Female psychopharmacology matters! Towards a sex-specific psychopharmacology.

There is increasing recognition that women have a higher prevalence of certain psychiatric illnesses, and a differential treatment response and course of illness compared to men. Additionally, clinicians deal with a number of disorders like premenstrual syndrome, premenstrual dysphoric disorder, and postpartum depression, which affect women specifically and for which treatment and biological pathways are still unclear. In this article we highlight recent research which suggests that different biological mechanisms may underlie sex differences in responsiveness to stress. Sex differences are evident at the receptor level; where the corticotropin-releasing factor receptor shows differential coupling to adaptor proteins in males and females. The neuropeptide oxytocin also shows sex-specific effects in a range of social behaviors. It may act as a biomarker in post-traumatic stress disorder where sex differences are evident. Studies in women using hormonal contraception show that some of these oxytocin-mediated effects are likely influenced by sex hormones. In female rats rapid changes in circulating progesterone levels are associated with exaggerated behavioral responses to mild stress and blunted responses to benzodiazepines that could be prevented by acute treatment with low-dose fluoxetine. Perceived barriers in research on women have hindered progress. The development of a sex-specific psychopharmacology as a basis for translating this type of research into clinical practice is vital to improve treatment outcomes for women.

A specific profile of luteal phase progesterone is associated with the development of premenstrual symptoms.

There is a consensus that the development of premenstrual dysphoric states is related to cyclical change in gonadal hormone secretion during the menstrual cycle. However, results from studies seeking to link symptom severity to luteal phase progesterone concentration have been equivocal. In the present study we evaluated not only the absolute concentrations of progesterone but also the kinetics of the change in progesterone concentration in relation to development of premenstrual symptoms during the last 10days of the luteal phase in a population of 46 healthy young adult Brazilian women aged 18-39 years, mean 26.5±6.7years. In participants who developed symptoms of premenstrual distress, daily saliva progesterone concentration remained stable during most of the mid-late luteal phase, before declining sharply during the last 3days prior to onset of menstruation. In contrast, progesterone concentration in asymptomatic women underwent a gradual decline over the last 8days prior to menstruation. Neither maximum nor minimum concentrations of progesterone in the two groups were related to the appearance or severity of premenstrual symptoms. We propose that individual differences in the kinetics of progesterone secretion and/or metabolism may confer differential susceptibility to the development of premenstrual syndrome.

Sex determinants of experimental panic attacks.

Panic disorder is twice a common in women than in men. In women, susceptibility to panic increases during the late luteal (premenstrual) phase of the menstrual cycle, when progesterone secretion is in rapid decline. This article considers the evidence for the midbrain periaqueductal grey (PAG) as a locus for panic and for the use of PAG stimulation as an animal model of panic in both sexes. We show in females how a rapid fall in progesterone secretion, such as occurs during the late dioestrus phase of the ovarian cycle in rats (similar to the late luteal phase in women), triggers a neuronal withdrawal response during which the excitability of the midbrain panic circuitry increases as a result of upregulation of extrasynaptic GABAA receptors on inhibitory interneurones in the PAG. The withdrawal effect is due not to the native hormone but to its neuroactive metabolite allopregnanolone. Differences in the kinetics of allopregnanolone metabolism may contribute to individual differences in susceptibility to panic in women.

Estrous cycle stage influences on neuronal responsiveness to repeated anxiogenic stress in female rats.

Experiments were carried out to investigate (i) whether estrous cycle stage influences nociceptive responsiveness to anxiogenic stress and (ii) whether prior experience of the stressor modifies the response. Exposure to mild anxiogenic vibration stress evoked hyperalgesia, reflected by a decrease in tail flick latency, only in animals in the late diestrus phase. Stress evoked hyperalgesia in late diestrus regardless of whether the rat was experiencing the stress for the first time or had been exposed to the stress previously, when in another cycle stage. Whilst the behavioral response to stress appeared to be determined exclusively by estrous cycle stage, the stress-evoked pattern of Fos expression in the periaqueductal grey matter (PAG) depended not only on cycle stage but also on whether the rat had previous experience of the stress. First exposure to stress in late diestrus evoked a 50% decrease in Fos expression compared to non-stressed controls, particularly in the lateral and dorsolateral sectors of the rostral PAG. In contrast, in experienced rats in late diestrus the pattern of Fos expression increased up to 4-fold, particularly in the ventral half of the caudal PAG but also in the lateral and dorsolateral parts. At other cycle stages Fos expression was not changed except for an increase in rats in proestrus. The results suggest that in females, changes in gonadal hormone levels during the estrous cycle impact significantly on the processing of fear-inducing stimuli by the PAG. These hormonal influences may also influence how the PAG responds to a subsequent anxiogenic challenge.

Differential activation of the periaqueductal gray by mild anxiogenic stress at different stages of the estrous cycle in female rats.

The effect of acute exposure to mild anxiogenic stress on cutaneous nociceptive threshold was investigated in female Wistar rats at different stages of the estrous cycle. Baseline tail flick latencies did not change significantly during the cycle. However after brief exposure to vibration stress (4 Hz for 5 min), rats in late diestrus, but not at other cycle stages, developed a hyperalgesia (decrease in tail flick latency). Animals in late diestrus revealed a more than fivefold increase in the density of Fos-like immunoreactive nuclei in the dorsolateral, lateral, and ventrolateral columns in the caudal half of the periaqueductal gray matter (PAG). There was no change in the density of Fos-like immunoreactive nuclei in the PAG in rats in estrus and early diestrus, although rats in proestrus showed a smaller (50%) but significant increase. Rats undergoing withdrawal from a progesterone dosing regimen (5 mg/kg i.p. twice daily for 6 days) designed to mimic the fall in progesterone that occurs naturally during late diestrus, exhibited a stress-induced hyperalgesia that was similar to animals in late diestrus and a significant increase in Fos-positive cells in the PAG. We suggest that falling levels of progesterone during late diestrus may be a predisposing factor for the development of stress-induced hyperalgesia, which is linked to differential activation of descending pain control circuits in the PAG. Similar changes in women, when progesterone levels fall during the late luteal phase of the menstrual cycle, may contribute to the development of premenstrual symptoms that include increased anxiety and hyperalgesia.

Hyperalgesia in the setting of anxiety: sex differences and effects of the oestrous cycle in Wistar rats.

Sex differences to noxious thermal cutaneous stimulation were compared in Wistar rats. Male and female rats showed similar baseline tail flick latencies. However, sex differences emerged when nociceptive testing was carried out in the setting of mild non-noxious anxiogenic stress (4Hz vibration for 5min). On cessation of vibration stress 16/35 (46%) of male rats showed hyperalgesia (decrease in tail flick latency lasting >20min) whist the reminder showed a brief (<2min) hypoalgesia. In 15 animals re-tested the next day, stress-induced hyperalgesia was reproducible (n=7) but the hypoalgesia initially present in 8 rats was less stable, being reduced (n=2) or replaced by weak hyperalgesia (n=3) in some cases. The response of females was oestrous cycle dependent. On cessation of the vibration stress, females in late dioestrus displayed rapid onset hyperalgesia lasting 10min (n=12) whilst others showed either brief (<2min) hypoalgesia (proestrus, n=13 and early dioestrus, n=9) or brief (<2min) delayed hyperalgesia (oestrus, n=16). On re-testing the next day, when most rats were in a different stage of their cycle, the responsiveness of individual female rats changed according to cycle stage. Thus in females, stage of the oestrous cycle rather than trait differences between individuals appears to be the important determinant of responsiveness to stress. Hyperalgesia in females in late dioestrus correlated with increased anxiety behaviour in a novel environment: rats in late dioestrus showed longer latencies to re-enter the inner zone of an open field compared to rats in other cycle stages. Rats undergoing withdrawal from a progesterone dosing regimen (5mgkg(-1) IP twice daily for 6 days) to mimic the fall in progesterone that occurs naturally during late dioestrus, exhibited a stress-induced hyperalgesia similar to animals in late dioestrus. Falling levels of progesterone during late dioestrus may therefore be a pre-disposing factor for the development of stress-induced hyperalgesia in females.