On the verge of a respiratory-type panic attack: Selective activations of rostrolateral and caudoventrolateral periaqueductal gray matter following short-lasting escape to a low dose of potassium cyanide.

Intravenous injections of potassium cyanide (KCN) both elicit escape by its own and facilitate escape to electrical stimulation of the periaqueductal gray matter (PAG). Moreover, whereas the KCN-evoked escape is potentiated by CO2, it is suppressed by both lesions of PAG and clinically effective treatments with panicolytics. These and other data suggest that the PAG harbors a hypoxia-sensitive alarm system the activation of which could both precipitate panic and render the subject hypersensitive to CO2. Although prior c-Fos immunohistochemistry studies reported widespread activations of PAG following KCN injections, the employment of repeated injections of high doses of KCN (>60µg) in anesthetized rats compromised both the localization of KCN-responsive areas and their correlation with escape behavior. Accordingly, here we compared the brainstem activations of saline-injected controls (air/saline) with those produced by a single intravenous injection of 40-µg KCN (air/KCN), a 2-min exposure to 13% CO2 (CO2/saline), or a combined stimulus (CO2/KCN). Behavioral effects of KCN microinjections into the PAG were assessed as well. Data showed that whereas the KCN microinjections were ineffective, KCN intravenous injections elicited escape in all tested rats. Moreover, whereas the CO2 alone was ineffective, it potentiated the KCN-evoked escape. Compared to controls, the nucleus tractus solitarius was significantly activated in both CO2/saline and CO2/KCN groups. Additionally, whereas the laterodorsal tegmental nucleus was activated by all treatments, the rostrolateral and caudoventrolateral PAG were activated by air/KCN only. Data suggest that the latter structures are key components of a hypoxia-sensitive suffocation alarm which activation may trigger a panic attack.

Evidence of a suffocation alarm system sensitive to clinically-effective treatments with the panicolytics clonazepam and fluoxetine.

Dyspnea, 'hunger for air', and the urge to flee are the cardinal symptoms of respiratory-type panic attacks. Patients also show baseline respiratory abnormalities and a higher rate of comorbid and antecedent respiratory diseases. Panic attacks are also precipitated by both the infusion of 0.5 M sodium lactate and the inhalation of 5-7% carbon dioxide (CO2) in predisposed patients, but not in healthy volunteers nor patients without panic disorder. Further studies show that patients with panic are also hyper-responsive to hypoxia. These and other observations led Klein (1993) to suggest that clinical panic is the misfiring of a suffocation alarm system. In rats, cytotoxic hypoxia of chemoreceptor cells by intravenous injection of potassium cyanide (KCN) produces short-lasting flight behaviors reminiscent of panic attacks. KCN-induced flight behaviors are blocked both by denervation of chemoreceptor cells and lesion of dorsal periaqueductal gray matter, a likely substrate of panic. Herein, we show that KCN-evoked flight behaviors are also attenuated by both acute and chronic treatment with clonazepam (0.01-0.3 mg/kg, intraperitoneally (i.p.)) and fluoxetine (1-4 mg/kg/day, i.p. for 21 days), respectively. Attenuation of KCN-evoked panic-like behaviors by clinically-effective treatment with panicolytics adds fresh evidence to the false suffocation alarm theory of panic disorder.

Evidence that the periaqueductal gray matter mediates the facilitation of panic-like reactions in neonatally-isolated adult rats.

Plenty of evidence suggests that childhood separation anxiety (CSA) predisposes the subject to adult-onset panic disorder (PD). As well, panic is frequently comorbid with both anxiety and depression. The brain mechanisms whereby CSA predisposes to PD are but completely unknown in spite of the increasing evidence that panic attacks are mediated at midbrain's dorsal periaqueductal gray matter (DPAG). Accordingly, here we examined whether the neonatal social isolation (NSI), a model of CSA, facilitates panic-like behaviors produced by electrical stimulations of DPAG of rats as adults. Eventual changes in anxiety and depression were also assessed in the elevated plus-maze (EPM) and forced-swimming test (FST) respectively. Male pups were subjected to 3-h daily isolations from post-natal day 2 (PN2) until weaning (PN21) allotting half of litters in individual boxes inside a sound-attenuated chamber (NSI, n = 26) whilst siblings (sham-isolated rats, SHAM, n = 27) and dam were moved to another box in a separate room. Non-handled controls (CTRL, n = 18) remained undisturbed with dams until weaning. As adults, rats were implanted with electrodes into the DPAG (PN60) and subjected to sessions of intracranial stimulation (PN65), EPM (PN66) and FST (PN67-PN68). Groups were compared by Fisher's exact test (stimulation sites), likelihood ratio chi-square tests (stimulus-response threshold curves) and Bonferroni's post hoc t-tests (EPM and FST), for P<0.05. Notably, DPAG-evoked panic-like responses of immobility, exophthalmus, trotting, galloping and jumping were markedly facilitated in NSI rats relative to both SHAM and CTRL groups. Conversely, anxiety and depression scores either did not change or were even reduced in neonatally-handled groups relative to CTRL, respectively. Data are the first behavioral evidence in animals that early-life separation stress produces the selective facilitation of panic-like behaviors in adulthood. Most importantly, results implicate the DPAG not only in panic attacks but also in separation-anxious children's predispositions to the late development of PD.