by
Leonard and Tuite [1].
Prolonged expression of the immediate early gene and
marker of neuronal activation has been reported in the

A. Harkin et al. / Clinical Neuroscience Research 3 (2003) 253262

basolateral amygdala following bulbectomy for up to 64

days post lesion. Such a prolonged activation is thought to
be related to some regenerative, remodelling or survival
capacity in this region and serves as a possible indicator of
hyperactivity within this structure [52]. In addition,
alterations in both serotonin and noradrenaline transmission
are implicated in the dysfunctioning amygdala following
bulbectomy [3,5].
2.6.3. Changes in excitatory/inhibitory amino acid
neurotransmission
Reduced glutamate and aspartate concentrations and
increased glycine concentrations in the olfactory cortex and
increased glutamate decarboxylase activity in the cortex
have been reported following bulbectomy [3]. More
recently, a reduction in the binding of the non-competitive
NMDA receptor antagonist MK-801 following bulbectomy
in discrete brain regions including the cortex, amygdala and
thalamus [53] and cerebral cortex [54] have been reported,
although Webster et al. [55] in an autoradiographical study
of the OB brain reported an increase in [I125]MK-801
binding in the prefrontal cortex. Such binding changes also
appear to possess functional significance as the behavioural
response to acute challenge with the NMDA receptor
antagonists phencyclidine (PCP) and MK-801 is significantly lower in the OB rat when compared to their shamoperated counterparts [53,56]. Redmond et al. [56] also
reported that the reduced behavioural response of OB rats to
acute challenge with PCP could be reversed following
chronic treatment with the tricyclic antidepressant amitriptyline. Nakanishi et al. [57] reported an enhancement of
NMDA receptor mediated synaptic potential evoked in
medial amygdala neurons following OB, a response which
may underlie the hyperexcitability of the amygdala. Overall,
glutamatergic transmission through the NMDA receptor
appears to be altered following bulbectomy, which may
contribute to associated behavioural changes including the
behavioural hyperactivity and deficits in learning. Of
interest also are the findings that chronic administration of
MK-801 attenuates the hyperactivity of OB rats in the open
field [58].
Glutamate release during novelty exposure is increased
in the striatum of OB rats when compared to sham-operated
controls [59]. The authors suggest that the OB-related
enhancement of glutamate release in response to novelty
could be related to the often reported elevation of plasma
corticosterone following bulbectomy, as there is evidence to
suggest that corticosterone levels affect stress induced
glutamate release in the brain [60]. Amygdalostriatal
connections may also be disrupted leading to abnormal
striatal responses to novelty stress.
GABAA receptor binding has been reported to increase in
the cortex following bulbectomy, a change that may be
reversed following chronic antidepressant (clorgyline,
paroxetine and desipramine) treatments [61]. Changes to
the binding properties of GABAA are however not unique to

257

the OB brain. Moreover it is unknown if GABAA receptor

down-regulation is implicit in the therapeutic actions of
antidepressants.
2.6.4. Dysfunction of the hypothalamic pituitary adrenal
(HPA) axis
Increased circulating concentrations of corticosterone
following bulbectomy under basal and stressful conditions
have been reported and have lead investigators to propose
that OB leads to a change in the function of the HPA axis.
Reported elevations of corticosterone in OB animals are
somewhat controversial and have not always been observed
in the published literature. Moreover, where bulbectomy was
associated with increased levels of corticosterone, antidepressant drugs have not always lead to an attenuation [62].
2.6.5. Changes in the neuro-immune axis
Changes in the immune system associated with the OB
rat have been previously reviewed [5]. Qualitatively similar
changes have also been reported to occur in patients with
major depression [63 66]. It is presently hypothesised that
changes in immune function in both the OB rat and in the
depressed patient may reflect an inflammatory state driven
by an increased secretion of and/or enhanced sensitivity to
pro-inflammatory cytokines including interleukins-1,-6 and
tumour necrosis factor alpha [67,68].
More recently, Song et al. [69] have investigated gene
expression following lipopolysaccharide (LPS) administration to OB rats and reported that LPS-induced expression
of the immediate early gene transcript for cFOS and the
prostaglandin receptor EP4 were significantly increased in
several limbic regions of the brain when compared to shamoperated controls. Such changes in the EP4 receptor have not
been reported to date in depressed patients, however, the
concentration of prostaglandin E2 is reported to be raised in
the cerebrospinal fluid of patients with major depression [70].
2.6.6. Long lasting and late developing changes
in neuropeptide concentrations
In the past few years there has been a focus of interest in
changes induced in neuropeptide concentrations in the brain
following bulbectomy. The reasons associated with this are
that neuropeptides are often co-localised with classical
neurotransmitters of interest and also changes in neuropeptide concentrations in brain regions can be triggered by
loss of input from the olfactory bulbs.
Corticotropin releasing factor (CRF) is a neuropeptide
that functions as a releasing factor in the regulation of the
HPA axis and as a neurotransmitter in a variety of extrahypothalamic brain regions. When CRF is administered
directly into the brains of laboratory animals, this
neuropeptide initiates behavioural responses that are somewhat analogous to symptoms of major depressive disorder
including changes in sleep, feeding, exploratory and sexual
behaviours and increased anxiety. Hypersecretion of CRF
has also been proposed as a state marker in depressed

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A. Harkin et al. / Clinical Neuroscience Research 3 (2003) 253262

patients [62]. Examination of the effects of bulbectomy on

the factors controlling corticosterone secretion have shown
that bulbectomy increases vasopressin, but not CRF content
in the external layer of the median eminence of male rats
[15]. In a second report, however, bulbectomy-induced
increases in CRF in the hypothalamus and bed nucleus of
the stria terminalis were attenuated following chronic
treatment with the 5-HT re-uptake inhibitor, sertraline
[62]. Differences in the outcomes of these studies may be
due to methodological issues. Other hypothalamic peptides
that are reported to change in response to bulbectomy and
normalise following antidepressant treatment are thyrotrophin releasing hormone and somatostatin [62].
CRF mRNA was reported to increase in the OB brain
following LPS challenge. Elevated serum corticosterone
and prostaglandin E2 concentrations and reduced serum
concentrations of the anti-inflammatory cytokine IL-10 in
response to administration of the pro-inflammatory cytokine
IL-1 were also reported [71]. The result of these studies
suggest that changes in the immune and endocrine systems
observed in the OB rat may be associated with an increased
response to the central effects of the pro-inflammatory
cytokines, which impact upon brain function by activating
CRF neurones and cyclo-oxygenase. The role of cytokines
and immunological activation in depressive disorders have
been reviewed elsewhere [67].
Increases in enkephalin and neuropeptide Y (NPY) have
been found in the olfactory tubercle and piriform cortex
following bulbectomy. Moreover, these changes were
shown to positively correlate with the time spent immobile
following footshock suggesting a relationship between
changes in peptide gene expression and the behavioural
deficits in the OB syndrome [12,72]. More recently,
however, Rutkoski et al. [73] failed to reproduce the effect
of bulbectomy on NPY in the pirifrom cortex although there
were procedural differences between the two studies, which
may account for this.
Prepro-galanin (p-Gal) co-localises with noradrenaline in
the LC and expression of this peptide is up-regulated in a
time dependent fashion in the LC of OB rats. P-Gal is
known to up-regulate in noradrenergic neurons in response
to injury suggesting that the peptide may serve a trophic or
regenerative function in the nervous system [74]. NPY also
co-localises and has an inhibitory action on the release and
synthesis of noradrenaline. NPY is therefore hypothesised
to play a role in depressive and anxiety related disorders.
Increased NPY immunoreactivity has been reported in the
medial amygdala following bulbectomy [73]. OB also
increases prepro-enkephalin mRNA levels in the ventral
striatum in rats [75]. These studies provide some support for
the hypothesis that altered neuropeptide gene expression
may underlie certain aspects of the OB syndrome as may be
the case in depressive illness. At present, however, there are
little data available on the effects of chronic antidepressant
treatments on OB-induced changes in neuropeptide
concentrations.

2.7. Potential benefit of antidepressant drugs on

neuronal survival
Despite a great deal of research into the potential
mechanisms underlying OB-associated behaviour the central question regarding why antidepressants alone are active
in this model largely remains unanswered. New strands of
evidence emerging from the antidepressant literature offer
potential answers to fundamental questions about the
mechanism of action of antidepressants in the OB rat
model of depression.
Reports demonstrating plasticity augmenting effects of
antidepressants and the antidepressant-like actions of
neurotrophic factors in animal models of depression suggest
that alterations in neuronal circuitry and plasticity following
antidepressant treatment may be a key factor. Antidepressants work acutely, primarily on serotonin and noradrenaline
pathways, but also possibly on neuropeptides and amino
acid transmitter systems. Long-term antidepressant treatments activate the cAMP signal transduction pathway and
increase the levels of cAMP element binding protein
(CREB) mRNA in the hippocampus of rats. The time
course for the induction of CREB is consistent with that for
the therapeutic actions of antidepressants. Other genes are
likely to be activated by CREB. In this regard, long-term
antidepressant treatment has been reported to increase the
expression of brain derived neurotrophic factor (BDNF) in
the hippocampus. Moreover, BDNF is reported to enhance
the growth of serotonin and noradrenergic neurons as well
as to protect these neurons from neurotoxic damage
[76 78]. Neuronal insult as a predisposing factor in
depression and a role for neurotrophins in the pathophysiology of depression is reviewed elsewhere [41,77 79].
As yet the neuro-regenerative capacity of antidepressants
via the induction of neurotrophic factors in the OB brain has
not been put to the test. Such an explanation would
compliment the already existing hypothesis that bulbectomy
can damage specific vulnerable populations of neurons
which underlie the OB syndrome. The neurotrophic actions
of antidepressants therefore provides a useful rationale to test
a potentially unifying hypothesis for antidepressant action
and the pathophysiology of the OB syndrome. To date, there
has been one report that bulbectomy induces an increase in
the levels of BDNF and nerve growth factor (NGF) in
cingulate cortex suggesting that olfactory ablation may affect
neurotrophin signalling in distant brain structures [80].
2.8. Is there evidence of a disturbance in olfactory
function in depression?
It is generally assumed that the perception and processing of emotional stimuli is altered in patients with major
depression. Such patients show a greater anticipation of
negative experiences and a reduced anticipation of positive
experiences [81]. Most studies in patients have concentrated
on language and visual stimuli as emotional cues, but

A. Harkin et al. / Clinical Neuroscience Research 3 (2003) 253262

recently deviant emotional perception of odours has been

detected in patients with major depression [82,83]. Pause
et al. [84] have also demonstrated that depressed patients
show a marked reduction in olfactory sensitivity, a change
that was predictive of the severity of depression. Following
successful treatment, olfactory sensitivity improved.
Such findings may implicate a disorder of limbic
function that provides the emotional substrate for olfactory
function. Indeed, positive emission tomography (PET)
studies have indicated that the piriform, orbitofrontal and
insular cortices are involved in odour perception [85]. Other
investigators have shown that the amygdala is activated
when an aversive or a novel odour is presented to a patient
[86]. It would appear that the piriform cortex and the
amygdala are the structures associated with the primary
olfactory cortex while the insular and orbito-frontal cortex
associate with the secondary olfactory cortex. PET imaging
studies in healthy volunteers have shown that the orbitofrontal cortex generally participates in the processing of
emotional information [87] and that the insula is activated
by negative emotions [88], while the amygdala plays a key
role in the encoding of pleasant, unpleasant and negative
emotions [89]. Changes in these areas have now been found
to occur in patients with depression [90]. Thus, from these
results, it may be hypothesised that a disorder of limbic
function that occurs in those patients with major depression
may be associated with a change in chemosensory
perception as indicated by a decrease in olfactory arousal.
To what extent are these changes in olfaction in
depressed patients relevant to the neuroanatomical changes
found in the OB rat? Connections between the olfactory
bulbs and the amygdala [17,91,92] are severed following
bulbectomy. As the basolateral amygdala is believed to
mediate fear conditioning and the encoding of negative
emotions [93] it can be surmised that bilateral OB would not
only lead to a loss of olfaction but also a change in the
experience of fear resulting from a disruption to normal
processing of environmental stimuli within the amygdala.
2.9. Is the OB rat a valid animal model for depression?
Criteria have been described that characterise the
adequacy of animal models of depression [2,94,95].
Since the very earliest attempts at simulating human
depression in laboratory animals to current practice in the
laboratory, re-defining of appropriate criteria which validate
such models has been on-going. From the outset a major
limitation is that it is not possible to precipitate defining core
symptoms of major depression such as low mood and
esteem, guilt and suicidal ideation in a laboratory animal.
Thus criteria that have emphasised the necessity for the
model to have analogous symptomatology to depression in
humans have proved to be beyond our capabilities. Since an
animal cannot relate to us what it is feeling we are
compelled to observe behaviour and make inference from
the performance regarding the subjects mental state. The

259

nature of the behavioural aberration, therefore, is not

perhaps as important as the necessity for any change
observed to be objectively identifiable, generate high interrater agreement and be responsive to clinically effective
antidepressant treatments.
The OB model of depression bears no apparent similarity
to the etiology of depressive illness in humans. Criteria on
the etiological validity of models for depression are
however practically impossible to fulfil as the etiology of
depression itself in humans remains to be understood. In this
regard, the model can be reduced to a testthat is
hyperactivity in a novel open field environmentwith a
clear behavioural difference, which is responsive to
antidepressant treatment in a fashion similar to that
observed in the clinic. The necessity of stress as a
precipitating factor in the OB syndrome further strengthens
the validity of the model as the subjects are sensitive to
behavioural stress in an antidepressant reversible manner.
Patients with depression show exaggerated response to
stressors in their daily lives [17,96]. As antidepressants have
a corrective action, both in human depression and the OB
syndrome, the question then arises if this animal preparation
could provide important initial uses in basic neurobiological
research yielding useful insights into the mode of action of
antidepressants and in drug discovery.

3. Conclusions
Following removal of the olfactory bulbs, rats display a
syndrome of behavioural deficits that reflect a disruption of
cortico, limbic and hypothalamic regions. The model is
unique in the range of animal models of depression as it is
the only one which arises from a neurodegenerative process.
Antidepressants in a selective fashion and following chronic
administration are capable of restoring normal behaviour in
these animalsin particular the hyperactive response of OB
rats in a novel open field environment. Olfactory
bulbectomy is therefore a useful model for studying a
neurodegenerative process, which produces behavioural
change responsive to antidepressant treatments. The similarities between this syndrome and clinical depression are
controversial. As there is uncertainty about the underlying
biochemical disorder in depressive illness, the model cannot
pre-suppose any particular mechanism of action.
Numerous studies have been conducted in an attempt to
find the underlying neurochemical basis of the observed
behavioural deficits in the model. However, there is often a
poor correlation between behavioural and neurochemical
changes in the model and correction of either following
antidepressant treatment. It is unlikely that a single
neurobiological marker should present itself as an index
of behavioural deficit or antidepressant response in a model
of a disorder as complex as depression. There is in fact
evidence to support the contrarya wide diversity of
associated macroscopic structural, cellular and biochemical

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A. Harkin et al. / Clinical Neuroscience Research 3 (2003) 253262

changes. It is more likely that disruptions to neurochemical

system interactions in the brain are responsible. One
possible advantage of the OB model is that it produces
a gross abnormality not likely to involve single parts of the
brain or single neurotransmitter systems.
Despite the symptom and biochemical diversity, a
unifying aspect to the model is its response to antidepressant
drugs. Antidepressants appear to restore balance to neural
activity within the OB brain. Placed together with reports
demonstrating plasticity augmenting and neurotrophic
effects of antidepressants, the OB rat may ultimately provide
a template for the future development of compounds directed
toward the neurodegenerative aspects of the affective
disorders and possibly towards negative symptoms of
schizo-affective disorders and Alzheimers disease.
Most models of depression have proven capable of
detecting the currently marketed antidepressants, which up
until now are believed to predominantly affect central
monoaminergic systems. Clinical experience with these
drugs demonstrates that they do not effectively treat all
patients, as well as having a lag phase of several weeks
before a therapeutic effect is observed and implies that
current drugs are far from ideal. Thus the on-going value of
the currently used animal models will be tested when new
drugs that depart from the traditional monoamine targets,
such as the metabotropic amino acid receptors, nitric oxide
synthase, neuropeptides and neurotrophic factors, are
assessed in such models.

Acknowledgements
A.H. would like to acknowledge the support of the
Health Research Board of Ireland.

[9]

[10]

[11]

[12]

[13]

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