Integrated Theories Of Anxiety

The evidence outlined so far does little to explain how monoamines or anti-anxiety drugs might influence anxiety states. To achieve this, an integrated view of the relevant brain systems is required, together with an appreciation of how their function is regulated.

One scheme focuses on the roles of the septum and hippocampus. Detailed justification of this theory is beyond the scope of this chapter but can be found in Gray (1987). Briefly, the 'septohippocampal system' is thought to form part of a neuronal network that functions as a 'comparator', i.e. it compares anticipated and actual stimuli. It is envisaged that, when the comparator detects a mismatch between events that are suggested by 'signals' and prevailing stimuli (as in novelty, conflict or frustrative non-reward), a 'behavioural inhibition system' is activated by the septohippocampal system (Fig. 19.9). This system arrests ongoing behaviour and increases vigilance, as is evident in animal models of anxiety (e.g. suppression of rewarded responses or exploration). Ascending noradrenergic and serotonergic inputs are thought to activate this behavioural inhibition system, with these two monoamines playing complementary roles. Moreover, there is extensive evidence that anti-anxiety drugs prevent activation of the behavioural inhibition system by blunting monoaminergic transmission in the hippocampus.

An additional ('defence') system was proposed as early as the 1960s which mediates the flight and fight response. This comprises the amygdala, hypothalamus and central grey in the midbrain. It is generally agreed that the periaquaductal grey area (PAG) of the central grey is responsible for eliciting the flight/fight response which incorporates autonomic changes and analgesia as well as the locomotor response. Gray (1987) proposes that the central grey is normally inhibited by the (ventromedial) hypothalamus and that the influence of the hypothalamus is governed in opposing ways by the behavioural inhibition system and the amygdala. Whereas the former augments hypothalamic inhibition of the flight/fight response, the latter inhibits it, thereby releasing the flight/fight response (Fig. 19.9).

A more recent hypothesis, which incorporates many features of Gray's hypothesis, has concentrated on the central serotonergic system and proposes that different sero-tonergic pathways underlie GAD and panic (Fig. 19.10). This theory, like that described above, focuses on the amygdala as part of the neuronal 'defence' system and highlights evidence for its key role in the response to conditioned fear. The amygdala is thought to be a major target for conditioned sensory inputs and to organise the conditioned fear response (LeDoux and Muller 1997); this is effected by its connections to the hypothalamus and PAG. Different zones of the PAG seem to evoke different components of this response: whereas stimulation of the dorsal PAG (dPAG) evokes 'explosive running', the ventral PAG (vPAG) is responsible for 'freezing', both of which are common features of a panic attack.

Serotonergic neurons, originating in the dorsal Raphe nucleus (DRN), innervate both the amygdala and the PAG. In the former region, they are thought to augment active avoidance of aversive signals by exaggerating the amygdalar response to conditioned aversive stimuli (Deakin and Graeff 1991; Graeff et al. 1996). Excessive serotonergic activity of neurons originating in the DRN is proposed to underlie anticipatory (or 'learned') anxiety which is regarded as akin to GAD. This response could be modulated, at the level of both the DRN and the amygdala, by neuronal inputs from both the frontal

Brain Stress Medicine

Figure 19.9 A schematic representation of key elements of Gray's explanation for anxiety and the flight/fight response. Noradrenergic and serotonergic inputs to the septohippocampal component of a neuronal 'comparator' activate a behavioural inhibition system which suppresses ongoing behaviour and increases vigilance ('anxiety'). Inputs from the behavioural inhibition system also augment the activity of the (ventromedial) hypothalamus which suppresses the flight/ fight response generated in the periaquaductal grey. In contrast, the amygdala inhibits hypothalamic activity and releases the flight/fight response. Anti-anxiety drugs are thought to inhibit monoaminergic activation of the behavioural inhibition system

Figure 19.9 A schematic representation of key elements of Gray's explanation for anxiety and the flight/fight response. Noradrenergic and serotonergic inputs to the septohippocampal component of a neuronal 'comparator' activate a behavioural inhibition system which suppresses ongoing behaviour and increases vigilance ('anxiety'). Inputs from the behavioural inhibition system also augment the activity of the (ventromedial) hypothalamus which suppresses the flight/ fight response generated in the periaquaductal grey. In contrast, the amygdala inhibits hypothalamic activity and releases the flight/fight response. Anti-anxiety drugs are thought to inhibit monoaminergic activation of the behavioural inhibition system cortex, which is thought to process the perception of sensory information, and the hippocampus, which processes contextual (environmental) cues.

Deakin and Graeff (1991) further propose the existence of a pathway, again arising in the DRN, which inhibits activation of the PAG. It is suggested that a reduction of serotonergic transmission in this area releases the flight/fight response. Under normal conditions, activity in this system is governed by higher centres in the forebrain (the cortex and hippocampus) so that, when interpretation of prevailing stimuli deems it appropriate, the flight/fight response is suppressed. A deficit in serotonergic inhibition of the PAG is thought to be the origin of panic. There are several ramifications of this interesting theory. For instance, during low arousal states, a decline in the activity of forebrain serotonergic systems would diminish the inhibition of the PAG. This would ensure that threatening stimuli would evoke a protective escape response by default until cortical systems switch off the PAG response, if appropriate, as arousal increases (Handley 1995). It could also explain why patients often report that they are woken up during the night by their panic attacks.

Anxiety And Brain Function

Figure 19.10 The influence of 5-HT pathways (represented by the dashed lines) projecting from the dorsal Raphe nucleus (DRN) on brain regions comprising the 'brain defence system'. This system comprises the amygdala, hypothalamus and periaquaductal grey (PAG) and coordinates behavioural and neuroendocrine responses to conditioned and unconditioned aversive stimuli. Activity within the defence system is governed by higher centres, such as the frontal cortex and hippocampus. Serotonergic neurons projecting from the dorsal Raphe nucleus are proposed to activate the amygdala (+) thereby promoting the response to conditioned aversive stimuli (anxiety). Projections from this nucleus to the dorsal and ventral periaquaductal grey (dPAG and vPAG) are thought to suppress ( —) the flight/fight response to aversive stimuli. A deficit in serotonergic transmission to this brain region is thought to underlie panic. Possible targets for anti-anxiety drugs, acting via the GABAA receptor, are indicated by the dotted arrows. See text for further details

Figure 19.10 The influence of 5-HT pathways (represented by the dashed lines) projecting from the dorsal Raphe nucleus (DRN) on brain regions comprising the 'brain defence system'. This system comprises the amygdala, hypothalamus and periaquaductal grey (PAG) and coordinates behavioural and neuroendocrine responses to conditioned and unconditioned aversive stimuli. Activity within the defence system is governed by higher centres, such as the frontal cortex and hippocampus. Serotonergic neurons projecting from the dorsal Raphe nucleus are proposed to activate the amygdala (+) thereby promoting the response to conditioned aversive stimuli (anxiety). Projections from this nucleus to the dorsal and ventral periaquaductal grey (dPAG and vPAG) are thought to suppress ( —) the flight/fight response to aversive stimuli. A deficit in serotonergic transmission to this brain region is thought to underlie panic. Possible targets for anti-anxiety drugs, acting via the GABAA receptor, are indicated by the dotted arrows. See text for further details

There is a good deal of evidence that postsynaptic 5-HT2a/2c receptors mediate the actions of 5-HT in both the amygdala and the PAG (Deakin, Graeff and Guimaraes 1992). Thus local infusion of 5-HT2A/2C antagonists into the amygdala has an anti-conflict effect in animals while their systemic administration might have (albeit controversially) anti-anxiety effects in humans. In contrast, these drugs promote the flight/fight response to aversive stimuli. This leads to the prediction that drugs that relieve anxiety, through inhibition of 5-HT transmission in the amygdala, will exacerbate panic by inhibiting the restraining influence of 5-HT in the PAG. In fact, this has been offered as an explanation for the panic attacks experienced by some patients given buspirone. It could also explain the increase in panic attacks in the early stages of treatment with antidepressants. These drugs first decrease the firing rate of serotonergic neurons and the terminal release of 5-HT; recovery of neuronal firing and increased release of 5-HT, like the relief of panic by these drugs, requires prolonged treatment (see Chapter 20).

Obviously, any explanation of anxiety must account for the actions of benzo-diazepines. Gray's theory suggests that they inhibit monoaminergic inputs to the septohippocampal system and switch off behavioural inhibition. A related suggestion is that, whereas the behavioural inhibition system is located in the medial septum/dorsal hippocampus, there is also a 'safety system' in the lateral septum/ventral hippocampus. According to this scheme, benzodiazepines might activate this latter system and generate spurious safety signals (see Handley 1995). Alternatively, Deakin and Graeffs theory suggests that benzodiazepines could directly inhibit activity generated in the PAG. However, they could also inhibit the activity of serotonergic neurons in the DRN and suppress the amygdala response to conditioned fear stimuli. In this case, suppression of the serotonergic inhibitory inputs to the PAG might also be anticipated, an action that could explain why benzodiazepines are ineffective in treating panic disorder.

The finding that noradrenergic neurons innervating the frontal cortex, but not those projecting to the hypothalamus, respond to conditioned environmental cues (McQuade and Stanford 1999) suggests that there could be a similar subdivision of function in this monoamine system as well. However, activation of 5-HT receptors modulates release of noradrenaline (Stanford 1999) and vice versa (Gobert et al. 1997). The function of both these neuronal systems is influenced by GABAergic systems. Clearly, any theory for anxiety must eventually take account of evidence that serotonergic and noradrenergic systems do not operate independently.

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