Figure 9.4. Summary of the inter-relationship between the noradrenergic, serotonergic and GABAergic systems that play a role g in generalized anxiety disorder. O
HT1A), leading to a decrease in serotonergic release. Despite the connection between the decreased functional activity of the serotonergic system and the anxiolytic effects of the benzodiazepines, it would appear that their effect on serotonergic transmission is indirect and probably mediated via a facilitation of the principal inhibitory neurotransmitter, GABA.
Unlike the biogenic amines, noradrenaline and 5-HT, GABA is one of the most widely distributed neurotransmitters in the mammalian brain, occupying some 40% of all synapses. Whereas noradrenaline and 5-HT are primarily excitatory in their actions, GABA is an inhibitory transmitter and therefore reduces the firing rate of excitatory neurons with which it is in contact. In various animal models of anxiety, the facilitation of GABAergic activity is associated with a reduction in anxiety. Conversely, drugs such as bicuculline, which specifically block GABA receptors, precipitate the symptoms of anxiety. There is also experimental evidence to show that the anti-anxiety effects of the benzodiazepines may be inhibited by GABA receptor antagonists or by drugs that reduce the synthesis of GABA. From such studies it may be concluded that the primary action of ''classical'' benzodiazepines such as diazepam is to facilitate central GABAergic transmission but, due to the modulatory effects of GABAergic neurons on other neurotransmitter systems in the brain, secondary changes occur in noradrenergic and serotonergic pathways which may contribute to their anxiolytic effects.
Several neuropeptides have been shown to play a role in anxiety but so far none has been developed as a drug largely because of their poor pharmacokinetic properties and difficulty in penetrating the blood-brain barrier. This situation may change in the future when drugs are developed that, though they may not be peptides, have a high affinity for the peptide receptors.
Angiotensin peptides - the angiotensin converting enzyme inhibitor (ACE), captopril, has anxiolytic activity in both experimental and clinical studies. It has recently been shown that the angiotensin 1 receptor antagonist, losartin, has anxiolytic properties whereas the angiotensin 2 antagonists are inactive.
Cholecytokinin ligands - agonists of the central CCK receptors cause anxiety and precipitate panic attacks in predisposed individuals. Two types of CCK receptors have been identified, CCK-A and -B (from the alimentary tract and brain respectively), both of which occur in the mammalian brain. CCK-B agonists initiate anxiety while the antagonists are anxiolytic in both experimental and clinical situations. So far the poor bioavailability and side effects have limited their clinical development.
Neurokinin receptor ligands - there are two types of NK receptors in the brain. NK2 agonists have been found to be anxiogenic while the antagonists are anxiolytic at least in animal studies. Some NK1 antagonists have also been shown to be anxiolytic in experimental studies.
Corticotrophin releasing factor ligands - alpha helical CRF has been shown to block the anxiogenic effects of alcohol withdrawal in rats. It is possible that CRF interacts with neuropeptide Y receptors; NPY 1 receptor agonists to have anticonflict effects in animal studies.
NMDA-glutamate ligands - the glycine antagonist, HA-966, has anxiolytic effects in animal studies.
Adenosine receptor ligands - the adenosine receptor antagonist, caffeine, induces anxiety in both animals and man while agonists have anxiolytic effects.
Pathophysiological basis of panic disorder and obsessive-compulsive disorder: pharmacological treatment
A number of models of anxiety disorder have been proposed which help to explain differences in human behaviour in terms of their possible genetic and biological determinants. Of these models the one developed by Gray is particularly appealing to the neuroscientist in that it seeks to link three interdependent systems in the brain to specific behavioural functions. Thus one system is concerned with behavioural variations in response to signals of reward and non-punishment, a system concerned with impulsiveness. The second is located in the septohippocampal area and is concerned with behavioural inhibition; this is particularly relevant to the genesis of anxiety. The third system controls the escape and defensive-aggressive behaviour (the fight-flight response) and involves the amygdala-hypothalamus-midbrain regions. Thus the model of Gray regards anxiety disorders as arising from variations in the activities of several interdependent regions of the limbic system (Figure 9.6).
In 1987, Jeffrey Gray proposed that the septohippocampal system acted as a ''comparator'' in that it compared anticipated anxiety with threatening stimuli. He postulated that when the anticipated anxiety did not match with the threatening stimulus then an inhibitory system operating through the septohippocampal circuit was activated which blocked the defensive behaviour, increased the vigilance and suppressed reward behaviour. The noradrenergic and serotonergic systems were thought to play a complementary role in these events.
An additional ''defence'' system mediates the fight-flight response. This involves the amygdala, hypothalamus and central grey matter of the midbrain (PAG). The fight-flight response occurs when the PAG is activated by the input from the amygdala. Figure 9.7 summarizes the inter-relationship between the septohippocampal system, the PAG and the hypothalamus. The original theory of Gray has been modified more recently by Deakin and Graeff to include the role of the serotonergic system.
In recent years there has been considerable interest in the neurobiological basis of the anxiety disorders. It is generally accepted that the noradrenergic and serotonergic systems are causally involved in the pathogenesis of these disorders. Both the locus coeruleus and the dorsal raphe project to the
frontal lobe parietal iobe^
occipital lobe hippocampus cerebellum locus ' coeruleus hypothalamus dorsal raphe nucleus environmental stimulus thalamus + hippocampus dorsal fnphí]* nucleus amygdala hypothalamus hypothalamus environmental stimulus autonomic nesprjnse
:^rct"niri hyprjfuicticn (lad; rj ¡ nh ibitnr:,' çffcccj n^iàdr^nallr^ hryperfuiictlon (iwssslvtt Kïilratùry putative pathway raawctrjremrtttrls) undoarj
Figure 9.6. Diagram of principal pathways involved in the genesis of anxiety based on Gray's integrated theory of anxiety. q r1
Frontal cortex: hippocampus
Figure 9.7. Diagram illustrating the role of the septohippocampal system in anxiety.
septohippocampal circuit which, in turn, projects to the other regions of the limbic system that mediate anxiety. The hippocampus and the amygdala are of particular importance in that they are interconnected and also project to both subcortical and cortical nuclei. Their main neurophysiological function appears to involve the integration of external and internal sensory perception. It is well established that infusion of lactate in patients who are vulnerable to panic attack can initiate the full symptoms of the attack. Positron emission tomography (PET) imaging studies on such patients show that there is an abnormal hemispheric asymmetry in the para-hippocampal gyrus blood flow and oxygen consumption together with an increase in glucose utilization in this area of the brain. Such studies help to locate the sites of the anxiety disorders in subcortical regions of the brain and also to provide a rational basis for defining the sites of action of the drugs that are used to treat them. They also suggest which of the numerous neurotransmitter systems found in these areas may be causally connected with the disorders.
Panic disorder is one of the most prevalent psychiatric disorders in industrialized countries. It is often associated with agoraphobia and has an estimated prevalence of between 1% and 6%. The use of imipramine in the treatment of anxiety by Klein and Fink, and the discovery by William Sargant that monoamine oxidase inhibitors (MAOIs) were effective in the treatment of ''atypical depression'' over 30 years ago led to the investigation of the efficacy of such treatments in patients with panic disorder. Since that time, such drugs have been shown to attenuate the symptoms of panic in addition to those of phobic avoidance and anticipatory anxiety. As both the
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septum cerebellum SJ W^ amygdala
gray ^^m hypothalamus locLS, rostral raphe
clmcjulatc cortex I pre-frontal cortex +
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