An overlooked area in the domain of panic research is the influence of the menstrual cycle and the menstrual cycle-related disorder, premenstrual dysphoric disorder (PDD), on behavioral sensitivity to panicogenic agents. In this regard, we have studied the behavioral effects of systemic administration of cholecystokinin-tetrapeptide (CCK-4) in normal women with and without PDD (CCK-4 is a neurotransmitter which is also a well validated panicogenic agent). The diagnosis of PDD was made following the prospective monitoring of at least four completed menstrual cycles using the Prism Calendar. A randomized placebo-controlled three-period design was used. Placebo was administered in the first study period which coincided with the luteal phase of the menstrual cycle (2-5 days before end of cycle). CCK-4 (35 [mu ]g) was administered in periods two and three under two conditions; during the luteal phase (2-5 days before end of cycle) and follicular phase (7-10 days after onset of menses) of the menstrual cycle. Subjects were blind to the phase order in which placebo and CCK-4 were administered and the order of the phases in which subjects received the CCK-4 injections was randomized (Follicular-Luteal or Luteal-Follicular). The accuracy of the timing of placebo and CCK-4 administrations was insured by the use of a kit for leutinizing hormone peak detection in urine allowing an accurate determination of ovulation. Behavioral response to CCK-4 was evaluated with an 18-item DSM-III-R derived Panic Symptom Scale (PSS). Preliminary analysis (12 women with PDD, 13 controls) of sum intensity scores (i.e., the sum of the intensity ratings) revealed that women with PDD were behaviorally hypersensitive to CCK-4, irrespective of menstrual cycle phase (F (1,21) = 10.49, p [lt ] 0.004). The mean ([plusmn]SEM) sum intensity score during the follicular and luteal phase of the menstrual cycle was 20.4 [plusmn] 2.8 and 22.9 [plusmn] 4.0 respectively for women with PDD, and 14.1 [plusmn] 2.2 and 15.4 [plusmn] 2.0 respectively for women without PDD. These preliminary data provide evidence to suggest that the presence of PDD can account for a significant proportion of the variance in behavioral response to CCK-4 in female subjects. Conceivably, the enhanced behavioral responsivity to CCK-4 evident in women with PDD is attributable, at least in part, to hypersensitivity of the CCK B receptor system and/or to alterations in neurotransmitter systems which interface with CCK.