Anti-panic effect of fluoxetine during late diestrus in female rats is mediated through GABAergic mechanisms in the dorsal periaqueductal gray

Panic disorder is more frequent in women than in men. In women, vulnerability to panic is enhanced during the late luteal phase of the menstrual cycle. At this time secretion of progesterone and its neuroactive metabolite allopregnanolone (ALLO), which acts as a positive allosteric modulator of the actions of GABA at GABA receptors, decline sharply. In female rats, responsiveness to a hypoxic panicogenic challenge increases during the late diestrus (LD) phase as ALLO concentration in the brain falls. During LD, short-term treatment with fluoxetine at a low dose (1.75 mg/kg i.p.) blocked panic-related escape behavior in response to hypoxia. At this dose fluoxetine increases brain concentration of ALLO without affecting 5-HT levels, thereby stabilizing brain ALLO concentration. We here report that the panicolytic-like effect of fluoxetine during LD is prevented by microinjection of the GABA receptor antagonist bicuculline (5 pmol) into the dorsal periaqueductal gray (dPAG), a key panic-related area. This result suggests that fluoxetine's effect is indirectly mediated via a GABAergic mechanism in the dPAG and highlights the important role of changes in GABAergic tone in regulating neuronal excitability in the panic circuitry during the estrous cycle. It also points to the potential for using short-term, low dose fluoxetine as an anti-panic medication in women.