Abstract
years ago, Deakin and Graeff proposed that whereas generalized anxiety disorder is produced by the overactivity of 5-HT excitatory projections from dorsal raphe nucleus to the areas of prefrontal cortex and amygdala which process distal threat, panic attacks are a dysfunction of 5-HT inhibitory projections from dorsal raphe nucleus to the dorsal periaqueductal gray matter, thereby releasing the responses to proximal threat, innate fear or anoxia. Besides, they suggested that the decrease in 5-HT1A neurotransmission in the hippocampus results in learned helplessness and depression. Accordingly, the Deakin Graeff hypothesis provided a unified frame to the widespread use of 5-HT selective reuptake inhibitors in generalized anxiety, panic disorder and depression. Competitor hypotheses implicate panic attacks with the abnormal functioning of locus coeruleus, basolateral amygdala, dorsomedial hypothalamus or an as-yet-unknown suffocation alarm system. Conversely, cognitive psychologists suggest that panic attacks result from the catastrophic (cortical) interpretation of bodily symptoms. In any event, translational models of panic attack are expected to reproduce the main features of clinical panic, namely, the patient's higher sensitivity to both lactate and CO2, the drug specific sensitivity, the lack of stress hormone responses during panic attacks, the higher vulnerability of women and the high comorbidity with agoraphobia, major depression and childhood separation anxiety. Therefore, here we review the main steps in the experimental approach to anxiety disorders which are paving the route towards a translational model of panic attack. Keywords: Panic, Anxiety, Stress, Suffocation, Serotonin, Periaqueductal Gray Matter
Highlights
About 20 years ago, Deakin and Graeff proposed that whereas generalized anxiety disorder is produced by the overactivity of 5-HT excitatory projections from dorsal raphe nucleus to the areas of prefrontal cortex and amygdala which process distal threat, panic attacks are a dysfunction of 5-HT inhibitory projections from dorsal raphe nucleus to the dorsal periaqueductal gray matter, thereby releasing the responses to proximal threat, innate fear or anoxia
MTZ had variable effects in the elevated plus-maze (EPM) which did not correlate with biochemical indices of hypothyroidism (Siqueira, Rossoni, Tiengo, Tufik, & Schenberg, 2010b). These studies support the attenuation of panic attacks in hypothyroidism. It remains to be elucidated whether these effects are mediated by dorsal half of periaqueductal gray matter (DPAG)-projecting TRHergic neurons of dorsal raphe nucleus (DRN) or by the unique population of TRH neurons in the ventrolateral PAG (VLPAG).In any event, the above studies suggest that experiments devised to reproduce the clinical features of panic disorder (PD) or the comorbidity of this disorder with other conditions are an obligatory step in the investigation of the neurobiology of PD
Even though the animal models are not expected to be the exact reproduction of human psychiatric disorders, the translational modelling of panic attacks is expected to reproduce the main clinical features of PD, including the CO2 and lactate hypersensitivity, the drug treatment
Summary
The reader is likely surprised by the omission of the amygdala. Deakin and Graeff (1991) suggested that this structure is crucial in anticipatory anxiety, evidence supporting this proposal stemmed from scientific traditions other than theirs. Was mediated through distinct pathways from central amygdala (CeA) to the lateral hypothalamus and caudal ventrolateral PAG (VLPAG), in the case of conditioned fear to a tone, or to the ventral cochlear nucleus and nucleus reticularis pontis caudalis, in the case of fearpotentiated startle (Hitchcock & Davis, 1991; Iwata et al, 1986; LeDoux et al, 1988) These data were amply corroborated in the following years, recent studies showed that rhesus monkeys which retained and expressed fear-potentiated startle to a visual cue learned before the complete lesion of the amygdala, failed in acquiring the fear-potentiated startle to an auditory cue when training occurred after the lesion.
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