Enhanced responsiveness to hypoxic panicogenic challenge in female rats in late diestrus is suppressed by short-term, low-dose fluoxetine: Involvement of the dorsal raphe nucleus and the dorsal periaqueductal gray

• Published in: Journal of psychopharmacology (Oxford) Vol. 35; no. 12; p. 1523
• Main Authors: Batistela, Matheus F, Vilela-Costa, Heloísa H, Frias, Alana T, Hernandes, Paloma M, Lovick, Thelma A, Zangrossi, Jr, Helio
• Format: Journal Article
• Language: English
• Published: United States 01.12.2021
• Subjects: Animals; Behavior, Animal - drug effects; Diestrus - drug effects; Disease Models, Animal; Dorsal Raphe Nucleus - drug effects; Female; Fluoxetine - pharmacology; Hypoxia - complications; Male; Menstrual Cycle - drug effects; Panic - drug effects; Panic Disorder - drug therapy; Periaqueductal Gray - drug effects; Rats; Rats, Sprague-Dawley; Serotonin Uptake Inhibitors - administration & dosage; Serotonin Uptake Inhibitors - pharmacology; Sex Characteristics; dorsal raphe nucleus; Panic; serotonin; estrous cycle; periaqueductal gray matter
• DOI: 10.1177/02698811211058986

Acute hypoxia, which is panicogenic in humans, also evokes panic-like behavior in male rats. Panic disorder is more common in women and susceptibility increases during the premenstrual phase of the cycle. We here investigated for the first time the impact of hypoxia on the expression of panic-like escape behavior by female rats and its relationship with the estrous cycle. We also evaluated functional activation of the midbrain panic circuitry in response to this panicogenic stimulus and whether short-term, low-dose fluoxetine treatment inhibits the hyper-responsiveness of females in late diestrus. Male and female Sprague Dawley rats were exposed to 7% O . Females in late diestrus were also tested after short-term treatment with fluoxetine (1.75 or 10 mg/kg, i.p.). Brains were harvested and processed for c-Fos and tryptophan hydroxylase immunoreactivity in the periaqueductal gray matter (PAG) and dorsal raphe nucleus (DR). Acute hypoxia evoked escape in both sexes. Overall, females were more responsive than males and this is clearer in late diestrus phase. In both sexes, hypoxia induced functional activation (c-Fos expression) in non-serotonergic cells in the lateral wings of the DR and dorsomedial PAG, which was greater in late diestrus than proestrus (lowest behavioral response to hypoxia). Increased responding in late diestrus (behavioral and cellular levels) was prevented by 1.75, but not 10 mg/kg fluoxetine. The response of female rats to acute hypoxia models panic behavior in women. Low-dose fluoxetine administered in the premenstrual phase deserves further attention for management of panic disorders in women.