Patients with Premenstrual Syndrome Have Reduced Sensitivity to Midazolam Compared to Control Subjects

Abstract

Premenstrual syndrome (PMS) depends on gonadal hormones produced by the corpus luteum. Given the facilitory actions on GABAergic inhibitory neurotransmission exerted by certain progesterone metabolites, further studies on the GABAA receptor system in premenstrual syndrome are warranted. This study evaluated the benzodiazepine sensitivity in PMS patients and control subjects, using saccadic eye velocity (SEV) and visual analogue ratings of sedation as dependent measures. PMS patients displayed a significantly reduced SEV responsiveness to benzodiazepines compared to control subjects in the follicular phase, whereas there was no difference between groups in the luteal phase. In the luteal phase, the sedation response to benzodiazepines was significantly reduced in PMS patients compared to control subjects. There was also an influence of PMS symptom severity on these measures, as high-severity PMS patients displayed blunted SEV and sedation responses to benzodiazepines compared to low-severity patients. These results indicate that PMS patients have a reduced functional sensitivity at the GABAA/benzodiazepine receptor complex throughout the menstrual cycle.

Steroid withdrawal in the mouse results in anxiogenic effects of 3α,5β-THP: a possible model of premenstrual dysphoric disorder

“…Further, this anxiogenic effect of flumazenil was not observed in the δ knockout mouse, suggesting that α4βδ GABAR mediate this atypical effect of the BDZ antagonist. Both the BDZ insensitivity (Sundstrom et al 1997) and anxiogenic effect of flumazenil (Le Melledo et al 2000) have been reported for women with PMDD, suggesting an additional comparison with the THP withdrawal model in the present study.…”

Neurosteroids in the context of stress: Implications for depressive disorders

“…PMDD women also report more traumatic life stress, including sexual and physical abuse histories (Paddison et al, 1990;Golding & Taylor, 1996Girdler et al, 2003Girdler et al, , 2007. Since allopregnanolone is stress responsive, at least in animal models (Purdy et al, 1991;Barbaccia et al, 1996Barbaccia et al, , 1997, greater allostatic load in PMDD resulting from more severe life stress could contribute to the elevated allopregnanolone concentrations that we have seen in PMDD women (Girdler et al, 2001) and result in the documented alterations in GABA A receptor function in PMDD (Sundstrom et al, 1997a(Sundstrom et al, , 1997b(Sundstrom et al, , 1998, including alterations in the agonism properties of the GABA A receptor as animal models (Smith et al, 2006) and human studies of PMDD suggest (Le Melledo et al, 2000). This could then explain the seemingly paradoxical association between increasing allopregnanolone concentrations in the luteal phase and increased dysphoric mood states in PMDD.…”

“…Behaviorally, PMDD women also generally report less sedation in response to the i.v. benzodiazepines (Sundstrom et al, 1997a(Sundstrom et al, , 1997b. The clinical significance of these results comes from their findings that when PMDD women are divided into lower versus higher symptom severity groups, the more severe PMDD symptom groups respond with less of a reduction in SEV (Sundstrom et al, 1997b(Sundstrom et al, , 1998 and with lower sedation ratings (Sundstrom et al, 1998) in response to benzodiazepines.…”

“…benzodiazepines (Sundstrom et al, 1997a(Sundstrom et al, , 1997b. The clinical significance of these results comes from their findings that when PMDD women are divided into lower versus higher symptom severity groups, the more severe PMDD symptom groups respond with less of a reduction in SEV (Sundstrom et al, 1997b(Sundstrom et al, , 1998 and with lower sedation ratings (Sundstrom et al, 1998) in response to benzodiazepines. Since there is no evidence that PMDD women differ in the density or affinity of peripheral benzodiazepine receptors, at least as measured on lymphocytes (Daly et al, 2001), the findings of Sundstrom and colleagues indicate diminished functional sensitivity of GABA A receptors in PMDD.…”

“…Since benzodiazepines, acting via the GABA A receptor, are known to reduce SEV in a dose-dependent fashion (Hommer et al, 1986), SEV is believed to be a sensitive measure of benzodiazepine/GABA A receptor sensitivity in humans. Using placebo-controlled designs, Sundstrom and colleagues have shown in a series of studies that PMDD women show less of a reduction in SEV to intravenous diazepam (Sundstrom et al, 1997a), midazolam (Sundstrom et al, 1997b), and pregnanolone (Sundstrom et al, 1998) than non-PMDD controls. Behaviorally, PMDD women also generally report less sedation in response to the i.v.…”