In humans and animals panic-like behaviour can be elicited by activating neuronal circuitry in the dorsal half of the periaqueductal grey matter (dPAG) (Lovick, 2000). In a recent study in female rats we have shown that late dioestrus (equivalent to the late luteal phase in women) is associated with an increase in the number of GABAergic neurones in the PAG that express α4, β1 and δ GABA_A receptor subunits (Griffiths & Lovick, 2005; Lovick et al, 2005). We have investigated whether the increase in expression of α4, β1 and δ GABA_A receptor subunits in late dioestrus is associated with an increase in the responsiveness of the PAG circuitry to a panicogenic compound compared with other phases of the cycle. All experiments were carried out on 200-250g urethane-anaesthetised female Wistar rats (1g kg^-1 i.p.) in proestrus (PRO) or late dioestrus (LD), chosen to represent states of low and high expression, respectively, of α4, β1 and δ GABA_A receptor subunits in the PAG (Lovick et al. 2005). Femoral arterial pressure, heart rate (HR) and respiratory rate (RR) were measured. The panicogenic cholecystokinin CCK_B receptor agonist pentagastrin (PG, 0.002-80μg kg^-1 i.v.) evoked a dose-related increase in mean arterial pressure, heart rate and respiratory rate. The pressor response and tachycardia evoked by 80μg kg^-1 PG in rats in LD (14.7±1.0 mmHg and 14.3±2.2 beats min^-1, means±S.E.M, n=8) was significantly greater than rats in proestrus (10.3±1.5 mmHg and 6.9±2.0 beats min^-1, n=7, p<0.05, ANOVA). Respiratory rate also increased in both groups but the difference between groups was not significant (increase of 17.7±3.3 and 11.9±1.4 breaths min^-1 for LD and PRO, respectively, p=0.13, ANOVA). In electrophysiological experiments, PG (40μg kg^-1 i.v.) evoked excitatory responses in 5/6 presumed output neurones recorded extracellularly in the dPAG using 5-barrelled glass micropipettes. Iontophoretic application of PG (13mM, pH 8-9, 10-30nA) evoked an increase in firing rate in 14/17 cells. Ongoing activity was increased from 5.1±0.4 Hz to 9.7±1.0 Hz (p<0.001). In the presence of the CCK_B receptor antagonist CR2945 (10mM, pH 8-9, 60nA, Sigma) the excitatory response to PG was reduced by 64±7% (p<0.05, n=4). The results suggest that the cardio-respiratory component of the response to i.v. PG may be mediated, at least in part, by activation of CCK_B receptors on neurones within the PAG. Rats in late dioestrus showed heightened responsiveness to PG, which may be linked to the increased expression of α4, β1 and δ GABA_A receptor subunits that occurs on neurones in the PAG at this time.