The wake-promoting drug modafinil stimulates specific hypothalamic circuits to promote adaptive stress responses in an animal model of PTSD.

Pharmacotherapeutic intervention during traumatic memory consolidation has been suggested to alleviate or even prevent the development of posttraumatic stress disorder (PTSD). We recently reported that, in a controlled, prospective animal model, depriving rats of sleep following stress exposure prevents the development of a PTSD-like phenotype. Here, we report that administering the wake-promoting drug modafinil to rats in the aftermath of a stressogenic experience has a similar prophylactic effect, as it significantly reduces the prevalence of PTSD-like phenotype. Moreover, we show that the therapeutic value of modafinil appears to stem from its ability to stimulate a specific circuit within the hypothalamus, which ties together the neuropeptide Y, the orexin system and the HPA axis, to promote adaptive stress responses. The study not only confirms the value of sleep prevention and identifies the mechanism of action of a potential prophylactic treatment after traumatic exposure, but also contributes to understanding mechanisms underlying the shift towards adaptive behavioral response.

Hippocampal microinfusion of oxytocin attenuates the behavioural response to stress by means of dynamic interplay with the glucocorticoid-catecholamine responses.

The neurohypophysial hormone oxytocin acts as a central nervous system neurotransmitter/neuromodulator. We evaluated the effects of oxytocin on behavioural responses to stress, as well as associated biophysiological responses, in a controlled, prospective animal model. The long-term effects of exogenous oxytocin microinjected to the hippocampus of male rats were assessed. Animals were exposed to predator scent stress and treated 1 h or 7 days later with oxytocin or vehicle. Behaviours were assessed with the elevated plus-maze and acoustic startle response tests, 7 days after microinjection and freezing behaviour upon exposure to a trauma-related cue on day 8. These data served for classification into behavioural response groups. Trauma cue response, circulating corticosterone and oxytocin, hippocampal expression of glucocorticoid and mineralocorticoid receptors, and oxytocin receptor mRNA levels were assessed. The interplay between oxytocin, corticosterone and norepinephrine was assessed. Microinfusion of oxytocin both immediately after predator scent stress exposure or 7 days later, after exposure to trauma cue significantly reduced the prevalence rates of extreme responders and reduced trauma cue freezing responses. Post-exposure treatment with oxytocin significantly corrected the corticosterone stress response, decreased glucocorticoid receptor expression and increased mineralocorticoid receptor expression in the hippocampus compared to vehicle treatment. High-dose corticosterone administration together with norepinephrine caused release of plasma oxytocin and hippocampal oxytocin receptor. Oxytocin is actively involved in the neurobiological response to predator scent stress processes and thus warrants further study as a potential therapeutic avenue for the treatment of anxiety-related disorders.

Anxiety and cerebral blood flow during behavioral challenge. Dissociation of central from peripheral and subjective measures.

To investigate the relationship between anxiety and regional cerebral blood flow, we administered behavioral challenges to 10 patients with obsessive-compulsive disorder while measuring regional cerebral blood flow with the xenon 133 inhalation technique. Each patient was studied under three conditions: relaxation, imaginal flooding, and in vivo (actual) exposure to the phobic stimulus. Subjective anxiety, obsessive-compulsive ratings, and autonomic measures (heart rate, blood pressure) increased significantly, but respiratory rate and PCO2 did not change across the three conditions. Regional cerebral blood flow increased slightly (in the temporal region) during imaginal flooding, but decreased markedly in several cortical regions during in vivo exposure, when anxiety was highest by subjective and peripheral autonomic measures. These results demonstrate that intense anxiety can be associated with decreased rather than increased cortical perfusion and that ostensibly related states of anxiety (eg, anticipatory and obsessional anxiety) may be associated with opposite effects on regional cerebral blood flow.