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Anxiety
- Evidence of involvement of the neurotransmitter GABA
(gamma-amino-butyric acid) and other implicated neurotransmitters
Jamie
Al-Nasir
12/02/2009 |
Abstract
This
paper looks at the evidence that the neurotransmitter GABA modulates
anxiety and also examines other neurotransmitters that are also
implicated in the pathophysiology of anxiety. The differences between
anxiety and fear, as well as anxiety and anxiety disorders is also
outlined with examples of approaches to treatment. The main focus of
attention is given to some of the specific neuronal pathways and
transmitters implicated, and we will examine the neuropharmacology of
processes underlying anxiety. Additionally, the evidence for the
involvement of these systems is also discussed along with drugs that are
used or could be potentially used to modulate them.
Introduction
What
is anxiety?
Before
we proceed to look into the neuropharmacological role of GABA and the
other neurotransmitters possibly implicated in the pathophysiology of
anxiety, it is necessary to start with a working definition and
understanding of what anxiety is, as well as its similarities and
differences to fear.
“Anxiety is a normal part of the response to a challenging or
threatening situation...Anxiety symptoms include palpitations, sweating,
trembling and feelings of fear and panic”. (Lader & Uhde, p.7).
According to Higgins and George, Anxiety serves as a mechanism to handle
adverse situations. It can be conceptualised as the brain’s alarm
system firing in response to perceived danger. The characteristic
responses including avoidance, hyper vigilance, and increased arousal
are implemented to avoid harm. (Higgins & George, p239) On
the reverse cover of his book, part of a clinical psychology series
entitled Anxiety, Professor Rachman, a leading expert on anxiety
disorders writes the following: -
“Anxiety
is a pervasive and significant negative effect that is a central feature
of many psychological problems, including those that were frequently
called "neuroses"...Anxiety is one of the most prominent and
pervasive emotions, and large numbers of people are distressed by
inappropriate or excessive anxiety.”
(Rachman, 1998)
Anxiety
vs Fear
The
main difference between anxiety and fear is aptly explained by Rachman,
as follows:
“Fear
has a specific focus, is episodic and recedes or ceases when the danger
is removed from the person, or the person from the danger...whereas
anxiety tends to be pervasive and persistent with uncertain points of
onset and offset.”
Anxiety
vs anxiety disorder
As
we can see from the above definitions of anxiety, its appearance during
certain situations is often a beneficial behavioural and physiological
strategy in helping the individual to adapt to meet the demands of a
challenging situation. This group of physiological changes, often termed
the “fight or flight response”, involves stimulation of the
sympathetic arm of the autonomic nervous system to cope with increased
physical and mental demand. Since both the sympathetic and
parasympathetic arms of the autonomic nervous system work in tandem it
follows that brief episodes of anxiety are a part of normal day-to-day
functioning.
The
trigger for anxiety is often a psychological one, i.e. “perceived
danger” as mentioned by Higgins and George, and this means
there will be subjective variation between how different individuals
react to the same stimuli. It is when anxiety symptoms are persistent,
disproportional to the situation and cause marked distress and
impairment to the patient that pharmacological intervention may be
required.
Learned fear
response; its’ transduction from stimuli to symptoms
An
area of the brain known as the Amygdala is responsible for emotional
processing, learned fear response (i.e. conversion of sensory stimuli
into neurological response). Sensory stimuli (i.e. visual & audible)
passes along two circuits of interest, one is the thalamo-cortical route
and this is involved in full transmission of the sensory data to the
cortex for “higher-level” processing. The second route, from the
thalamus to the amygdala is of even more relevance to our discussion as
it is responsible for the transmission of a compacted, rudimentary
version of the same sensory data that travelled on the thalamo-cortical
route. The reason for this and its’ relation to anxiety, is this
faster transmission route facilitates the intevention of the amygdala,
allowing it to activate a neuronal response to stress given a
“percieved” danger, usually based on previous learning. For evidence
for the amygdalas’ role in the processing of emotional memories and
the learned fear response please refer to Higgins
and George, p.241-243.
During
such a stressful event, the amygdala co-ordinates with a nucleus in the
brain stem known as the locus ceruleus which activates these
physiological changes utilising nor-adrenaline
(US Surgeon General, chapter 4), which we shall discuss later.
Approaches
towards the understanding and treatment of anxiety disorders
– the old and the new
Psychoanalytical
The
founder of psychoanalytical theory, a renowned German neurologist,
Sigmund Freud posited that persistent anxiety was due to an overwhelmed
Ego. The Ego, Id (Pronounced
Eye-Dee) and Super-Ego are Freud’s constructs that represent
conscious, preconscious and unconscious processes; namely that of the
conscious will (Ego), instinctual drives for aggression and pleasure
(Id), and what we call moral conscience (Super-Ego). This proposed
overwhelmed Ego state could, to use Freud’s terminology, result from a
pathologically harsh SuperEgo acting to “repress” (i.e. block) the
demands of the Id (drives for pleasure, aggression) with the Ego unable
to satisfy the id’s instinctual demands, resulting in anxiety.
Although
Freud is often criticised for lack of reproducible results in treatment
and for discrepancies in his case histories, psychoanalytical based
theories are useful in trying to assign a symbolic meaning to states of
intense mental distress especially where intrapsychic conflict is
concerned. The main concerns with Psychoanalytical treatment of anxiety
disorders is that it often takes many years of talking-based therapy
when the patient is often under immediate distress that requires
alleviation – something often better achieved by direct
pharmacological intervention (i.e. with benzodiazepines or anxiolytics).
Behavioural
On
the basis of behavioural studies it is postulated that anxiety is a
conditioned and learned response and often responds to controlled
exposure to the problematic stimuli, a treatment methodology known as
ERP, exposure response prevention. This form of treatment serves to
break the cycle of avoidant behaviour resulting in reinforcement of
mal-adaptive coping strategies. (Lader & Uhde, p. 61) through
re-training the learned fear response mentioned earlier.
It
would be interesting to understand in greater detail the neurochemical
changes and activity within the brain that occur during such treatment
sessions, especially in to Obsessive compulsive spectrum disorders where
patients are conditioned to resist indulging in their compulsive
behaviour, since it is at these specific times that marked states of
anxiety occur in sufferers. Current studies along these lines implicate
the serotonergic system, basal ganglia and CTSC circuitry, which we will
discuss later.
How Psychiatry
treats anxiety
Psychiatry
is a clinically based discipline and utilises a diagnostic protocol
known as the DSM (Diagnostics and Statistics Manual) of mental
disorders. The current version, the DSM-IV categorizes anxiety into a
range of different disorders, namely GAD (generalised anxiety disorder),
panic disorder, PTSD (Post traumatic stress disorder), social anxiety
disorder, and OCD (obsessive compulsive disorder). These categorisations
are of significant relevance to this article as we shall see later.
The
DSM is a useful tool in deciding how to define a patients mental state,
however it does have it’s disadvantages: “It is a categorical
classification where a dimensional system would be preferable, and it
encourages the unfortunate idea that all problems with anxiety are
pathological—that they are indeed mental disorders” (Rachman)
Psychiatry
relies heavily on the understanding of neurochemistry and
neuropharmacology, and with greater understanding of the
neurotransmitters and pathways involved can practically implement drug
treatment of anxiety disorders.
Neuronal Pathways
and their neurotransmitters
The
role of GABA (γ-Amino-Butyric Acid)

(Figure 1.0)
GABA
molecule
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GABA,
the only Gamma amino acid (the others are -beta in relation to
the amino functional group), is an inhibitory neurotransmitter
found in high concentrations throughout the brain. It is most
abundant in the nigrostriatal system (10μmol/g of tissue)
and to a lesser extent in the grey matter (2-5μmol/g of
tissue). Both the widespread distribution of GABA throughout the
brain and the sensitivity of most neurones to its action are
indicative of its “blanket like” inhibitory effects.
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GABA
receptors that the GABA neurotransmitter acts on are heteropentameric,
consisting of five sub-units. There are two main types of which numerous
variations exist; GABAA which mediates the fast response and
GABAB which mediates the slow response. There is some
controversy of a third proposed type of receptor GABAC, some
advocate it being an entirely separate class whilst others view it as a
variant of GABAA. It is noteworthy that GABAC is
insensitive to benzodiazepines and barbiturates.
(Figure
2.0, left)
–Bird’s eye view of heteropentameric GABAA receptor,
showing it’s five sub-units, notice the Cl- ion flowing
through the channel (the center lumen) (Figure 2.0, right) –
Side-on view of the GABAA receptor as it is located across
the neuronal membrane.
GABA
acts on the GABAA receptor to increase the conductance of
chloride ions through the neuronal membrane thereby hyperpolarising
post-synaptic neurones and thus reducing their excitation. Additionally
GABA acts on the GABAB receptor to inhibit voltage gated
calcium channels (reducing neurotransmitter release) and by opening
potassium channels (reducing excitability). (Rang & Dale, p487).
Noteworthy is that GABA receptors are abundant in the amygdala, which as
we discussed earlier triggers the “fight or flight” response. (LeDeux, 1992)
Evidence of the
anti-anxiety effect of GABA; The involvement of the GABAergic system in
anxiety
In
terms of endogenous phenomena, as mentioned earlier, GABA is well
distributed within the brain and a large number of neurones are
sensitive to its inhibitory effects. In addition dysregulation of GABA
may lead to mania due to “unopposed” excitatory neurotransmitters. (Pharmacy
Review, p880).
Evidence
GABAergic involvement in modulating anxiety is that certain classes of
drugs such as the Benzodiazepines, Barbiturates and Alcohol all bind to
GABA receptors to increase its’ post-synaptic inhibitory effect and
reduce anxiety. Benzodiazepines bind allosterically to the GABA receptor
and have their own binding site. Additionally,
Benzodiazepine inverse agonists such as Flumazenil decrease effects of
GABA and cause anxiety. Anxiety may be brought on in non-anxious
subjects through the administration of Bicuculline, a competitive
antagonist of GABA and Picrotoxin a non-competitive GABA antagonist. The
former (now obsolete) was used to stimulate the respiratory system in
cases of respiratory depression (note that overdose of benzodiazepines
causes respiratory depression). (Rang & Dale)
In
terms of GABA receptors’ involvement in anxiety, apart from the
examples described above, one theory is that mutation in GABA receptors
predisposes individual to anxiety, although there is not much conclusive
research on this. (Higgins & George) Additionally the
dysregulation (particularly down-regulation) of GABA receptors in
Alcoholics, and Alcohol withdrawal was shown to cause marked anxiety. (Dargham,
Krystal, Anjilvel et al) and this further illustrates the role of
the GABAergic system in modulating anxiety.
Other
pathways and neurotransmitters implicated in the pathogenesis of anxiety
Earlier
we looked at the DSM-IV diagnostic criteria, and mentioned its
significance to our discussion. It so happens, and it would be fair for
us to surmise based on the mass of research that has been conducted,
that for each of the specific anxiety disorders in the DSM-IV criteria a
certain specific pathway or neurotransmitter is theoretically
implicated.
In
a broader view of anxiety, there are at least five neurotransmitters
that are “peturbed”, namely GABA, nor-adrenaline, serotonin,
corticotropin-releasing hormone (CRH), and cholecystokinin (Coplan &
Lydiard 1998; Rush et al., 1998). The interaction between these
neurotransmitters is carefully orchestrated in the brain and changes in
one neurotransmitter system elicit changes in another. All of these
neurotransmitters have become important targets for therapeutic agents
either already marketed or in development. (US
Surgeon General).
Nor-adrenaline

(Figure 3.0)
Noradrenaline
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Evidence
for the role of the neurotransmitter Nor-adrenaline in anxiety
(and depression) comes from studies such as the original “The Catecholamine
Hypothesis of Affective Disorders” posited by Schildkraut
in 1965. It was shown that an increased concentration of
Nor-adrenalines’ metabolite MHPG
(4-Methoxy-3-Hydroxy-Phenyl-Glycol) was found in the CSF
(Cerebral Spinal Fluid) of anxiety sufferers and lower levels of
MHPG in the CSF samples of depressed patients. (Lambert and
Kinsley).
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As
we discussed earlier, the “fight or flight” response, once triggered
by the amygdala is
co-ordinated via the Locus Ceruleus and modulated via Nor-adrenaline.
Nor-adrenaline also triggers the release of CRF, corticotropin releasing
factor that activates the HPA (Hypothalamo-Pituitary-Adrenal) axis to
release stress hormones such as Nor-Adrenaline, Adrenaline and Cortisol.
It follows that abnormally high levels of Nor-adrenaline increases
symptoms of anxiety. (Higgins
& George)
Corticotropin
releasing factor
CRF
(Corticotrophin releasing factor) is secreted by the anterior pituitary
and induces the release of other hormones such as ACTH (Adreno-Corticotropic
Hormone). CRF and several types of CRF receptors are involved in the
coordinatation of behavioral, endocrine, autonomic, and immune responses
to stress. Antagonists of CRF (acting on CRF-Receptor 1) such as
Antalarmin are currently being intensively studied in order to test
their efficacy as anxiolytics. In animal tests, orally administered
Antalarmin was shown to significantly influence the behavioural and
physiologic responses to intense social stressors. Antalarmin
significantly decreased their stress-induced plasma concentrations of
ACTH and cortisol whilst increasing their exploratory behaviour (showing
a decrease in anxiety response). The animals’ anxiety scores were
significantly lower after CRF-Receptor 1 antagonism than in controls. (Zoumakis,
Rice, Gold et al, 2006)
Serotonin and the
Serotonergic system

(Figure
4.0)
Serotonin
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The
serotonergic system is interesting because it has 7 distinct
subtypes of receptor for a single neurotransmitter, Serotonin.
Serotonin is an inhibitory neurotransmitter involved in
suppressing stress response (amongst other roles). There are
different classes of antidepressant drugs that modulate
serotonin and increase the concentration of free serotonin at
the synaptic cleft, namely the Tricyclics, MAOIs (Monoamine
Oxidase Inhibitors), SSRIs (Selective Serotonin Inhibitors) and
the newer SNRIs (Serotonin and Noradreanline re-uptake
inhibitors). The SSRI class of
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drugs
are routinely prescribed for long-term treatment of anxiety disorders
such as Panic disorder, obsessive compulsive disorder & Social
Phobia, and the new SNRI Venlafaxine is indicated for generalised
anxiety disorder (BNF 56).
The
OC spectrum (obsessive-compulsive) disorders have also been linked with
dysregulation of the serotonergic system. In these disorders there is a
specific neuronal circuit implicated in a more elucid way, namely the
CTSC, Cortical-Striatal-Thalamo-Cortical circuitry and its dysregulation
that is believed to be responsible for the persistant thoughts/images
and compulsive actions associated with the anxiety. (Stein
and Fineberg, 2007, p.29-30 & 75-76).
Clomipramine,
an older drug belonging to the Tricyclic class is well known for its
Anti-obsessional effects and due to its potentially serious side-effects
is often reserved for use in cases of OC-spectrum disorder non
responsive to SSRIs. Benzodiazepines have limited anti-obsessional
effects but do alleviate associated anxiety. In situations where
patients are distressed and impaired by their obsessive compulsive
anxiety clinicians will often advocate the use of benzodiazepines with
an SSRI to allow time for SSRIs to exert anti-obsessional effects, i.e.
to remove the anxiety component earlier on.
Of
interest is a finding that of sudden OCD onset in otherwise healthy
children post streptococcal infection. The condition known as PANDAS (Paediatric
Auto-immune Disorder Associated with Streptococcal) is thought to be
caused by an immune response which causes damage to the basal ganglia.
Further
evidence of the serotonergic systems’ involvment in modulating anxiety
comes from the drug Buspirone, an anxiolytic that does not act on GABA
receptors and is void of the sedating and withdrawal effects of
benzodiazepines. Buspirone, in a class of it’s own, is a 5HT1A partial
agonist, and has been found to be useful treating anxiety for longer
than 6 week limit of benzodiazepines. However it takes 2 weeks for
treatment effects to manifest and cannot be substituted for
benzodiazepines to counter their withdrawal effects.
Cholecystokinin
Cholecystokinin is
a peptide hormone and is recognised neurotransmitter in that it is known
to modulate neuronal activity. CCK4 (Cholecystokinin tetrapeptide) is a
smaller molecular
version

(Figure
5.0)
CCK-4
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of
CCK which has been found to exacerbate and increase anxiety in
sufferers of anxiety disorders as compared with normal controls.
CCK4 is a potent angiogenic in that as little as dose
of as little as 50μg is sufficient to induce severe anxiety
symptoms. (Eser et al)
Furthermore, CCK antagonists that selectively bind to CCK-B
receptors (the target of CCK4) reduce anxiety in sufferers of a
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number
of anxiety disorders. It is believed that future anxiolytic drugs will
work via selective CCK-B antagonism. (Lader
and Uhde, p.26)
Adenosine
(Inhibitory effect on Anxiety)

(Figure
6.0)
Adenosine
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Like
GABA, Adenosine is another amino acid neurotransmitter. It slows
the heart-rate and decreases the stress response; it serves an
inhibitory role.
Caffeine, due to its similar structure, binds to adenosine
receptors blocking the inhibitory effect of Adenosine. Chronic
consumption of caffeine containing foods causes an up-regulation
of adenosine receptors.
Interestingly
adnosine also modulates the effects of other neurotransmitters
such as GABA, dopamine and glutamine.
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Neurokinins
(Substance P)
Substance
P is a neuropeptide belonging to a broad family of related peptides
known as
tachykinins that share a common sequence of residues. Characteristic of many neuropeptides is

(Figure
7.0)
Substance P
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an
amine group at the C-terminal.
Substance
P can trigger the “fight or flight” response by acting on NK
receptors in the amygdala. Various studies on animals
demonstrate that antagonists of Substance P are able to inhibit
this response via blockade of NK receptors and are therefore of
importance as therapeutic agents in the treatment of of anxiety
disorders. (Ebner, Rupniak et al)
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Conclusion
As
we have seen, there is an interesting overlap between different
phenomenon, cognitive, behavioural and neurochemical and therefore
disciplines (psychology, behavioural and pharmacology), i.e. psychiatry.
The
pharmacists’ understanding of anxiety disorders and knowledge of the
different treatment approaches available to the patient is therefore
invaluable especially since this healthcare profession is most
accessible to the general public.
Anxiety
is a neurologically complex phenomenon,with numerous neurotransmitter
systems interacting with each other (Lader & Udhe, p.26). We
have seen that overall, the GABAergic system acts to provide a blanket
like inhibitory effect on neuronal activity and is therefore of
consequence for pharmacological action.
Benzodiazepines
are an extremely useful anxiolytic. Drugs in the same class exhibit
marked variation in Half-life and rate of elimination as well as some
such as diazepam having active metabolites. These characteristics allow
a particular drug of this class to be chosen based on its profile.
However, they are associated with withdrawal symptoms and dependency and
have the potential for abuse.
As
discussed, specific systems however are implicated in certain anxiety
disorders, and therefore more specifically acting agents are often
required, as we have seen with the serotonergic system, SSRIs, and
Clomipramine. As more detailed knowledge and studies is becomes
available there is likely to be the potential to target specific
dysregulations and neurochemical abnormalities and therefore ironically
the future looks brighter for those suffering from anxiety disorders!
References
- Stein,
D.J, Fineberg, N. A. (2007), Oxford Psychiatry Library: Obsessive
Compulsive Disorder, Oxford: Oxford university Press
- Rachman,
S. (1998), Clinical Psychology: Anxiety
- Higgins,
E.S. & George M.S. (2007) The Neuroscience of Clinical
Psychiatry: The Pathophysiology of Behavior and Mental Illness, 1st
Edition
- Trimble,
M.R. (1996) Biological Psychiatry, 2nd Edition
- The
US Surgeon General, Mental Health: A report by the Surgeon
General – Chapter 4, Anxiety disorders
[Online]: http://www.surgeongeneral.gov/library/mentalhealth/chapter4/sec2_1.html
- LeDeux
(1992) The amygdala and emotional memory
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Lundbeck Institute Online (2005) Anxiety – Anxiety Disorders, Denmark:
The Lundbeck Institute
[Online]: http://www.cnsforum.com
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D. et al. (2005). "Panic
Induction with Cholecystokinin-Tetrapeptide (CCK-4) Increases Plasma
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