The role of the Amygdala GABA receptors and benzodiazepines in anxiety

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Abstract Discussed is some of the research that has been conducted on the role of the amygdala in anxiety, as well as the role of GABA and benzodiazepines in anxiety. Research has indicated through amygdala lesions and stimulation that the amygdala does indeed play a major role in the expression of anxiety. Research has also indicated, through drug infusions to the amygdala, that benzodiazepines cause anxiolysis (by increasing GABA transmission), and that benzodiazepine antagonists increase anxiety (by decreasing GABA transmission). Also discussed are some limitations and problems found with benzodiazepine use. On the Role of the Amygdala in Anxiety and How Treatment is Effective The functional anatomy of anxiety involves amygdala-based neurocircuits with critical reciprocal connections to the medial prefrontal cortex (i.e. Mailizia, 1999). An understanding of the functional anatomy of anxiety allows for a new perspective on the various anxiety disorders. The neurotransmitters involved in these circuits are reviewed for their relevance to the pharmacologic choices in the treatment of anxiety (i.e. Kang, Wilson & Wilson, 2000). Much research has been conducted on gamma-aminobutyric acid (GABA) as it is the major inhibitory neurotransmitter in the mammalian Central Nervous System (CNS) (i.e. Vekovischeva, Haapalinna & Sarviharju, 1999). GABA participates in the regulation of neuronal excitability through specific membrane proteins (the GABAA receptors). The binding of GABA to these postsynaptic receptor results in an opening of chloride channel integrated in the receptor, which allows the entry of Cl-. As a consequence, this leads to the hyperpolarization of the recipient cell, which is allosterically modulated by a wide variety of chemical entities that interact with distinct binding sites at the GABAA receptor complex. One of the most thoroughly investigated modulatory sites is the benzodiazepine-binding site. The purpose of this paper is to examine some of the research that has been conducted on the relationship between the amygdala and anxiety. As well, the paper examines how benzodiazepines interact with GABAA receptors in the amygdala and the resulting effects on anxiety. The Amygdala and Its Role in Anxiety Anxiety is a fundamental emotion that is characterized by an increase in autonomic activity, motor tension, vigilance, and apprehension in response to a present danger or impending threat (Wolkowitz & Paul, 1985). While there is no complete theory of the biological basis of anxiety, there is considerable evidence that anxiety may be primarily modulated by limbic sysem structures (i.e. Davis & Shi, 1999), including the septum and the amygdala. The amygdala's contribution to emotional processes--particularly to the recognition of emotional events and the production of appropriate responses--is the most extensively investigated and best understood function of this part of the brain. The amygdala is a critical part of the circuitry involved in fear in rats, as well as in nonhuman primates (i.e. Hode, Ratomponirina, & Gobailles, 2000). Unfortunately, it has been difficult to study the involvement of the amygdala to anxiety in humans, due to ethical considerations and and due to the lack of a sufficient population of patients with brain damage restricted to the amygdala. However there is some evidence for the existence of similar mechanisms in humans (i.e. Mailiza, 1999). Recent reviews strongly support the working conclusion that the amygdaloid complex is a major brain site at which fear-inducing conditional associations can be acquired and can educe a physiological expression of fear (i.e. Pitkanen, Savander, & LeDoux, 1997). Evidence supporting the above claim can be seen in studies exploring the effects of electrical stimulation of the central nucleus of the amygdala which show a production of fear behaviour (i.e. Petrovitch & Swanson, 1997); as well as studies conducted on the effects of lesions on the amygdala. The assumptions underlying the above approaches of lesions and electrical stimulation is that behavioural changes observed following lesions or stimulations reflect the functions of the lesioned structures. For example, if a structure is involved in the expression of anxiety, then destruction of that structure should theoretically produce a disruption of normal anxiety reactions. Research conducted by Davis and Shi (1999) and others (i.e. Pitkanen et al., 1997) suggests that lesions of the amygdala can inhibit both unconditioned fear reactions and fear elicited by conditional associations. As well, an investigation by Moller, Wiklund, and Sommer (1997) indicates that specific nuclei in the amygdala and in other nearby brain regions appear to play differing roles in various models of anxiety and effects of anxiolytics. More expressly, activation of the lateral and central nuclei, in addition to the bed nucleus of the strai terminalis may mediate anxiety. Lesions on the aforementioned localities of the rat amygdala block the expression of fear-potentiated startle (when using either a visual of auditory conditioned stimulus) (Davis & Chi, 1999). One of the few ways to scrutinize the human amygdala and its responsibility in the expression anxiety is to study people with a disorder known as Urbach-Wiethe disease. This genetic disorder involves the steady deterioration of the amygdala as calcium augments there (Kalat, 2001). People with this disorder experience almost no fear and have problems identifying facial expressions such as fear and anger in others (Adolphs, Tranel, Damasio, & Damasio, 1994). According to Kalat (2001), it is in all probability difficult for a person, who experiences no fear to be able to identify someone else's expression of fear. The Role of GABA and Benzodiazepines in Anxiety Neurons in the brain communicate through chemical messengers called neurotransmitters. These molecules are released by the signal-emitting neuron and bind to specific proteins (i.e. GABAA receptors) on the signal-receiving neuron. Two main types of neurotransmitters and neurotransmitter receptors--inhibitory and excitatory--determine the response of the of the signal-receiving neuron. Excitatory neurotransmitters (i.e. glutamate) and their receptors increase the neuron's intrinsic electrical activity and excitability, whereas inhibitory neurotransmitters (i.e. GABA) and their receptors reduce neuronal excitability. Excessive excitation can lead to panic attacks and seizures, whereas excessive neuronal inhibition can lead to sedation (Kalat, 2001). Recent advances in molecular biology and complementary information derived from neuropharmacology, biochemistry, and behaviour have dramatically increased our understanding of various aspects of GABAA receptors. Various techniques such as mutation, gene knockout and inhibition of GABAA receptor subunits (by antisense oligodeoxynucleotides) have been used to establish the physiological and pharmacological significance of the GABAA receptor subunits and their native receptor assemblies' in vivo (Delaney & Sah, 1999). It has been shown that there is a close connection between the therapeutic action of anxiolytic drugs and their capacity to facilitate transmission in GABA synapses (Davis, 1989). As well, it has been estimated that 40% of the synapses in the brain are GABAergic, making GABA the most universal neurotransmitter. As stated by Kalat (2001), central to the GABAA receptor complex (which contains a location that binds the neurotransmitter GABA as well as locations that bind other chemicals, which alter the responsiveness of the GABA site) is a chloride channel. Of the four receptor sites on the GABAA receptor complex that are sensitive to GABA, three of these are also sensitive to benzodiazepines (Schmitt, Lueddens, & Hiemke, 2000). By allowing benzodiazepine molecules to attach, the shape of the receptor is altered so that GABA can attach more easily and can bind more tightly to the receptor site (Delaney & Sah, 1999). In other words, benzodiazepine receptor agonists exert their initial effects by increasing the inhibitory actions of GABA. There is growing evidence that benzodiazepine receptors exist in various forms, or functional subtypes, and are widely distributed in the CNS, with particularly high concentrations being found in limbic system structures such as amygdala, septum, and hippocampus (Delaney & Sah, 1999). Benzodiazepine full agonists such as diazepam bind with a high affinity to almost all of the benzodiazepine receptor subtypes. This binding produces a wide variety of pharmacological effects such as reducing feelings of agitation and restlessness, slowing mental activity, rela effect on muscles, and drowsiness (Taylor & Arnow, 1988). It would seem that for a structure--such as the amygdala--to mediate the anxiolytic effects of benzodiazepines, the following two criteria seem logical. Firstly, direct application of benzodiazepines into the structure (in this case, the amygdala) should produce anxiolytic effects that are similar to those produced by peripheral administration. Secondly, the anxiolytic effects produced by direct application of a benzodiazepine into a structure should be antagonized by the co-administration of a benzodiazepine antagonist. Numerous studies including research conducted by Vekovischeva et al. (1999) show experimental evidence that injections of benzodiazepine agonists locally to various brain regions--such as the amygdala--causes anxiolysis in rodents. Furthermore, a study by Malkani & Rosen (2000) examined whether different areas of the amygdala (in this instance, the lateral and central nuclei) are involved in the actions of benzodiazepines. The results demonstrated that a diminution in contextual fear conditioning (in rodents) by diazepam is associated with "differential regulation of the immediate-early gene EGR-1" in the central and lateral amygdala. The above data suggests that both the central and lateral amygdala could possibly be important sites for the anxiolytic action of benzodiazepines. In addition, EGR-1 expression is not apparent in other amygdaloid nuclei (such as the basomedial or basolateral) which indicates that these areas may not play as large a role in the expression of anxiety as do the lateral and central amygdala. The effects of benzodiazepine antagonists can be seen in many experiments (i.e. Bradwejn et al., 1994). Data from the above and other such experiments suggests that benzodiazepine receptor antagonists such as flumazenil (Ro 15-1788) interact competitively with the benzodiazepine binding site to block the actions of both the receptor agonists and inverse agonists, but have no essential effect on GABAergic function themselves. The GABAA /Benzodiazepine Receptor Complex and Anxiety There are different types of benzodiazepine receptor ligands, which exert different pharmacological effects in addition to anxiety modulation. Full benzodiazepine receptor agonists (such as diazepam) have anxiolytic, anti-convulsant , anti-aggressive, sedative, and muscle relaxant properties (Bradwejn, Koszycki, & Couetoux du Tertre et al., 1994). Their potencies as anxiolytics are correlated with their relative affinities for the benzodiazepine receptor binding sites in both humans and other animals in vivo. Evidence for the above can be seen in the study by Mailizia (1999) which looked at positron emission tomography (PET) and radio labelled benzodiazepines. The benzodiazepine receptor inverse agonists (i.e. FG 7142) which produce effects opposite to those of agonists at the benzodiazepine receptor site, also possess opposite pharmacological properties. Full inverse agonists are anxiety provoking in humans (i.e. Bradwejn et. al., 1994), as well as anxiogenic and convulsant in animals (i.e. Petrovitch & Swanson, 1997). The effects that the different types of benzodiazepine receptor ligands have in modulating anxiety appear to be exerted through their actions at the benzodiazepine receptor site. The above can be assumed since pure antagonists (i.e. flumazenil) block both the anxiolytic effects of full agonists (i.e. diazepam) and the anxiogenic effects of inverse agonists (Haefely, Polc, & Pieri et al., 1983). The Problems With Benzodiazepines The benzodiazepines constitute a well-known class of therapeutics displaying hypnotic, anxiolytic, and anticonvulsant effects. A broad range of side effects comprising of sedation, ataxia, amnesia, tolerance development, alcohol and barbiturate potentiation, and abuse potential, however, limits their usefulness. Benzodiazepines are transformed by the liver into long-acting forms that can persist in the body for 24 hours or longer. With the continuous use of this drug on a daily basis, the active drug forms accumulate and increases the intensity of the side effects elicited (Long, 1980). Consequently, there has been an intensive search for modulatory agents with improved profile and a diversity of chemical entities distinct from the benzodiazepines, but with GABA modulatory effects. Partial agonists of GABAA receptors are being developed as anxiolytics which have fewer and less severe side effects as compared to conventional benzodiazepines because of their lower efficacy and better selectivity for the GABAA receptor assemblies (Gazzaniga, 1995). Discussion Numerous studies conducted currently and in previous decades support the theory that anxiety may be primarily modulated by limbic system structures, especially the amygdala. Research involving amygdala lesions, electrical stimulations and drug infusions produces data that shows a disruption of normal anxiety reactions. Thus, it can be shown that the amygdala does play some role in the expression of anxiety. A large body of literature indicates that the amygdaloid complex is a major site of action for the anxiolytic effects of benzodiazepines--the most widely used therapeutic drugs for anxiety. In the last several years, major advances have been made in understanding the pharmacology of anxiety. In general, two broad classes of experimental approaches have been used to analyse this question. One approach is to study the mechanism of action of drugs, such as benzodiazepines, that are known to treat anxiety clinically. For example, receptor binding, electrophysiological, and molecular approaches have indicated that benzodiazepines act by increasing GABA transmissions. This indicates that GABA must be important for anxiety and understanding the molecular basis of benzodiazepine-GABA interactions. A second approach is to use various animal models of fear and anxiety that are sensitive to known anxiolytic drugs to see if they will detect new compounds. This experimentation allows our awareness of neurotransmitter systems that may be involved in anxiety to broaden. Although there have been major advances in our understanding of the underlying processes in human anxiety, more research needs to be conducted to fully comprehend the intricacies of anxiety. References Anderson, L.I., Faerevik, G., & Boe, E.K. (2000). Effects

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