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)

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; GABA_A which mediates the fast response and GABA_B which mediates the slow response. There is some controversy of a third proposed type of receptor GABA_C, some advocate it being an entirely separate class whilst others view it as a variant of GABA_A. It is noteworthy that GABA_C is insensitive to benzodiazepines and barbiturates.

(Figure 2.0, left) –Bird’s eye view of heteropentameric GABA_A 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 GABA_A receptor as it is located across the neuronal membrane. 

GABA acts on the GABA_A 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 GABA_B 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

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

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

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)

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

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

1. Stein, D.J, Fineberg, N. A. (2007), Oxford Psychiatry Library: Obsessive Compulsive Disorder, Oxford: Oxford university Press
2. Rachman, S. (1998), Clinical Psychology: Anxiety
3. Higgins, E.S. & George M.S. (2007) The Neuroscience of Clinical Psychiatry: The Pathophysiology of Behavior and Mental Illness, 1^st Edition
4. Trimble, M.R. (1996) Biological Psychiatry, 2^nd Edition
5. 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
6. LeDeux (1992) The amygdala and emotional memory
7. The Lundbeck Institute Online (2005) Anxiety – Anxiety Disorders, Denmark: The Lundbeck Institute
   [Online]: http://www.cnsforum.com
8. Abi-Dargham A, Krystal JH, Anjilvel S, et al. Alterations of benzodiazepine receptors in type II alcoholic subjects measured with SPECT and [123I]iomazenil. American Journal of Psychiatry. 1998;155[11]:1550–1555.)
9. Eser D. et al. (2005). "Panic Induction with Cholecystokinin-Tetrapeptide (CCK-4) Increases Plasma Concentrations of the Neuroactive Steroid 3α, 5α Tetrahydrodeoxycorticosterone (3α, 5α-THDOC) in Healthy Volunteers".  Neuropsychopharmacology 30: 192
   [Online]: http://www.nature.com/npp/journal/v30/n1/pdf/1300572a.pdf.
10. Ebner K, Rupniak NM, Saria A, Singewald N. Substance P in the medial amygdala: emotional stress-sensitive release and modulation of anxiety-related behavior in rats. Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4280-5
11. Ashton, C.H. (2009), The Ashton Manual: Benzodiazepines: How they work and how to withdraw from them
    [Online] http://www.benzo.org.uk