A variety of neuroanatomical, neurochemical, neuroendocrine, and neurophysiological systems have been implicated in the pathogenesis of anxiety states. Much of this information has come from animal models and research on the effects of stress. Studies of neurobiological functioning in humans with GAD are limited. Some of the physical systems that may be involved in the emotion of anxiety are summarized below. Additional information may be found in reviews by Brawman-Mintzer and Lydiard,(29 Connor and Davidson/27' and Gray and McNaughton.(29
Noradrenergic pathways (the locus coeruleus-noradrenaline-sympathetic nervous system) have long been associated with fear and arousal and play an important role in the body's response to threat. However, their role in persistent anxiety states is not clear. Resting catecholamine levels in patients with GAD appear to be normal. On the other hand, GAD patients exhibit subnormal responses to both stimulation (29> and blockaded of a2-adrenergic receptors and a reduced density of a2-receptors in platelets. (3!> Those findings could reflect downregulation of the a 2-receptors due to initially high levels of noradrenaline (norepinephrine).
Consistent with those neurochemical findings, somatic measures of autonomic nervous system function (e.g. skin conductance, respiratory rate, heart-rate variability, blood pressure) in patients with GAD tend to show normal resting values with blunted and sometimes prolonged responses to stressful stimuli. (3 32) Those findings may indicate diminished autonomic nervous system responsiveness in individuals with GAD.
The hypothalamic-pituitary-adrenal axis and its end-product, cortisol, also are involved in reactions to stress. Activity in the hypothalamic-pituitary-adrenal axis is subject to a variety of influences. Primary control is by means of hypothalamic secretion of corticotrophin-releasing factor, which stimulates pituitary secretion of ACTH, which in turn stimulates adrenal secretion of cortisol. Circulating cortisol, and analogues such as dexamethasone, exert inhibitory feedback at the level of the pituitary gland and apparently also by means of receptors on the hippocampus.
In rats, chronic exposure to stress or exogenous steroids results in a reduction of corticosteroid receptors in the hippocampus and a consequent decrease in feedback inhibition by cortisol.(33) These animals exhibit reduced dexamethasone suppression of cortisol secretion and greater or more prolonged adrenocortical responses to stress. Reduced dexamethasone suppression also has been observed in approximately one-third of patients with DSM-III-diagnosed GAD. (34) This reduction in the normal regulatory control of cortisol secretion may be one mechanism through which chronic or repeated stress can lead to persistent anxiety.
The amygdala and the bed nucleus of the stria terminalis
LeDoux(3 36) and others have demonstrated the central role played by the amygdala in the mediation of fear reactions. The amygdala is thought to be responsible for the detection of potential threats to the organism and the mobilization of a range of defensive responses ( Fig 1). Through connections with the hypothalamus, it can activate the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. Through efferent fibres to the central grey area of the midbrain, it can mediate behavioural defence responses such as the fight-or-flight response and behavioural 'freezing.' Through connections to the nucleus reticularis pontis caudalis, it can enhance the defensive startle reflex.
Fig. 1 Fear pathways (based on descriptions by LeDoux(36) and Davis(3Z>): ANS, autonomic nervous system; HPA, hypothalamic-pituitary-adrenal axis.
The extent to which these pathways are involved in the neurobiology of anxiety (as opposed to fear) is unclear. However, a structure closely related to the amgdala, the bed nucleus of the stria terminalis, may be involved in this emotion. The bed nucleus resembles the amygdala in its neurotransmitter content, cell morphology, and hypothalamic and brainstem connections and, like the amygdala, it exerts a modulating effect on the startle reflex. (3Z> Studies of this latter effect implicate it in the experience of anxiety.
Administration of corticotrophin-releasing factor into the cerebral ventricles of rats produces a state of generalized arousal resembling anxiety. Under those conditions, the startle reflex also is enhanced. Exposing rats to bright light for 5 to 20 min has similar effects. These effects are not blocked by damage to amygdala but are by lesions to the bed nucleus of the stria terminalis and by treatment with benzodiazepines or buspirone. Conversely, infusion of corticotrophin-releasing factor directly into the bed nucleus of the stria terminalis, but not the amygdala, produces a rapid increase in startle. Based on these observations, Davis (3Z> has suggested that the stria terminalis may play a role in anxiety analogous to that of the amygdala in fear reactions and, further, that prolonged or repeated stimulation of the stria terminalis by corticotrophin-releasing factor during periods of stress might lead to sustained activation and thus to persistent anxiety.
The septohippocampal system (behavioural inhibition system)
The bed nucleus of the stria terminalis is part of the larger septohippocampal system. (38> In 1982, based on data from several lines of research, Gray hypothesized that the septohippocampal system, together with the Papez circuit (a neural loop connecting the subicular area in the hippocampal formation to the mammillary bodies, anterior thalamus, cingulate cortex, and back to the subiculum), is responsible for mediating the emotion of anxiety as well as the major effects of anxiolytic drugs.(38) Gray called this network the behavioural inhibition system, because he believed that, when activated, it interrupts ongoing behavior and redirects the organism's attention to signs of possible danger.
According to Gray's model/2,,38> the behavioural inhibition system receives information about the environment from the sensory cortex via the temporal lobe and hippocampal formation. The system checks the information for consistency with predictions, which are updated continuously by the Papez circuit based on preceding information and stored patterns, as well as for consistency with the immediate goals of the organism. When a mismatch is found, or if a predicted event is aversive, the outputs of the behavioral inhibition system are activated, resulting in a constellation of emotional and behavioural effects consistent with anxiety ( Fig 2).
Fig. 2 Behavioural inhibition system (based on descriptions by Gray and McNaughton (28)): ANS, autonomic nervous system; 5-HT, serotonin; NA, noradrenaline.
The activation of the behavioural inhibition system appears to be moderated by ascending noradrenergic and serotonergic projections to the septohippocampal complex, providing a possible mechanism for the anxiolytic actions of some drugs. The amygdala also provides inputs to the behavioural inhibition system and may relay its outputs to the hypothalamus and autonomic nervous system, thereby mediating anxious arousal. Sustained activation of the behavioural inhibition system might therefore account for many of the features of GAD.
The powerful anxiolytic and sedative effects of benzodiazepines are believed to be mediated by benzodiazepine recognition sites located on g-aminobutyric acid (GABA) type A receptor complexes in the central nervous system. When bound to those complexes, benzodiazepines allosterically modulate the GABA receptors to enhance the normal inhibitory effects of GABA on neurotransmission. Activation of central benzodiazepine-GABA receptor complexes also suppresses hypothalamic-pituitary-adrenal axis axis activity and, consequently, cortisol levels.
In addition to these central receptor complexes, benzodiazepine recognition sites of a different type are present widely in cells outside the central nervous system. These so-called peripheral benzodiazepine receptors are believed to be instrumental in controlling the synthesis of regulatory steroids. Their role in the anxiolytic actions of benzodiazepines is unknown; although they bind some drugs (e.g. diazepam), they have low affinity for others (e.g. clonazepam). Interestingly, peripheral benzodiazepine receptors are decreased in blood cells of individuals with untreated GAD but return to normal levels after successful treatment with benzodiazepines Their numbers also vary in response to stress, being elevated following acute stressors and reduced during chronic stress.
A possible explanation for those changes has been suggested by Rocca et al.(39) The investigators note that peripheral benzodiazepine receptors in brain glial cells control the production of neurosteroids that act as modulators of GABAa receptor sensitivity. Their effect on GABA functioning appears to be opposite to that of clinically effective benzodiazepines, that is, they decrease rather than increase the inhibitory effects of GABA. It is hypothesized that an endogenous ligand of these glial cell receptors (possibly diazepam binding inhibitor) is released during stress, initiating the cycle of events depicted in Fig 3.
Fig. 3 Possible involvement of peripheral benzodiazepine receptors in acute and chronic stress reactions (based on descriptions by Rocca et a/.BZ, benzodiazepine.
The immediate effect of these events would be to enhance the stress-induced release of cortisol. However, prolonged cortisol excess is hypothesized to downregulate peripheral benzodiazepine receptors, resulting in the reduced receptor densities found in GAD. Administration of a clinically effective benzodiazepine drug would interrupt the proposed pathway at the point of the central GABA receptor, lowering cortisol levels and restoring synthesis of peripheral benzodiazepine receptors.
Individuals with GAD have been reported to have reduced serotonin levels in the cerebral spinal fluid (40) and decreased platelet binding of paroxetine, a selective serotonin reuptake inhibitor. (4!> In addition, drugs that affect serotonergic transmission (e.g. buspirone and venlafaxine) are effective in the treatment of GAD. These findings suggest that serotonin regulation may be abnormal in GAD.
Cholecystokinin neuropeptides (CCK-4 and CCK-8S) have been implicated in the genesis of arousal and fear responses. (42) It is unclear how those effects are mediated; however cholecystokinin interacts with several neurotransmitters and systems believed to be involved in anxiety responses, including the noradrenergic nervous system, the hypothalamic-pituitary-adrenal axis, the benzodiazepine-GABA system, and serotonin.
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