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Question
Describe the mechanism of pharmacological action of benzodiazepine drugs in the treatment of clinical anxiety (50%) and discuss some of the most recent drug targets for the treatment of clinical anxiety (50%).

Answer
Clinical anxiety disorders
Clinical anxiety disorders are described as psychological and physiological conditions characterized by somatic, emotional, cognitive, and behavioural changes in which an individual experiences negative emotions, fear independently of external events and demonstrates behavioural changes.
Clinical anxiety disorders include the following conditions:
Panic Disorders which are described as recurrent, unexpected (out of the blue) feelings of fear or discomfort associated with, racing or pounding heart, sweating, trembling, shortness of breath, feeling unrest or detached, and fear of dying.
Specific Phobias (fear) are marked, excessive, unreasonable or persistent fear of a specific objects (dogs, spiders, injections, thunder) or situation (flying, heights, driving, bridges).
Social Phobia (Social Anxiety Disorder) are fears associated with social or performance situations. Patients with social phobia commonly fear, public speaking, being the centre of attention, meeting new people, being assertive, voicing their opinion
Obsessive-Compulsive Disorder (OCD) are persistent (obsessive), intrusive and distressing thoughts or images. Obsessions can include fears of contaminations, throwing things away, making mistakes. In response to the obsessions, the patient engages in compulsions or rituals to help decrease or prevent the anxiety
Generalized Anxiety Disorder (GAD) are excessive and difficult to control worry about a number of events or matters. May include worrying about ones/others health, world affairs, minor matters (getting to places on time, fixing things around the house). These lead the patient to become restless, having difficulty concentrating and developing sleep disturbance.
Posttraumatic Stress Disorder (PTSD) are recalls of a traumatic event that involved an actual threat of death or serious injury in which the patient experienced intense fear and helplessness.

Pathophysiology of anxiety and anxiolytic drugs
Clinical anxiety develops as a result of dysregulated inhibitory GABAnergicergic neurotransmission in certain areas of the brain that include the amygdale, hippocampus, pre-frontal cortex and anterior cingulate cortex. It has been shown that in anxiety there is a reduction in GABAnegric inhibitory neurotransmission. Based on the above dysregulated neurotransmitter functions benzodiazepines (BZP) as GABAA receptor agonists are used to treat clinical anxiety. The pharmacological actions of BZPs include, reduction of anxiety and aggression, sedation and induction of sleep, reduction of muscle tone and coordination, anticonvulsant effect and anterograde amnesia. BZPs work by binding to a regulatory site on GABAA receptors, helping to enhance the GABA-mediated opening of chloride ion channels leading to the development of inhibition of transmission (IPSP).
GABAA is an iontropic pentamer receptor formed from the combination five alpha, beta and gamma subunits. BZPs work by binding allosterically to the alpha subunits. Binding to alpha2 subunits mediates the anxiolytic action of BZPs and binding to alpha1 mediates their hypnotic action. Therefore, the rationale behind the development of BZP drugs that are able to induce anxyiolysis, but not hypnosis would be to develop drugs that selectively bind to the alpha2 (but not alpha1) subunit on the GABAA receptor.
Research paper

Overview on the paper by Li et al (2015):
In the research paper by Li et al (2015), the effect of the GABA-B receptor positive modulator BHF177 was investigated in rat models of clinical anxiety. In this paper the authors differentiate between conditioned and non-conditioned fear models of anxiety, in which BHF177 showed efficacy against non-conditioned fear models. In comparison to BHF177, two direct GABA-B receptor agonists, Baclofen and CGP44532 did not have anxiolytic effects, while demonstrating sedative action.

Background leading into this research:
In the introduction the authors justify this work by affirming the significance of targeting the inhibitory GABAnergic neurotransmission in the treatment of clinical anxiety and that the GABA-A receptor has been for many decades the predominant target by many clinically important drugs that include the benzodiazepine drugs, which have limited efficacy due to the development of addiction and dependency. The authors provide further justification for this research on the GABA-B receptor in models of clinical anxiety by citing some preliminary research in which Baclofen has been shown to have effiacacy against anxiety associated with alcohol withdrawal, panic disorder and post-traumatic stress and to lack abuse potential. The authors also discuss data in which mice with a genetic deletion of the GABAB1 receptor subunit showed increased anxiety-like behaviour in the light-dark box, elevated zero maze and staircase test anxiety models and that mice with a deletion in the GABAB2 receptor subunit also exhibit increased anxiety-like behavior in the light-dark box procedure.

Justifications for this research:
If Baclofen works in animal models of anxiety, why then test BHF177 as a positive allosteric modulator? The authors justify this point by stating that Baclofen has a narrow therapeutic window and to have several undesirable effects (sedation, muscle relaxation and hypothermia) and that unlike direct agonists, which bind on the extracellular domain of the receptor, positive allosteric modulators, which bind to the transcellular domain of the GABA-B receptor hence are expected to alter GABAnergic synaptic activity, are expected to have a better therapeutic profile. The authors go on to justify the use of BHF177 in their studies by providing some pharmacodynamic (pEC50 5.78 – 9.6┬ÁM) and pharmacokinetic (good CNS bioavailability) properties of this compound.

Mythological considerations:
Leading into the methods section, the authors describe the anxiety models used in this study; light-enhanced startle (LES) and fear-potentiated startle (FPS) tests both of which assess passive reflex reactivity and startle responses in unconditioned (not primed or trained) rats. Such startle responses have good translational potential for anxiolytic drugs as these responses are conserved across species. However there is no mention on the similarity or differences in these responses between rats (used in the current study) and humans, which would give this work more validity and credit. A good point to bring up here is the inclusion of several clinically active anxiolytic drugs such as busiprone in this study for comparison purposes. In the methods section, the authors provide detailed information on the animal models used, drugs, experimental design, and data analysis. The author cite several papers to justify the doses used for each and every drug used in this study. However there is no mention on the reason for the varied pre-treatment times/durations for each drug.

Results:
Rats showed 2 different responses to light-enhanced startle, high and low responders. As seen in Figure 1B, BHF had no effect on the low responders, but showed a dose-dependent decrease in the startle response in the high responder group of rats. Busiprone at 1 and 3 mg/kg showed a similar profile to BHF177 in the light-enhanced startle model in the low and high responder rats (Figure 2B). It is not clear why busiprone was used at only 2 doses. The authors report that Baclofen significantly reduce startle responding independently of light condition and that CGP44532 inhibited startle reactivity in the dark-dark but not dark-light session. However the authors did not mention what the significance of these results are (Supplementary)

Type Of Service: Academic Paper writing
Type Of assignment: Essay
Subject: Health and Medicine
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Academic Level: Undergraduate
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