ANTIANXIETY PROPERTY OF BASELLA ALBA LINN LEAVES EXTRACT IN EXPERIMENTAL ANIMALS - REVIEW OF LITERATURE
3. REVIEW OF LITERATURE
WHO defines
herbal medicine as finished, labeled medicinal products that contain as active
ingredients, the aerial or underground parts of plants or other plant material,
or combinations thereof, whether in the crude state or as plant preparations.
Plant materials include juice, gums, fatty oils, and any other substances of
this nature.
Review of
literature was made from various sources, including e-sources, to access
various pharmacological and chemical natures of herbs. For the sake of
convenience, it is divided into three parts.
In part I, preliminary details of herbs viz.,
taxonomical data, vernacular names, geographical distribution, chemical nature,
constituents, traditional uses, folk lore uses and reported pharmacological
activities of plant.
In part II
contains detail information of anxiety disorders from various journals and web
sources (abstract data bases) etc., relevant for current study have been
reviewed.
In part III,
animal models for screening and evaluating anxiolytic potential of plant with
including rodent models of anxiety.
PART-I
3.1.1 About plant:
Botanical Classification50:
Ø Kingdom: Plantae
Ø Order: Caryophyllales
Ø Family : Basellaceae
Ø Genus: Basella
Ø Species:
Basella alba
Ø Binomial name: Basella alba L.
Vernacular
Names50:
Ø English: Malabar-, Malabar climbing-, Ceylon-, Indian-,
East-Indian-, spinach
Ø Gujarati: Poi ni bhaji
Ø Kannada: Basale
soppu
Ø Marathi: Mayalu
Ø Bengali: Pui shak
Basella
alba is a wildly cultivated,
cool season vegetable with climbing growth habit. It is a succulent,
branched, smooth, twining herbaceous vine, several meters in length. Stems are
purplish or green. Leaves are fleshy, ovate or heart-shaped, 5 to 12 cms long,
stalked, tapering to a pointed tip with a cordate base. Spikes are axillary,
solitary, 5-29 cm long. Fruit is fleshy, stalkless, ovoid or spherical, 5-6 mm
long, and purple when mature. Mainly leaves and stems are used for the
medicinal purpose. 50
Ethanobotany
Basella
alba has been used for many of
its useful product from ancient times. Nowadays its properties have been
utilized for the extraction of some useful material so that it can be used for
the beneficial human activities. Some of the uses of this plant parts in the
cure of certain problems occurred to humans has been explained here:
Ø The paste of root of red Basella alba along
with rice washed water is taken in the morning in empty stomach for one month to cure irregular periods by the rural people of Orissa, India 34,35.
Ø Leaves of Basella alba is used for the treatment of hypertension by Nigerians in Lagos36
Ø .Basella alba is used as antimalarial in
cameroonian
folk
medicine37.
Ø The daily consumption of Indian spinach has a positive effect on
vitamin A stores in populations at high risk of vitamin A deficiency38.
Ø The cooked roots and leaves have been reported to be used in the
treatment of diarrhoea and as laxative, respectively38
Ø The flowers are used as an antidote for poisons38.
Ø It is also a safe aperient for pregnant women and its decoction has
been used to alleviate labour38.Basella
alba traditionally claimed to increase libido39
Ø Aqueous extract of Basella alba leaves increases red blood cell count in albino rats38.
Ø Basella
alba leaves extract possess
anti inflammatory activity40.
Ø Betacyanin present in Basella alba fruit gives antioxidant activity31.
Ø Basella alba extracts significantly
enhances testosterone production in bull and rat Leydig cells in a concentration-dependent
manner41.
Ø Extract of aerial parts of Basella alba shows CNS depressant activity30.
Ø Basella
alba leaves extract possess
gastro protective action42.
Pharmacognosy and
Phytochemistry
The
relevant work has not been carried out on B. alba till date, and hence
research focusing on pharmacognostic profile is undertaken in near future. The
chemical composition of the leaf extract include: proteins, fat, vitamin A,
vitamin C, vitamin E, vitamin K, vitamin B9 (folic acid), riboflavin, niacin,
thiamine and minerals such as calcium, magnesium and iron. Kaempherol is the
flavonoid present in Basella alba at a concentration of 1.4mg/100g. 51Basella
mucilage is viscous with low swelling capacity. Its pH is good for skin
(5.3-5.4). Partial purification of Basella mucilage proved to be
composed of polysaccharide with D-galactose as a major compound. The cell
toxicity to Chang liver cell shows tendency of mild toxicity. The gel
preparation of Basella mucilage provide good stability that serve for
further development as cosmetic and medicine for skin diseases. Basella alba
contains basellasaponins 52, amino acid such as arginine,
leucine, isoleucine, lysine, threonine and tryptophan 53, peptide,
phenolic compounds in various extracts. 54Basella fruit
contains gomphrenin derivative which is betalain pigment. 55
The mucilage of B. alba consists of mixture of polysaccharides 56, and starch-type
glucan which can be separated by starch iodine complex. 57 Plant
mucilage is composed of water soluble polysaccharide, which functions as water
retention, germination, food reservoir and secondary metabolite storage24.
Basella mucilage was also proposed for the applications of medicine and
cosmetics. The antityrosinase which was accorded to traditional used for anti
freckle is tested. Antioxidant activity related to the inflammation mechanisms
caused by free radicals is assayed. Then formulation of gel from Basella
mucilage was prepared which can be used for further development of cosmetic and
anti-inflammatory purposes as topical usage. Anthocyanins are a natural pigment
which is responsible for the blue, purple,
violet and red colours in fruits, flowers, stem and leaves. 55
Antioxidant activities, total phenolic, flavonoid and
ascorbic acid contents of B. alba commonly consumed in Nigeria are
determined. A high and significant correlation existed between antioxidant
activity and total phenolic content indicating that total phenolic content is
the major contributor to the antioxidant activity of the plant. Ascorbic acid
fairly correlated with antioxidant and phenolic content. 59 B.
alba contains β carotene. 60 The phytochemical contents of the
leafy vegetables serve as supplements for food and also have the potential to
improve the health status of its users as a result of the presence of various
compounds vital for good health. Their fiber content provides bulk in the diet
and this helps to reduce the intake of starchy foods, enhances gastrointestinal
function, prevents constipation and may thus reduce the incidence of metabolic
diseases like maturity onset, diabetes mellitus and hypercholesterolemia. They
are also potent antibiotics, antihypertensives and blood building agents and
improve fertility in females when eaten in soups. Total oxalate, soluble
oxalate and nitrate were determined for leaves of Basella alba L. grown
on soils of medium and high fertility. Higher soil fertility resulted in
increased total oxalate in Basella. Leaves grown on high-fertility soil
had more nitrate than those from medium fertility. 61
Pharmacology
In vitro pharmacology62
Mucilaginous
substances from Basella alba was studied for in vitro glucose
entrapment and compared to glucomannan powder. The mucilage solution
showed gel-forming characteristics and concentration response on glucose
entrapment activity. Anthocyanin pigments are reported to have many therapeutic
benefits including vasoprotective and anti-inflammatory properties, anti
cancer, chemo protective and anti-neoplastic properties, reversing age related
deficits and useful in controlling oxidative stress during pregnancies complicated by intrauterine growth
retardation.
It
has also been suggested that anthocyanins has got the ability to stabilize DNA triple helical
complexes and can also protect the
chloroplast against high light intensities. In the present
scenario, there is a rising demand for natural sources of food colorants with
nutraceutical benefits with anthocyanins. Antioxidant assays were done by
enzymatic assay methods like Super oxide dismutase, Catalase and Peroxidase, Basella
alba showed higher activity. Crude
aqueous extract possess mild antioxidant, and no tyrosinase inhibitory
activity. Basella alba is used traditionally in Thailand for
anti-inflammatory, cytotoxicity and antioxidant activities of anti-inflammatory
remedies. This allowed the selection of lead extracts for various
ethnopharmacological researches by Nisarat et al. The methanolic extracts exhibited marked
antimicrobial activity against gram positive and
gram negative bacteria and fungi. Basella alba showed good inhibitory
activity against Aspergillus niger.
The leaf extracts (methanolic extract and aqueous extract) of Basella
alba Linn.var. alba were investigated for in-vitro anti-inflammatory
activity by human red blood cell membrane stabilization method (HRBC). Aqueous
extract showed significant in vitro anti-inflammatory activity compared
to methanolic extract. The in-vitro anti inflammatory activity of the
extracts were concentration dependent, with the increasing concentration, the
activity is also increased. Basella alba L. leaf extracts exhibited membrane
stabilization effect by inhibiting hypotonicity induced lysis of erythrocyte
membrane. The erythrocyte membrane is analogous to the lysosomal membrane and
its stabilization implies that the extract may as well stabilize lysosomal
membranes. Stabilization of lysosomal membrane is important in limiting the
inflammatory response by preventing the release of lysosomal constituents of
activated neutrophil such as bactericidal enzymes and proteases, which cause
further tissue inflammation and damage upon extracellular release. Antioxidant and antimutagenic activities of
plant extracts act as functional foods for cancer prevention. Antioxidant
activity was expressed as the ability of each extract to scavenge the free radicals
1, 1-diphenyl-2-picrylhydrazyl (DPPH). Antimutagenic activity was evaluated
with the Ames test using Salmonella typhimurium strains TA 98 and TA
100. Basella alba Linn. extract had the strongest antimutagenicity with
both strains of S. typhimurium with high percentage of inhibition
value. Flavonoids and phenolic compounds from the herbal extracts are
proposed to be antioxidant and antimutagenic agents, respectively. The apparent
antioxidant and antimutagenic activities of the plant further suggests their
potential usefulness in cancer prevention. The possible mechanisms may
be classified as: Firstly, B. alba extracts might include the blocking
of the mutagen transfer into the cytosol by phenolic binding or insertion into
the transporters of the outer membrane of the cell. Secondly, B. alba
extracts modified the permeability for
mutagens across bacterial membranes.
In-vivo pharmacology62
The effects of the aqueous leaf
extract of Basella alba on haematological and biochemical parameters
were studied in Wistar strain albino rats. The results showed that B. alba
significantly increased red blood cell count, white blood cell count, packed
cell volume, haemoglobin concentration and platelet count. However, the extract
significantly reduced the activity of the liver enzymes such as ALP, ALT and AST.
Totally, adding B. alba leaves as part of daily diet may reduce anemia
and maintain good health. Basella alba is a plant used in traditional
medicine in the West Cameroon region to treat sexual asthenia and infertility
in man. Its methanol extracts stimulated testosterone production in testicular
fractions and Leydig cell cultures, and in normal adult albino male rats. In
Leydig cells, testosterone is partly metabolized into estradiol by aromatase.
The stimulatory effect on estradiol level may result from its effect on
aromatase gene transcription and translation into a biologically active
enzyme.CNS depressant activity of the aerial parts of B. alba was
determined by Anandarajagopal et al.
Petroleum ether, methanol and aqueous extracts were prepared from dried
aerial parts of Basella alba by cold maceration method and CNS (Central Nervous System) depressant activity was
evaluated by pentobarbitone induced sleeping time test, open field test and
hole cross test in mice. Methanol extract showed highly significant CNS depressant activity than other extracts
tested. An attempt was made to screen the
anti-inflammatory activity of Basella alba leaf in experimentally
induced inflammations in rats. The aim was met by two methods, one is
carrageenan induced paw edema and another is cotton pellet granuloma. Basella
alba extract showed a significant activity at a dose of 500 mg/kg. Basella
alba possesses a good anti-inflammatory activity and shows a dose depending
activity. Basella alba has been used from a long time back for the treatment
of many diseases like dysentery, diarrhea, anemia, cancer etc. It has also been
utilized for different kinds of healing activities. Various kinds of extract
like aqueous extract, methanolic extract, petroleum extract, chloroform extract
has been prepared from different parts of the plant has been utilized in the
treatment of many diseases since time immortal all over the world. India and
China are the two major countries harbouring this plant and utilizing it for
the benefit of human being. It also consists of compounds that can be used for
the preparation of medicine by pharmacological industry. The chemical
composition of the leaf extract has been found to be: proteins, fat, vitamin A,
vitamin C, vitamin E, vitamin K, vitamin B9 (folic acid), riboflavin, niacin,
thiamine and minerals such as calcium, magnesium and iron. Some unique
constituents of the plant are basellasaponins, kaempherol and betalain. The
pharmacological activities of Basella alba has been tested by both in-vitro
as well as in-vivo methods. Antioxidant activity, antimutagenic activity
has been carried out by the scientist to explore the dynamics of the plant for
the advancement in the treatment of the diseases. CNS depressant activity, anti
inflammatory activity has also been observed for this plant. Knowing that
plants have a large number of chemical substances, which have several
pharmacological actions, we should exploit more natural products, which in the
future could show the cure for many illnesses. It is hoped that compilation of
this review will serve as a guide to all those involved in this particular
field of research.
3.1.2
The other plants having Anxiolytic activities :
There have been several reports of natural drugs which possessing
anxiolytic activities . Plant extracts, teas and food provide an ever
increasing number of constituents and ingredients which seem to interact
functionally with different organ systems of body including brain 32.
Following research work of plant extracts reveals that their
constituents posses anxiolytic activity and this has lead us to investigate
anxiolytic activity of Basella alba leaves
extracts.
- Methanol and ethyl acetate extract of Eriobotrya japonica leaf
extracts contains flavinoids, at dose 300 mg/kg markedly increased the
average time spent in the open arm of EPM hence show anxiolytic effect64
- Ethanolic extract of Pisonia grandis R. Br leaves contains
flavinoids, posses anxiolytic activity at doses 150 mg/kg and 300 mg/kg in
mice65.
- Anxiolytic effect of hydroalcoholic extract of teprosia
purpuria (L) pers on EPM, EZM, Y-Maze and hole / board at doses 200 mg/kg
and 400 mg/kg in swiss alwino mice66.
- Anxiolytic effect of Equisetum arvense Linn. Extract could be
related at least in part to flavinoids or specifically to apigenin, which
recognise and bind with high affinity BZD site of GABA receptor and exerting
anxiolytic and slightly sedative effect67.
- Anxiolytic effect of acute administration of ursolic acid,
active principle of Ocimum Sanctum on EPM, and L/D tests at doses 0.1 and
0.2 mg/kg in rats68.
- Hydroalcoholic extract of Boerhaavia diffusa leaves contains
flavinods, exhibited anxiolytic activity in rats at a dose 100 mg/kg on
EPM69.
- Evaluation of anxiolytic activity of ethanolic extract from the
leaves of Trichosanthes cucumerina L. in mice at doses 200 and 400 mg/kg70.
- Effect of the active constituent of Crocus sativus L., crocins, in light/dark animal model of
anxiety in mice shows significant results at 50mg/kg dose 71.
- Anxiolytic effect of saponins from Panax quinquefolium on EPM, L/D, HB, in mice shows significant
results at 25 – 100mg/kg dose 72.
- Evaluation of anxiolytic properties of Gotukola- (Centella asiatica) extracts and
asiaticoside- is active triterpenes found in this plant in rat behavioral
models 73.
- Anxiolytic effect of Stachys
lavandulifolia Vahl on the elevated plus maze model at 100mg/kg dose
on mice 74.
- Lemon grass (Cymbopogon
citratus) A placebo-controlled, double-blind RCT of Lemon grass
extract included 18 patients suffering from trait anxiety. The extract was
administered as a single dose of abafado (Brazilian lemon grass tea), and
its effects were quantified 30 min later under the stress of a cognitive
test. The results revealed no significant inter-group differences to
suggest an anxiolytic effect 75.
- Passion flowers (Passiflora incarnata) in a double-blind RCT,
32 patients with generalized anxiety disorder were randomized to receive
45 drops of a passionflower tincture or 30 mg oxazepam per day. After 4
days of treatment, no significant differences in terms of anxiety levels
were noted. Patients treated with passionflower reported fewer adverse
effects than those receiving the synthetic anxiolytic 76.
- Aqueous extract of dried Ginkgo leaves have been reported to
inhibit MAO-A and MAO-B.Ginkgo biloba (Ginkgoaceae)
leaves contain active constituent flavonol glycosides and it shows effect
on behavior, learning and memory. It also shows anxiolytic effect at
0.01-10 mg/kg dose range 77.
- Anxiolytic effects of the aqueous extract of Uncaria
rhynchophylla78.
- Evidence that total extract of Hypericum perforatum affects
Exploratory behavior and exerts anxiolytic effects in Rats79.
- Coriandrum sativum: evaluation of
its anxiolytic effect in the elevated plus maze80.
- The anxiolytic-like effects of Aloysia polystachya (Griseb.)
Moldenke (Verbenaceae) in mice81.
- Kaempferol from the leaves of Apocynum venetum possesses anxiolytic activities in the
elevated plus maze test in mice82.
- Flavonoids from Tilia Americana with
anxiolytic activity in plus-maze test83.
- Anxiolytic-like effect of Sonchus oleraceus L. in mice84.
- Barakol: A potential
anxiolytic extracted from Cassia
siamea85.
- Comparative studies on anxiolytic activities and flavonoid
compositions of Passiflora edulis ‘edulis’ and Passiflora edulis
‘flavicarpa86.
- An
anxiolytic effect of Dolichandrone Falcata leaves extract in
experimental animals87.
- Anxiolytic Activity of Seed Extract of Caesalpinia Bonducella (Roxb) In Laboratory Animals88.
- Studies on the anxiolytic effect of Sponndias Mombin L
(Anacardiaceae) extracts89.
- Anxiolytic effects of Elaeocarpus sphaericus fruits on the
elevated plus-maze model of anxiety in mice may be related to their
content of flavinoids90.
- Anxiolytic effect of hydroethanolic extract of Drymaria cordata
L. Willd91.
- Bioactivity-directed separation of an anxiolytic fraction from
Aethusa cynapium Linn, flavinoids constituents present in the plant may
responsible for its anxiolytic activity92.
- Methanolic extract of Sapindus Mukorossi Gaertn. contains
flavinoids, may be responsible for anxiolytic activity in mice93.
- Anxiolytic and sedative effects of Byrsocapus coccineus Schum.
and Thonn. (Connaraceae) extract94.
- Evaluation of anti-anxiety activity of Actaea spicata Linn95.
PART-II
3.2.
ANXIETY:
3.2.1 Introduction:
Anxiety disorders
are conditions in which extreme, often disabling, anxiety or fear is the shared
primary symptom. Normal anxiety may be defined as “a diffuse, unpleasant, vague
sense of apprehension, often accompanied by autonomic symptoms-such as
headaches, palpitations, tightness in the chest, restlessness, mild stomach
discomfort that can be an appropriate response to a threatening situation or
stimulus” 96.
Whereas fear
is considered specific and targeted, anxiety is considered more diffuse and
unfocused. Pathological anxiety and fear, as compared to normal symptoms, are
diagnosable conditions when the anxiety, fear, or both cause significant
distress, interfere with functioning, or are marked by time consumption 97.
3.2.2 Epidemiology:
Several large,
methodologically rigorous epidemiological studies have indicated that anxiety
disorders are one of the most prevalent categories of childhood and adolescent
psychopathology 98. The most recent prevalence estimates from a
paediatric primary care sample including more than 700 families suggest that
approximately 20% of children (ages 8–17 years) were above the clinical cut off
on a brief anxiety screen measure by Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition (DSM-IV) 99.
Although
comorbidity rates vary depending upon the primary diagnosis, there exists a
strong comorbidity among anxiety disorders in youth 100. For
example, an epidemiological study of paediatric OCD revealed that 84% of youth
diagnosed with OCD had comorbid disorders, including major depression (62%),
social phobia (38%), alcohol dependence (24%), and dysthymia (22%) 101.
The most common comorbid diagnoses include other anxiety disorders and
depressive disorders 102. Additionally, children with anxiety
disorders frequently experience other psychiatric conditions, including
attention deficit/hyperactivity disorder and the disruptive disorders 103.
3.2.3 Etiology:
The etiology of child and adolescent anxiety may be of a biological
and/or learned nature. Indeed, researchers posit that anxiety arises from a
complex interaction of specific characteristics related to the child (e.g.,
biological, psychological, and genetic factors) and his or her environment
(e.g., conditioning, observational learning, family relations, traumatic events
104. There are an abundance of theoretical models that would define
child and adolescent anxiety, some are as follows.
Biological Model:
Within a
biological model of etiology, researchers have investigated genetic influences
as well as neurobiological structures and circuits. A recent meta-analysis of
the genetic epidemiology of anxiety disorders demonstrated that PD, phobias,
OCD, and GAD aggregate in families and concluded that genetic factors have a
moderate influence on the development of anxiety disorders 105.
Researchers have suggested that, although clearly not the only contributing
influences, genetic factors may help us understand why certain individuals
exposed to similar experiences have different responses and outcomes concerning
the development of pathological anxiety 106.
Research aimed
at identifying specific brain areas and circuits underlying anxiety disorders
has provided support for neurobiological influences in anxiety. The most
support for neuroanatomical influences has come from research investigating the
amygdala's role in fear conditioning. Research in this area has implicated the
amygdala in the pathophysiology of anxiety disorders 107.
Neurochemical factors have also been implicated in the development of anxiety
symptoms. Abnormal functions of serotonin, norepinephrine, dopamine, and
γ-aminobutyric acid systems as well as abnormal chemoreceptor reactivity have
all been implicated in anxiety 108.
Cognitive–Behavioral Model:
Within a
cognitive–behavioural model, abnormal thoughts, feelings, and behaviours are
described as reactions that have been learned as a result of conditioning and
observation 109. A behavioural theorist highlighted behavioural
conditioning as an important etiological factor in the development and
maintenance of anxiety and posited that an individual associates a threatening
stimulus with a non threatening stimulus so that the latter by itself triggers
anxiety. Once the fearful or anxious reaction has been learned through
classical conditioning, the fear or anxiety is maintained through the operant
mechanism of negative reinforcement.
Negative reinforcement is manifested by avoidance learning, escape
learning, or both. Escape learning involves terminating an aversive situation,
whereas avoidance learning involves avoiding fear- or anxiety-provoking
situations. Consequently, without opportunities for new learning provided by
exposure, the fear or anxiety does not extinguish. This process of acquisition
and maintenance of fears is known as Mowrer’s two factor theory 110.
In addition to
the two-factor theory, observational learning influences the development of
anxiety. Children learn about anxiety-provoking situations by observing others
experience such situations or by acquiring information through activities like
reading or watching the news on television 111. Furthermore, they
are capable of retaining and reproducing event memories acquired via
observational learning 112.
Ecological Models:
Ecological
models focus on the impact of the family system and other environmental
influences on the development of anxiety disorders and particularly highlight
the bidirectional relationships among child, family, and other environmental
contributions to anxiety. For example, research has revealed relationships
among levels of child temperamental characteristics (i.e., behavioural
inhibition), insecure parent–child attachment, and anxious and controlling
parenting styles 113. Parental modelling of fearful and anxious
expressions and behaviours has also been found to contribute to the development
of anxiety in children 114.
3.2.4 Types of Anxiety Disorders:
The core symptoms for six anxiety disorders are listed in the
Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition, Text
Revision (DSM-IV-TR) 97, are described below.
Separation Anxiety Disorder (SAD):
SAD is
characterized by excessive worry about separation from another person who
represents safety for the affected child, typically a parent. In new,
unfamiliar, or feared situations, youth with SAD are often dependent on their
safety figure. Common features of the disorder include excessive demonstration
of distress upon real or threatened separation (e.g., tantrums, crying, somatic
complaints), fear of harm or permanent separation from caretaker, and fear of
getting lost, kidnapped, or dying. School refusal is a common symptom of SAD, occurring
in approximately 75% of children with the diagnosis 115.
Within
the clinical setting, children with SAD may present with sleep problems, such
as nightmares. Furthermore, these children may experience a number of somatic
complaints (e.g., stomach-ache) related to the distress associated with SAD.
The presence of clingy and whiny behaviour within the clinical setting may also
be an indicator of SAD. The clinical presentation of SAD may vary with age,
with younger children exhibiting excessive crying and temper tantrums upon
separation from the attachment figure and older children displaying social
withdrawal and manipulative behaviour to avoid school or separation 116.
Panic Disorder (PD):
PD
is characterized by both the actual occurrence of panic attacks and persistent
worry and vigilance about prospective symptoms of another panic attack. Panic
attacks involve an overwhelming fear of being in danger for no apparent reason
as well as physiological symptoms such as pounding heart or chest pain, sweating,
trembling or shaking, shortness of breath or choking sensation, nausea, dizziness, feelings of unreality or depersonalization,
and fear of going crazy or dying 97.
The most
common symptoms reported are palpitations, shortness of breath, sweating, faintness,
and weakness. In adolescence, chest pain, flushes, trembling, headache, and
vertigo are also commonly reported symptoms. In youth, cognitive symptoms are
less common, with the most frequent cognitive symptoms being a fear of losing
control. As with adults, there is a strong association between PD and
agoraphobia in youth 115.
The presenting
problem for youth with PD will pertain to one or more of the many physiological
symptoms of panic attacks. Parents of youth with PD may also report agoraphobic
symptoms related to their child's panic attacks. Unlike in adulthood,
catastrophic interpretations of physiological symptoms may not be part of the
clinical presentation 117. PD is less common in childhood than in
adolescence, and the clinical presentation of PD varies across the
developmental span 118. Specifically, younger children's panic
attacks are often related to particular triggering events whereas adolescent's
panic attacks are more often reported as unexpected and not linked to a
particular antecedent event 117.
Social Phobia:
Social
phobia, or the fear of embarrassment or negative evaluation in social or
performance situations, is manifested by the avoidance of situations in which
the child fears acting in a humiliating or embarrassing manner 97.
Three main factors in the development and maintenance of social phobia are
highlighted: (a) cognitive biases (e.g., beliefs that individuals will
predictably interact with others in a manner that will elicit rejection and/or
negative evaluation from others), (b) deficits in social skills, and (c)
operant conditioning (e.g., negative reinforcement for avoidance behaviours 119.
Within the
clinical setting, youth with social phobia may present as shy and socially
withdrawn and may exhibit noticeable anxious–somatic symptoms, including
blushing, sweating, and shaking, when interacting with unfamiliar people.
Limited eye contact is also quite common. In extreme presentations, youth may
have difficulty with articulation or may become mute. Interpersonal deficits
may be evident when interacting with socially phobic youth, who often report
having few close friendships with their peers. Whereas younger children with
social phobia tend to hide behind adults or attempt to physically escape from a
social situation, elder children tend to remain in the social situation but
with few efforts to engage or participate 120.
Obsessive–Compulsive Disorder (OCD):
OCD
is characterized by recurring intrusive thoughts or excessive worries
(obsessions) and/or activities or habits the person feels driven to perform to
reduce anxiety (compulsions). The obsessions and/or compulsions are
distressing, time-consuming (more than one hour per day), or debilitating
(interfere with normal functioning) 97.
The most
common obsessive themes in the paediatric population include fears of contamination (e.g., dirt, germs, toxins);
preoccupations about harm to self or others; the need for symmetry, exactness,
and order; concerns with religious or moral conduct (e.g., being concerned with
committing a sin); lucky or unlucky numbers; and preoccupations concerning
forbidden sexual or aggressive thoughts. The most common compulsive themes
include cleaning or decontamination rituals (e.g., excessive washing, bathing,
or grooming); checking, counting, repeating, straightening, and routinized
behaviours (e.g., doors, locks, homework, appliances); confessing, praying, and
reassurance seeking; touching, tapping, and rubbing; measures to prevent harm
to self or others; and hoarding and collecting 121.
Youth with OCD
may present to health professionals with a number of physical or behavioural
complaints that are consequences of obsessive–compulsive symptoms. For example,
dermatological problems may arise secondary to compulsive hand washing or skin
picking. Weight loss may occur due to refusal to eat certain foods that are
perceived as contaminated. Compulsive avoidance of bathrooms due to
contamination fears may lead to the development of secondary encopresis or
enuresis. Additionally, youth may present to their dentists with bleeding gums
as a result of excessive teeth cleaning 122.
Research has
supported a distinction between early- and late-onset OCD, such that
early-onset (i.e., prepubertal) OCD is more likely to occur in males, to be
characterized by symptom presentations characteristic of compulsions without
obsessions and more primitive compulsions (i.e., touching, tapping, rubbing),
to have comorbid tic symptomatology, and to involve family members in their
rituals 123.
Posttraumatic Stress Disorder (PTSD):
PTSD
is characterized by recurrent symptoms of anxiety related to past trauma, such
as physical abuse or natural disasters 97. Cognitive, autonomic, and
behavioural symptoms of anxiety are typically involved. The main manifestations
of traumatic reactions include repetitive and intrusive thoughts about the
trauma, flashbacks or nightmares in which the child reexperiences the trauma,
heightened arousal, avoidance of stimuli associated with the trauma, sleep
disturbances, and separation difficulties Cognitive changes, such as
difficulties in concentration and memory problems, are also common.
Additionally, a child may report a sense of foreshortened future or a premature
awareness of his or her own mortality 124. This disorder always
involves significant distress and can result in marked interference with
functioning 97.
Primary
complaints of youth with PTSD in the clinical setting may involve physiological
arousal symptoms such as difficulty sleeping or exaggerated startle response.
Parents of youth with PTSD may report a temporal association between a
particular traumatic event and the onset of atypical behaviour such as sexual
acting out or aggression. It is common for youth with PTSD to be reluctant
about discussing the traumatic event, and their descriptions of the traumatic
event often lack a discussion of their associated emotional experience 120.
Generalized Anxiety Disorder (GAD):
GAD involves diffuse excessive
worry over a wide variety of routine daily activities such as school
performance, social concerns, or family interaction. It is characterized by 6
months or more of chronic, exaggerated worry and tension that are unfounded or
much more severe than the anxiety that most people experience. The excessively
anxious thoughts generally involve thoughts related to negative,
uncontrollable, or catastrophic outcomes. Studies of youth with GAD have
demonstrated that youth selectively attend to negative and the threat-related
information 125.
Avoidant
behaviour is common for situations that provoke anxiety. GAD may be accompanied
by physiological or somatic symptoms, including trembling, twitching, muscle
tension, irritability, hot flashes, nausea, frequent urination and fatigue 125.
Symptoms must interfere with some aspect of daily functioning to meet the
diagnostic criteria of GAD 97. Within the clinical setting, nurses
may observe children with GAD engage in excessive attempts to seek approval
from their parents or other adults. Whereas younger children report anxiety
pertaining to specific situations, older children increasingly report
“generalized” anxiety about a number of different situations 120.
3.2.5 Symptoms of anxiety:
According to
Lang's multiple-systems theory of emotion, symptoms are of a cognitive (e.g.,
worry thoughts), physiological (e.g., racing heart rate), or behavioural (e.g.,
avoidance) nature. The cognitive component of anxiety is related to the anxious
thoughts that develop in response to cognitive distortions in the attention,
interpretation, and memory components of information processing 127.
The
physiological component of anxiety disorders consists of the associated
autonomic or somatic sensations. Although individuals experience physiological
arousal symptoms in response to feared situations, individuals with anxiety
disorders experience physiological symptoms that are excessive in duration or
intensity for the particular situation or stimulus 128.
Sleep-related
problems are more prevalent among clinically anxious youth and are associated
with increased anxiety severity and interference in family functioning. In a
recent study of sleep-related problems in children with generalized anxiety
disorder (GAD), separation anxiety disorder (SAD), and/or social phobia. Alfano
reported that the most common sleep-related problems were insomnia, nightmares,
and refusal/reluctance to sleep alone 129.
The followings
are the complete list of the most common physiological symptoms associated with
anxiety disorders 97.
Systems |
|
Symptoms |
Cardiac |
- |
Accelerated
heart rate, Heart palpitations, Chest pain Shortness
of breath, Heart pounding. |
Gastrointestinal |
- |
Difficulty
swallowing, Nausea, Diarrhea, Gastrointestinal
discomfort, Frequent urination. |
Respiratory
|
- |
Shortness
of breath, Smothering sensation, Choking sensation, Dry mouth. |
Neurological
|
- |
Numbness,
Tingling,Trembling/Shaking |
Temperature
regulation |
- |
Sweating,
Hot flashes,Chills, Cold, clammy hands |
Vestibular
system |
- |
Dizziness,
Lightheadedness, Faintness, Feeling unsteady |
Sleep
related problem |
- |
Insomnia,
Reluctance/Refusal to sleep alone, Nightmares, Talks/Walks in sleep,
Excessive tiredness |
Other
|
- |
Exaggerated
startle response, Muscle tension |
The
behavioural component of anxiety refers to the action that individuals take to
prevent exposure to feared stimuli or to reduce anxiety associated with
exposure to the feared stimuli. Among the most common behavioural symptoms
associated with the anxiety disorders is avoidance, in which individuals avoid
specific stimuli (e.g., bridges) or situations (e.g., public speaking) to
prevent anticipated harm. Avoidance often leads to impairment in maintaining
normal routines or in family, academic and/or social domains of
functioning.Another behavioural symptom associated primarily with
obsessive–compulsive disorder (OCD) is the engagement of rituals (e.g., hand
washing) that serve to reduce anxiety. These rituals are either excessive or
unrealistic strategies for preventing the feared situation from occurring 130.
3.2.6 Treatment 131:
Antianxiety drugs include the
benzodiazepines and the nonbenzodiazepines. Benzodiazepines:
- Alprazolam.
- Chlordiazepoxide.
- Clorazepate.
- Diazepam.
- Lorazepam.
- Oxazepam
- Flurazepam
All benzodiazepines are classified as Schedule
IV in the Controlled Substances
Act by the Drug Enforcement Agency
(DEA) regulations.
Nonbenzodiazepines:
- Zolpidem
- Zolpiclone
- Zoleplon
Atypical Anxiolytics:
- Buspirone
- Ipsapirone
- Gepirone
Mechanism of Action:
Benzodiazepines (once thought to be acting as 'non-specific
depressants') act selectively on GABAA receptors, which mediate fast
inhibitory synaptic transmission throughout the central nervous system (CNS).
Benzodiazepines enhance the response to GABA by facilitating the opening of
GABA-activated chloride channels. They bind specifically to a regulatory site
of the receptor, distinct from the GABA-binding site, and act allosterically to
increase the affinity of GABA for the receptor. Single-channel recordings show
an increase in the frequency of channel opening by a given concentration of
GABA, but no change in the conductance or mean open time, consistent with an
effect on GABA binding rather than the channel-gating mechanism.
Benzodiazepines do not affect receptors for other amino
acids, such
as glycine or
glutamate 4.
Uses:
Antianxiety drugs are used in the
management of anxiety disorders and short-term treatment of the symptoms of
anxiety. Long-term use of these drugs is usually not recommended because
prolonged therapy can result in drug dependence and serious withdrawal
symptoms. Some of these drugs may have additional uses as sedatives, muscle
relaxants, anticonvulsants, and in the treatment of alcohol withdrawal. For
example, clorazepate and diazepam are used as anticonvulsants4.
Adverse reactions:
Transient,
mild drowsiness is commonly seen during the first few days of treatment with
antianxiety drugs. Discontinuation of therapy because of the undesirable
effects of the antianxiety agent is rare. Depending on The severity of anxiety
or other circumstances, it may be desirable to allow some degree of sedation to
occur during early therapy. Other adverse reactions include lethargy, apathy,
fatigue, disorientation, anger, restlessness, constipation, diarrhoea, dry
mouth, nausea, visual disturbances, and incontinence. Some adverse Reactions
may be seen only when higher dosages are used4.
Dependence:
Long-term use
of antianxiety drugs may result in physical drug dependence (addiction) and
tolerance (increasingly larger dosages required to obtain the desired effect).
Withdrawal syndrome has occurred after as little as 4 to 6 weeks of therapy
with a benzodiazepine. Withdrawal syndrome is more likely to occur when the
benzodiazepine is taken for 3 months or more and is abruptly discontinued. The
antianxiety drugs must never be discontinued abruptly because withdrawal
symptoms, which can be extremely severe, may occur. The onset of withdrawal
symptoms is usually within 1 to 10 days after discontinuing the drug, with the
duration of withdrawal symptoms from 5 days to 1 month4.
Symptoms of Withdrawal4:
Increased
anxiety Fatigue
Hypersomnia Metallic
taste
Concentration difficulties Fatigue
Headache Tremors
Numbness in
the extremities Nausea
Sweating Muscle
tension and cramps
Psychoses Hallucinations
Memory
impairment Convulsions
(possible)
Contraindications4:
The
antianxiety drugs are contraindicated in patients with known hypersensitivity,
psychoses, acute narrow-angle glaucoma, and shock. These drugs are also
contraindicated in patients in a coma or with acute alcoholic intoxication with
depression of vital signs. The benzodiazepines are Pregnancy Category D drugs,
and the drug metabolite freely crosses the placenta. Use of these drugs during
pregnancy is contraindicated because of the risk of birth defects or neonatal
withdrawal syndrome manifested by irritability tremors and respiratory problems.
The benzodiazepines are contraindicated during labor because of reports of
floppy infant syndrome manifested by sucking difficulties, lethargy, and
hypotonia. Lactating women should also avoid the benzodiazepines because of the
effect on the infant, who becomes lethargic and loses weight.
Precautions4:
Antianxiety
drugs are used cautiously in patients with impaired liver or kidney function
and in elderly and debilitated patients. The metabolism of the benzodiazepines
is slowed in the liver, increasing the risk of benzodiazepine toxicity.
Lorazepam and oxazepam are the only benzodiazepines whose elimination is not
significantly affected by liver metabolism. Two nonbenzodiazepines are
Pregnancy Category B drugs (buspirone and zolpidem); hydroxyzine is a Pregnancy
Category C drug. No adequate studies have been performed in pregnant women.
These drugs should be used during pregnancy only when clearly needed and when
the potential good would outweigh any harm to the fetus.
Interactions4
Central
nervous system (CNS) depressants such as alcohol, narcotic analgesics,
tricyclic antidepressants, and the antipsychotic drugs, increase the sedative
effects of the antianxiety drugs. Combination of any of these drugs with the
antianxiety drugs is dangerous and can cause serious respiratory depression and
profound sedation. Ingestion of alcohol with the antianxiety drugs can cause
convulsions and coma. Buspirone causes fewer additives CNS depression than do
the other antianxiety drugs. However, it is recommended that concurrent use
with a CNS depressant be avoided. Buspirone may increase serum digoxin levels,
which increases the risk of digitalis toxicity.
PART - III
3.3 The use of animal behavioural
models to assess anxiety
3.3.1 Introduction:
Animal models of psychiatric diseases
attempt to capture various feature of the human condition, from behavioral and
physiological changes that are indicative of the emotional state to the disease
and the effects of therapeutic intervention. According to Mc.Kinney, animal
models are “experimental preparation developed in one species for the purpose
of studying phenomena occurring in another species. In the case of animal
models in human psychopathology one seeks to develop syndromes in animals which
resemble those of human in certain ways in order to study selected aspects of
human psychopathology”. Currently, the third criteria is regarded as having
heuristic value because the central nervous processes that lead to anxiety
still have to be elucidated; therefore this criterion is regarded as desirable,
but not essential. Thus, in an ideal and perfect model one would like to have
causative conditions, symptom profiles and treatment response identical to
those seen in the human disease state 132.
The
anti-anxiety and antipsychotic indicate a qualitative distinction in the
clinical use and mode of action of the drug. Pathological anxiety in man has
been defined by its interference with normal functions, by manifestations of
somatic disorders, emotional discomfort, interference with productivity at
work, etc. This complex characterization of anxiety in man already indicates
the difficulties to find appropriate pharmacological models. Therefore, several
tests have to be performed to find a spectrum of activities which can be considered
to be predictive for therapeutic efficacy in patients.
For in vivo
studies, most investigators use a battery of anticonvulsive tests,
anti-aggressive tests and evaluation of conditioned behaviour. Most of the
actions of benzodiazepines are thought to be mediated by potentiation of
g-amino-butyric acid (GABA). Two subtypes of GABA receptors (GABAA
and GABAB) have been described. Moreover, specific binding sites for
benzodiazepines have been discovered near these GABA receptors in various areas
of the brain. These sites occur in a macromolecular complex that includes
GABA-receptors, benzodiazepine receptors and receptors for other drugs, and a
chloride channel. The benzodiazepines potentiate the neurophysiological actions
of GABA at the chloride ion channel by increasing the binding of GABA to GABAA
receptors. This implies that the GABAA receptor is involved in
anxiety and that its direct activation would have an anxiolytic effect. Based
in these findings various in vitro tests have been developed 133.
3.3.2 Animal models of
anxiety:
Anxiety enables the individual to recognize danger and to deal
with an unknown or vague internal or external threat. Fear is a similar
alerting signal, but differs from anxiety in that it is regarded as response to
a known, definite, nonconflictual threat. Clinicians assessing anxiety
distinguish between “normal” and “pathological” anxiety. Normal anxiety is an
advantageous response to a threatening situation that accompanies many aspects
of daily life. By contrast, pathological anxiety is an inappropriate response
to an external or internal stimulus. In light of the high complexity of anxiety
disorders and the comorbidity with major depressive disorder, the chance of
succeeding in developing comprehensive animal models that accurately reflect
the relative influences of contributing factors in human is probably quite poor134.
3.3.3 Validity criteria
for animal models of anxiety disorders:-
Numerous procedures with experimental animals have been developed to
facilitate preclinical research on the behavioral pharmacology of anxiety. The
discovery of benzodiazepines (BZs) about 50 years ago, and their therapeutic
and commercial success in the treatment of anxiety, has stimulated the
development of a number of experimental test procedures. Because BZs were the only effective anxiolytic drugs at that
time, the predictive validity of the animal models has been mainly based on
their ability to detect the pharmacological action of BZs and related compound.
Later, clinicians discovered that patients can become addicted to BZs, and
consequently paid more attention to non-benzodiazepine anxiolytics. However, it
turned out that these new drugs were a challenge to the validity of the
existing screening models. The best known example is Buspirone, a clinically
effective serotonin (5-HT) 1A receptor partial agonist whose
anxiolytic potential was missed by conventional screening procedures in
animals, in particular conflict tests in rats, and was only recognized during
clinical assessment for possible anti psychotic efficacy135. This
was the time when unconditioned conflict tests such as the elevated plus maze
were developed136.
A further complication appeared when it became evident that
anxiety is not a unitary phenomenon, but could be divided into various forms
including normal or state anxiety, on the one hand and pathological or trait
anxiety on the other hand. According to today’s terminology, pathological
anxiety should not be considered just as an excess of normal anxiety, but it
rather appears that the pathological forms have a different neurobiological
basis. Furthermore, the various forms of human disorders have been shown to be
differentially sensitive to pharmacological treatment.
Most of the experimental paradigms involve exposure of animals
to external stimuli (e.g., cues paired with foot shock, bright light for
rodents or exposure to a predator) or internal stimuli (e.g., drugs) that are
assumed to induce anxiety. Because none of these models involves pathological anxiety,
that is an anxiety-like state independent of an obvious (external) stimulus, Lister described them as animal
models of state anxiety. In these
experimental set ups, subjects experience normal anxiety at a particular moment
in time and their emotional state is just potentiated by an external anxiogenic
stimulus.
Despite these problems
in the use of animals to study anxiety, these models have been, and are still,
indispensable for neurobiological/ neuropharmacological research. Much of our
understanding of the neural substrates of anxiety has emerged from studies
employing animal models that emulate aspects of the presumed etiology,
physiology, and behavioral expression of fear and anxiety. A survey of current
literature reveals a confusing diversity of experimental procedures with more
than 30 behavioural paradigms claiming face, construct, and/or predictive
validity as animal models of anxiety disorders.
I. Models for normal anxiety:
An overview of the existing models for normal anxiety is
schematically represented (scheme 1). As proposed by Griebel137, these
models are distinguished according to the following categories: (i. Models
based on unconditioned responses; and ii. Models based on conditioned
responses). The first category is further divided into four subgroups: models
based on exploratory behaviour in rodents (e.g., elevated plus maze and the
light-dark test), models based on social behaviour in rodents (social
interaction test) or in non-human primates (human threat), and models based on
somatic stress reactions (e.g., stress-induced hyperthermia).
In
the fourth group, other paradigms are summarized which do not fit easily into
the other sub groups such as the anxiety/fear test battery.
1.
Elevated plus maze (EPM):
Today, the majority of studies using animal
models of normal or state anxiety employ unconditioned-based procedures that
rely on the natural behavior of the animals. Among these, the elevated plus
maze has become one of the most popular behavioral tests136, 138.
Its popularity is mainly due to practical reasons, because the elevated plus
maze permits a quick screening of potential anxiety-modulating drugs or of
genetically modified laboratory rodents without training the animals or
involvement of complex schedules139. The elevated maze consists of two opposite open and two closed
alleys. When the animal is taken straight from its home cage it explores the
different alleys and the total number of entries is counted. Anxiolytics help
to overcome the fear induced inhibition of open-alley exploration, while
anxiogenic agents suppress open-alley exploration. Unfortunately, the plus maze
behavior patterns may be influenced by variations in the parameters that are
not always obvious, e.g., the species or strain investigated, housing conditions,
day time of the testing, intensity of the light, and scoring method140.
As a result, a vast number of studies employing the elevated plus maze have
yielded inconsistent findings. To overcome these problems, Rodgers and Johnson
have developed an “ethological” version of the mouse plus maze that
incorporates species specific behavioral postures (e.g., risk assessment, head
dipping) together with the conventional spatiotemporal measures of open arm
avoidance141.
The elevated zero
maze is a recent modification of the plus maze designed for investigations in
mice. It is an elevated annular platform with two opposite open and two closed
quadrants. Animals are placed in one of the closed quadrants designated as the
starting quadrant and anxiety related behaviors are recorded142.
Open field test:
Rodents are
night-active animals that prefer darkness and avoid bright areas. This has to
be taken in to account when using the open field test, a very common
observation method. For the open field test, the animal is taken from its home
cage and placed in a novel and relatively lit arena that is large enough for
the animal to move around in. The area is divided in to peripheral and central
units, and locomotion and rearing can be recorded in these units. Because of
its photophobicity, the animal avoids the brightly lit open spaces and prefers
to stay close to the walls. Exploratory or locomotor behavior is therefore
measured while determining the distance from the wall, and autonomic activity
such as urination and defecation is evaluated. By using infrared beam array
system, locomotion, rearing and time spent in certain predefined areas of the
open field are measured automatically. One also has to consider that the
behavior displayed in the open field- similar to that in the elevated plus maze
is remarkably sensitive to a variety of internal and external factors143.
3. Social interaction
test:-
The social
interaction test that was originally introduced by File144, and that
quantifies the level of social behavior between animals, is a valuable
behavioral paradigm for testing anxiolytic drugs. Experimental animals
unfamiliar to each other are placed
in pairs in to an open arena. When the arena is brightly illuminated the
situation is aversion for the animals, so that they reduce their social
interactions. Anxiolytic usually increase the time spent in social interaction.
4. Fear-potentiated
startle test:
David and colleagues have
utilized the fear-potentiated startle test to study the fear circuitry in the
brain. This test includes a classical fear conditioning in that a stimulus
(e.g., light) is paired with a mild electric foot shock. During the
fear-conditioning phase a light stimulus signals the occurrence of a shock. The
startle response is elicited by a loud noise, and its amplitude is augmented
when the light and the noise are presented together. BZs have anxiolytic
effects in this paradigm in that they inhibit the enhancement of the startle
response but do not block the startle response per se. Briefly, the paradigm involves placing the
animal in a cage equipped to measure the amplitude of the presence or absence
of a light previously paired with an electric shock. Animals that have already
been exposed to the shock-paired light show a greater startle response to the
noise in the presence of light than in its absence. Using this kind of
potentiated startle response as an operational measure, it was found that the
central nucleus of the amygdale and a variety of hypothalamic and brain stem
areas are involved in physiological (e.g., activation of the sympathetic and
the parasympathetic system, release of “stress hormones”) and behavioral
responses (e.g., changes in locomotors activity, freezing) that reflect fear
and anxiety145, 146.
5. Defense tests:-
Defensive behaviors in mammals are thought to
constitute a significant parameter that can be studied to understand human
emotional disorders, including anxiety147. These
behaviours occur in response to a number of threatening stimuli including
predators, attacks by nonspecific, or presence of dangerous objects. The Mouse
Defense Test Battery (MDTB) consists of an oval runway that allows the
extensive investigation of state anxiety following drug treatment148,149.
Specific situational and behavioural components of the anxiety defense
test battery, including reactivity to stimuli associated with potential threat
such as presentation of an anesthetized predator (a rat), are incorporated into
the MDTB. Drug experiments have demonstrated that anxiolytic compounds
generally tend to decrease defensive behaviours. These tests may thus represent a considerable methodological
improvement because a major concern with traditional animal models of state
anxiety that are based on single measures is that they are often unable to
discriminate between effects of different classes of anxiolytics.EPM and the
MDTB provide new tools to differentiate anxiolytic drugs of various classes
that induce specific behavioural profiles.
II. Animal models for pathological anxiety:
Pathological anxiety in humans is often an enduring feature of
the individual, at least in part due to a genetic predisposition. To model
genetically based anxiety, mice with target mutation in distinct genes were
created that exhibit phenotypic changes indicative of increased anxiety. In
addition, rat or mouse lines were bred to select for high or low emotional
reactivity.
The neurotransmitter 5-HT is centrally involved in the
neuropathology of many neuropsychiatric disorders. More than a dozen pharmacologically
distinct serotonin receptor sub types regulate a wide range of functions in
different brain areas and in the periphery of the body. There is
pharmacological and neuroanatomical evidence that at least one 5-HT receptor;
5-HT1A is involved in the regulation of anxiety like behaviors150,151.
Results of recent studies employing mutant mice with targeted deletions of the
5-HT1A receptor gene further support a role of this receptor in
anxiety151.
Further examples of models for pathological anxiety are mice
that were gene targeted for the corticotrophin-releasing factor (CFR) 152
or for the γ2 subunit of the GABAA receptor. This
receptor subunit is known to be essential in mediating the anxiolytic actions
of benzodiazepines153. An “anxious” phenotype was also observed in
mutant mice lacking the gene for the neuroactive peptide NPY154. At
first glance, these lines of mutant mice seem to provide a unique opportunity
to model pathological or trait anxiety. Moreover, compared with the state
anxiety, here anxiety is increased artificially by exposure to external
(aversive) stimuli, the new models seem be advantageous in that they may
represent a kind of “general anxiety” due to a certain genetic modification.
This sounds reasonable since genetic studies in humans have indicated that
there are genetic components contributing to the development of anxiety
disorders. However, one has to consider that in humans, the modulation of
anxiety processes involves multiple genes. In the future, the use of mice strains
that display elevated emotionality due to a distinct “genetic back ground” or
mice selected for their high levels of anxiety using gene targeting experiments
may lead to greater progress in our understanding of the neurobiological
substrate of anxiety. Such animals would exhibit increased anxiety not because
of a defect in a single gene, but because of a complex set of genes that result
in an enduring feature of the strain/individual, thus determining its phenotype
in combination with environment factors155.
Inbred strains which show
constantly high levels of anxiety/fearfulness have already been created. In
mice, the BALB/c strain has been considered to be a realistic model of trait
anxiety, which is probably not related to only one particular target gene but
to abnormalities in various neurotransmitter circuits such as the GABAergic,
dopaminergic and the opioid system155. Also in rats, several strains
of trait anxiety have been described, e.g., the Maudsley rat156, the
Wistar-Kyoto157, the Roman158, or the Sardinian
alcohol-preferring line159. Recently, two breeding lines were
generated from the same strain of Wister rats showing a maximum difference in
other behaviours as well as in physiological parameters not directly related to
anxiety. These two rat lines are now called high anxiety-related behaviour
(HAB) and low anxiety-related behaviour (LAB) 160. Their overall
performance in various behaviour tests suggests that selective breeding has
resulted in lines not only differing markedly in their innate anxiety-related
behaviour but also in stress-related behavioral performance, suggesting a close
link between the emotional evaluation of a novel and stressful situation and a
subject’s capability to cope with such situations.
In conclusion, animal
models are indispensable tools for research on the neurobiological mechanisms
underlying anxiety disorders and for the development of new anxiolytic drugs.
It appears that the use of several models, either successively or in parallel,
provides the greatest chance to elucidate the neurobiological processes of
psychiatric diseases and to identify new, effective anxiolytic compounds.
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