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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.

Clinical evidence suggests that depression and trauma predispose the subject to panic. Accordingly, here we examined the late effects of uncontrollable stress, a presumptive model of depression and/or traumatic disorder, on panic-like behaviors evoked by electrical stimulation of the dorsal periaqueductal gray (DPAG). Changes in anxiety and depression were also assessed in the elevated plus-maze (EPM) and forced-swimming test (FST), respectively. Rats with electrodes in the DPAG were subjected to a 7-day shuttle-box one-way escape yoked training with foot-shocks either escapable (ES) or inescapable (IS). The day after the end of one-way escape training, rats were trained in a two-way escape novel task (test-session) to ascertain the effectiveness of uncontrollable stress. DPAG stimulations were carried out in an open field, both before the escape training and 2 and 7 days after it, and EPM and FST were performed on the 8th and 10th days afterwards, respectively. Controls were either trained with fictive shocks (FS) or subjected to intracranial stimulations only. Although the ES rats performed significantly better than the IS group in the two-way escape task, groups did not differ with respect to either the anxiety or depression scores. Unexpectedly, however, IS rats showed a marked attenuation of DPAG-evoked freezing and flight behaviors relative to both the ES and FS groups, 2 and 7 days after one-way escape training. The conjoint inhibition of passive (freezing) and active (flight) defensive behaviors suggests that IS inhibits a DPAG in-built motivational system that may be implicated in depressed patients' difficulties in coping with daily-life stress.

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