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Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

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Review

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Sex determinants of experimental panic attacks

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Thelma A. Lovick ∗ Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK

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Article history: Received 17 September 2013 Received in revised form 15 January 2014 Accepted 1 March 2014

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Keywords: Panic Animal models Females Periaqueductal gray Progesterone withdrawal Allopregnanolone Menstrual cycle Mouse Rat

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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. © 2014 Published by Elsevier Ltd.

Panic in women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Incidence of panic in women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Menstrual cycle and panic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Panic in animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Animal models of panic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. PAG and panic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. GABAergic control of PAG excitability during the oestrous cycle in rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Increased susceptibility to panic during the late diestrus phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Withdrawal from progesterone and GABA receptor function in rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Estrous cycle and GABA receptor function in mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Panic and other hormone-linked physiological states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Progesterone metabolism as a therapeutic target for panic in females . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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A panic attack is a form of sudden onset episodic anxiety, usually accompanied by marked autonomic changes. Attacks are characterised by sudden surges of intense fear or terror, a desire to flee, feeling of imminent death, going crazy or loosing control. Associated autonomic changes include palpitations, raised blood pressure, difficulty in deep breathing, sweating, urge to void the bladder and increased gut peristalsis (DSMIV).

∗ Tel.: +44 0121 427 1001. E-mail address: [email protected]

Those who experience repeated attacks are diagnosed as suffering from panic disorder (DSMIV); sufferers may develop anticipatory anxiety about the next attack and avoid places where a panic attack would be embarrassing. Ultimately, generalised avoidance or agoraphobia may ensue. At least two panic subtypes are thought to co-exist, one characterised by a respiratory component and a second class typified by general somatic symptoms (Roberson-Nay and Kendler, 2011). Panic attacks may occur mainly at night (nocturnal panic) and panic may present with agoraphobia. So far, differences in aetiology have not been shown.

http://dx.doi.org/10.1016/j.neubiorev.2014.03.006 0149-7634/© 2014 Published by Elsevier Ltd.

Please cite this article in press as: Lovick, T.A., Sex determinants of experimental panic attacks. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.03.006

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1. Panic in women

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1.1. Incidence of panic in women

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Panic attacks are surprisingly common. It has been estimated that 7–10% of the population will experience at least one panic attack during their lifetime and about 2–5% of the population have panic disorder (i.e., frequent and/or disabling panic attacks) (Goodwin et al., 2005). The lifetime prevalence of panic disorder in women is more than twice that of men (Eaton et al., 1994; McLean et al., 2011; Sheikh et al., 2002). Age is another confounding factor in women, in whom panic disorder is rare before puberty or after menopause. The peak age for onset occurs during the period of young adult hood (i.e. >15 years) and the incidence declines markedly in middle age (Eaton, 1995; Von Korff et al., 1985). Panic is therefore most common in premenopausal females. 1.2. Menstrual cycle and panic Women with panic disorder commonly show menstrual cyclelinked fluctuations in the symptoms of panic anxiety. An increase in anxiety symptoms and in the frequency of panic attacks has been reported to occur during the late luteal (premenstrual) phase (Breier et al., 1986; Cameron et al., 1988; Kaspi et al., 1994; Sigmon et al., 2000 but see Stein et al., 1989). In susceptible individuals panic symptoms can also be induced experimentally by chemical provocation, e.g., by intravenous infusion of sodium lactate, CCK-4 or pentagastrin or by inhalation of CO2 -enriched air (Eser et al., 2007; Facchinetti et al., 1992; Lapierre et al., 1984; Liebowitz et al., 1986; Leibold et al., 2013). As with ‘spontaneous’ panic, responsiveness to such panicogenic challenges is enhanced during the premenstrual period (Landén and Eriksson, 2003; Nillni et al., 2011). The premenstrual period is a time when many women who are not panic sufferers, as well as those who are, experience a constellation of adverse psychological symptoms known as premenstrual syndrome (PMS). These symptoms, which include irritability, mood swings and anxiety, are triggered by everyday stressful psychological challenges that, at other times of the monthly cycle, are not perceived as especially troublesome. PMS afflicts 30–80% of premenopausal women during the late luteal phase of their menstrual cycle, with a minority (around 5%) who experience extremely severe symptoms being classified as suffering from the psychiatric condition premenstrual dysphoric disorder (PMDD) (O’Brien et al., 2011). Interestingly, patients with PMDD but no history of panic, showed a greater responsiveness to experimental panicogenic challenge than healthy control subjects (Le Mellédo et al., 1999, 2000; Gorman et al., 2001; Sandberg et al., 1993). Indeed panic can be induced both in PMDD sufferers and in patients suffering with panic disorder by administration of the benzodiazepine antagonist flumazenil, suggesting a common involvement of GABA systems in the two disorders (Le Mellédo et al., 2000; Nutt et al., 1990). The association between increased susceptibility to panic and development of PMS-like symptoms, together with the co-morbidity of panic and PMDD and the overlapping pharmacology, lend credence to the suggestion that PMDD may be a variant of panic disorder (Vickers and McNally, 2004). Equally, the reverse may hold true. In terms of PMS, there is a clear link between onset of symptoms and cyclical changes in ovarian hormones; symptoms do not appear in anovulatory cycles (Bäckström et al., 2003; Hoyer et al., 2013). Ovulation itself is not the key factor however, since many women taking the combined contraceptive pill on a 21 day on, 7 day off dosing regimen, which prevents ovulation, also experience PMS-like symptoms that peak during the 7 day drug-free period (Coffee et al., 2008; Kadian and O’Brien, 2012). Comparable data

are not available for panic sufferers who take the contraceptive pill. However, given the link between PMDD and susceptibility to panic during the late luteal phase in spontaneously cycling women (see above), withdrawal from progesterone may be a contributory factor that increases the susceptibility of women to panic as well as to developing PMS. In terms of PMS, symptoms occur at a time when blood levels of progesterone or synthetic progestins are dropping rapidly, i.e., during the late luteal phase or as women taking the contraceptive pill begin the 7 day drug-free period. Thus progesterone withdrawal may be the trigger for PMS. In this article we will explore possibility that withdrawal from progesterone also confers an increased susceptibility to panic in females.

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2. Panic in animals

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2.1. Animal models of panic

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Progress in understanding the neuronal dysfunction that underlies the development of anxiety states such as panic is critically dependent on the availability of good animal models of the human condition (for critical analysis of animal modelling of human anxiety states see Donner and Lowry, 2013). Various animal models have now been developed in order to investigate the neural mechanism underlying panic and to screen potential anti-panic agents. Predator-elicited flight responses, e.g., confrontation of a mouse by ˜ et al., 2012) and expo- Q2 a snake (Griebel et al., 1996; Uribe-Marino sure to ultrasound in rats (Beckett et al., 1996; Klein et al., 2010) both induce panic-like flight behaviour and autonomic changes characteristic of panic. The elevated T-maze has been validated as a sensitive behavioural test that can discriminate between paniclike and anxiety-like behaviour in rats and mice (Graeff et al., 1998; Teixeira et al., 2000; Pobbe et al., 2011; see also Zangrossi and Graeff, in this issue). The mouse defense test battery is another powerful tool in this respect (Blanchard et al., 2001). In rats, disinhibition of neuronal activity in the dorsomedial hypothalamus induced by microinjection of a GABAA antagonist is a procedure that has been shown to render animals panic prone. Indeed, the panicprone rat exhibits many of the characteristics of panic patients in that it responds with fearful behaviour and autonomic arousal to chemical panicogenic challenges that do not provoke a response in normal rats (Johnson and Shekhar, 2012; Johnson et al., 2008). 2.2. PAG and panic Whilst there is much merit in these models, perhaps the most translational model of panic in animals, which equates directly with the human condition, is the response evoked by stimulation in the dorsal part of the midbrain periaqueductal grey matter (PAG). More than 40 years ago neurosurgeons investigating deep brain stimulation at midbrain sites as a method for relieving intractable pain reported that the procedure often evoked intolerable side effects, which resembled the symptoms of panic (Kumar et al., 1997; Nashold et al., 1969; Richardson and Akil, 1977). As a consequence this procedure was soon abandoned. However, in terms of understanding the neural basis of panic, the experience of those pain patients was important since it validated stimulation in the dorsal part of the PAG as a panic model in animals. In rats dorsal PAG stimulation evokes flight behaviour and autonomic changes characteristic of panic (Yardley and Hilton, 1986). Animals find the stimulation highly aversive; rats readily learn to carry out tasks that will terminate the stimulus (switch-off behaviour) (Jenck et al., 1995). In rats experimental provocation of panic by inhalation of hypercarbic gas leads to functional activation of neurones in the dorsal part of the PAG (Johnson et al., 2011). In humans too, imaging studies have demonstrated activation of a midbrain region

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Fig. 1. Cartoon to depict functional consequences of increased ␣4␤1␦ GABAA receptor expression in the PAG. (A) When expression of ␣4␤1␦ receptors is low, spontaneous activity in GABAergic interneurones in the PAG limits the excitability of the output neurones. (B) Increased expression of ␣4␤1␦ receptors when progesterone levels fall leads to an increase in tonic current carried by GABAergic cells, which limits their on-going activity. The output neurones therefore become intrinsically more excitable, and the threshold for activation by panicogenic stimuli is lowered. Reproduced from Lovick (2006). 178 179 180 181 182 183 184

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corresponding or close to the PAG during experimentally induced panic (Eser et al., 2009). Based on the similarities between the human experience of PAG stimulation and responses evoked by stimulation at the same region in animals, the response to stimulation in the dorsal PAG is now considered a validated animal model for panic (Brandão et al., 2008; Del-Ben and Graeff, 2009; Lovick, 2000; Schenberg et al., 2001).

2.3. GABAergic control of PAG excitability during the oestrous cycle in rats Although panic afflicts both men and women, the incidence in women is double that of men (see Section 1.1), suggesting that one or more sex-specific aspects of female brain function confer an increased susceptibility to panic. Given the association between susceptibility to panic and the phase of the menstrual cycle in women (see Section 1.2) the effect of sex hormones on the panic circuitry may be particularly important. Basic research on panic using animal models has, until very recently, been confined almost exclusively to males. The female brain, unlike its male counterpart, operates in a constantly changing chemical milieu caused by cyclical changes in production of gonadal sex hormones, which are neuroactive. These highly lipophilic molecules pass readily through the blood brain barrier. Changes in secretion in the periphery are paralleled by changes in their concentration in the brain where they have the potential to influence neuronal excitability (Corpéchot et al., 1993). The PAG of both males and females is rich in GABA-containing cells (Barbaresi, 2005; Griffiths and Lovick, 2005a; Lovick and Paul, 1999). The excitability of the PAG circuitry is normally held in check by ongoing activity in its GABAergic population. In males, disinhibition of GABA tone in the PAG by microinjection of GABA antagonists evokes a panic-like reaction similar to that evoked by direct electrical stimulation (Brandão et al., 1982; Schenberg et al., 1983). GABAA receptors expressed by the GABAergic cell population in the PAG show considerable plasticity during the estrous cycle in females. During the late diestrus phase the expression of ␣4, ␤1 and ␦ GABAA receptor subunits increases markedly (Lovick et al., 2005). In recombinant systems these subunits co-assemble to form functional ␣4␤1␦ receptors, which display electrophysiological properties characteristic of extrasynaptic receptors that carry tonic currents (Lovick et al., 2005). In vivo this GABA receptor upregulation results in a decrease in ongoing inhibitory GABAergic activity, which manifests as an increase in excitability of the output neurons of the PAG (Fig. 1) (Brack and Lovick, 2007).

Fig. 2. Change in plasma concentration of progesterone during the oestrous cycle of the rat. Data redrawn from Butcher et al. (1974).

2.4. Increased susceptibility to panic during the late diestrus phase In the anaesthetised female rat preparation one of the functional consequences of the decrease in GABAergic tone in the PAG during the late diestrus phase is an increase in cardiovascular and respiratory responses to systemic administration of panicogenic agents (Brack et al., 2006). Estrous cycle-linked responses to these agents have not been tested in conscious animals. However, using the elevated plus maze test (EPM) modest indications of increased anxiety have been reported during the diestrus phase in some studies (DíazVéliz et al., 1997; Mora et al., 1996; Marcondes et al., 2001) but not in others (Nin et al., 2012; Sadeghipour et al., 2007). Transfer latency in the EPM (an index of learning and memory) was also longer during diestrus (Reddy and Kulkarni, 1999). In the elevated T-maze test female rats in diestrus, but not at other stages of the cycle, displayed higher inhibitory avoidance scores than males (Gouveia et al., 2004). These behavioural models indicate a tendency towards increased anxiety levels in females during the diestrus phase. However the models are not specific to panic-like anxiety. Neither do they take into account the fact that the level of secretion of some sex hormones is not constant during the diestrus phase. Diestrus in the rat is characterised by steady, low level secretion of oestrogen (Butcher et al., 1974). However, progesterone secretion rises during the first half of diestrus and then declines sharply during the latter half (Butcher et al., 1974) (Fig. 2). When behaviour during the diestrus phase is subdivided into early (high progesterone) and late (low progesterone) phases, identified by characteristic

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Fig. 3. Photomicrographs showing the characteristic cytology of vaginal smears obtained from rats in proestrus (PRO), oestrus (OEST), early dioestrus (ED) and late dioestrus (LD). Proestrus: round-nucleated epithelial cells (e) and occasional larger, a nucleated cornified cells (c). Oestrus: cornified cells only (c). Early dioestrus: polymorphonuclear leucocytes with distinctly lobed nuclei (li) and occasional epithelial cells (e). Late dioestrus: polymorphonuclear leucocytes lose lobed appearance (lii) and disintegrating (liii). Some epithelial cells (e). Figure reproduced from Brack et al. (2006) with permission.

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vaginal cytology (Fig. 3), significant differences in behaviour begin to emerge. During late diestrus, but not at other stages of the cycle, exposure of female rats to anxiogenic vibration stress (a mild form of unconditioned fear) evoked hyperalgesia (Devall et al., 2009). When placed in an unfamiliar open field arena, rats in the late diestrus phase also showed a higher level of anxiety, taking longer to re-enter the centre of the field compared to other cycle stages (Devall et al., 2009). Supporting these findings, preliminary data using the response to direct stimulation of the PAG as a more robust panic model (see Section 2.2), have shown that the panic circuitry is more excitable during the late diestrus phase (Santos and Brandão, 2010). Thus the behaviour of female rats in late diestrus appears to resemble that of women who show increased susceptibility to panic during the late luteal (premenstrual) phase of their cycle.

this brief surge in progesterone secretion, which lasts only a few hours, does not appear to be sufficiently long-lasting to cause significant changes in GABAA receptor subunit expression (see Lovick, 2006 for further discussion on this point). Direct evidence for a causal relationship between progesterone withdrawal and changes in GABAA receptor expression has been provided from studies in animal models in which progesterone concentration is manipulated by external means. In female rats abrupt cessation of a daily regimen of dosing with progesterone triggered up-regulation of ␣4, ␤1 and ␦ subunits of the GABAA receptor in several brain structures including the PAG (Griffiths and Lovick, 2005b; Gulinello et al., 2003; Smith and Gong, 2005). The withdrawal effect was due not to progesterone itself but to the fall in concentration of its neuroactive metabolite allopregnanolone (ALLO) (Follesa et al., 2000; Gangisetty and Reddy, 2010; Gulinello et al., 2003; Smith et al., 1998). Recombinant ␣4␤1␦ receptors show electrophysiological properties characteristic of ␦ subunit-containing receptors that are located extrasynaptically and act tonically to modify the level of ongoing GABAergic inhibitory activity that regulates the excitability of neuronal ensembles (Farrant and Nusser, 2005; Lovick et al., 2005; Mody, 2005). In a similar manner to the progesterone withdrawal response evoked during late diestrus, the functional consequences of exogenous progesterone- and hence allopregnanolone withdrawal-induced receptor upregulation are also manifested as increases in neuronal excitability and an increase in anxiety-linked behaviours (Löfgren et al., 2006; Smith et al., 1998; Hsu and Smith, 2003; Griffiths and Lovick, 2005b; Devall et al., 2009). An interestingly series of studies in mice has revealed a paradoxical response to allopregnanolone when ␣4␤␦ GABAA receptor expression is high. Thus during allopregnanolone withdrawal, which induces ␣4␤␦ receptor upregulation, acute administration of allopregnanolone was anxiogenic, in direct contrast to the anxiolytic effect seen in mice not undergoing steroid withdrawal (Smith et al., 2006). Since allopregnanolone is released from the adrenal gland in response to acute stress, these findings are important as they may go some way towards explaining the increased responsiveness to acute anxiogenic stress and the susceptibility to panic commonly seen in women during the late luteal (premenstrual) phase of their cycle. The progesterone withdrawal effect is not specific to females. Withdrawal effects have also been reported in the hippocampus of progesterone-treated male animals (Gulinello et al., 2002) but interestingly, not in the amygdala (Gulinello et al., 2003). Hippocampal pyramidal cells and cerebellar granule cells grown in culture also show a similar withdrawal response to progesterone (Follesa et al., 2000; Mostallino et al., 2006). However it is debatable whether the events seen in males would occur under physiological conditions since the level of progesterone in males is very low compared to females (Corpéchot et al., 1993) and remains relatively stable.

2.5. Withdrawal from progesterone and GABA receptor function in rats

2.6. Estrous cycle and GABA receptor function in mice

In women the premenstrual (late luteal) phase of the menstrual cycle is characterised by a sharp decline in progesterone secretion (Lovick et al., 2005; Griffiths and Lovick, 2005a). Studies on spontaneously cycling rats indicate a correlation between falling progesterone, increase in panic-like anxiety behaviours and plasticity of GABAA receptor expression. In rats in their late diestrus phase: a time when progesterone concentration is falling, up-regulation of ␣4, ␤1 and ␦ subunits of the GABAA receptor occurs in the PAG, which is associated with changes in the excitability of its neural circuitry (Brack and Lovick, 2007, 2005b). A spike in progesterone secretion also occurs during the proestrus phase (Fig. 2). However,

Mouse models are being used increasingly for studies on stress and anxiety because of the opportunities offered for probing underlying mechanisms using genetically modified animals. Withdrawal from an exogenous progesterone dosing regimen in mice triggers upregulation of ␣4 and ␦ subunit expression in the hippocampus and changes in behavioural responsiveness, as it does in rats (Gangisetty and Reddy, 2010; Smith et al., 2006). However, studies of oestrous cycle-linked changes in receptor expression and behaviour in spontaneous cycling mice reveal species differences. Mice showed hippocampal subfield-specific upregulation of ␦ subunit mRNA of the GABAA receptor in diestrus 1 compared to

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2009). Moreover, the emergence of ␣4␤2␦ receptors reversed the effect of allopregnanolone, from an inhibitory to an excitatory role. Thus acute administration of allopregnanolone evoked an increase in anxiety at the onset of puberty in female mice whereas in prepubertal mice or in adults, it was anxiolytic. Thus at puberty acute stressors that increase allopregnanolone are likely to exacerbate the response to stress, which may contribute to some of the socially inappropriate behaviour characteristic of adolescence. So far, investigations of plasticity of GABAA receptor expression at puberty have been confined to the hippocampus. However, similar events occurring in the PAG could give rise to increased susceptibility to panic. Fig. 4. Change in plasma and brain concentration of progesterone during the estrous cycle of the mouse. Thick lines and thin horizontal lines indicate dark and light periods over 24 h. Pro: proestrus; Met: metestrus.

4. Progesterone metabolism as a therapeutic target for panic in females

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the oestrus phase, which was accompanied by an increase in ␣1 and ␣2 subunit mRNA expression but no change in ␣4 (Maguire et al., 2005; Wu et al., 2013). This contrasts with rats, which show upregulation of ␣4 and ␦ subunits during late diestrus (Lovick et al., 2005; Griffiths and Lovick, 2005a). Since ␣2 subunit-containing receptors are typically synaptically located and unlikely to co-assemble with ␦ subunits, which are typically extrasynaptic (Wu et al., 2013), the functional consequences of increased ␣2 and ␦ subunit expression (mice) rather than ␣4 and ␦ expression (rats) are likely to differ. Indeed, in direct contrast to rats, mice in their diestrus 1 phase, equivalent to early diestrus in rat, when progesterone concentration is high (Fig. 3) (Butcher et al., 1974) showed a decreased level of anxiety in the elevated plus maze test compared to animals in oestrus (Maguire et al., 2005). On the other hand, in rats responsiveness to anxiogenic stress increased (Devall et al., 2009) but not until late diestrus (diestrus 2 of Wu et al., 2013). At first sight it is not easy to rationalise the discrepancies between the findings in rats and mice. However, in female mice, the normal diurnal variation in secretion of progesterone has been shown to be greater than the estrous cycle-linked changes (Corpéchot et al., 1997) (Fig. 4). Moreover, in male mice, basal serum allopregnanolone concentration is, depending on the strain, some 5–10 times higher than in rats (Porcu et al., 2010). If this species difference in basal allopregnanolone concentration extends to females, the effect of estrous cycle-linked variations in concentration of the steroid superimposed on a high basal level may be insufficient to produce the same type of withdrawal response seen in cycling rats. The spontaneously cycling mouse may not therefore be a suitable model for investigating menstrual cycle-associated effects on panic behaviour.

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3. Panic and other hormone-linked physiological states

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In addition to the menstrual cycle the brains of women are subjected to several other significant chemical upheavals during their lifetime: these include puberty, childbirth and menopause. All three states are characterised by changing concentrations of neuroactive steroids. At present it is not clear whether the post partum or peri-menopausal periods are associated with increased risk for onset of panic disorder (Bryant et al., 2012; Ross and McClean, 2006). In contrast, it is well-established that puberty is associated with a marked increase in incidence of panic disorder, especially in females (Eaton, 1995; Von Korff et al., 1985). The onset of puberty is a hormone transition state associated with a decline in hippocampal levels of allopregnanolone (Palumbo et al., 1995) and is therefore a form of allopregnanolone withdrawal. In female mice expression of ␣4␤␦ GABAA receptors increases markedly at extrasynaptic sites at the onset of puberty (Smith et al.,

Studies using rat models have identified a progesterone withdrawal-induced increase in susceptibility to panic-related anxiety. This finding sits well with the observed increase in incidence of panic during the premenstrual phase of the menstrual cycle in women, suggesting that falling secretion of progesterone may be an important precipitating factor. However, not all women panic during their premenstrual period, yet progesterone secretion declines in all women at this time. Despite several investigations, there is no consensus on a direct relationship between absolute progesterone or allopregnanolone levels and susceptibility to panic (see Brambilla et al., 2013 for recent discussion of the literature). However, the key may not be the absolute concentration of progesterone reached but the rate at which it is metabolised. More than 20 years ago Halbreich and colleagues (Halbreich et al., 1986) noted an association between clinical features of premenstrual symptoms and the rate of decrease of progesterone during the late luteal phase. More recently Doornbos et al. (2009), using a rat model showed that abrupt withdrawal from long term dosing with exogenous progesterone and oestrogen triggered increased stress reactivity and anxiety-like behaviour whilst a gradual withdrawal regimen did not. As discussed above (see Section 2.5), the trigger for progesterone withdrawal effects is not the native steroid hormone but its neuroactive metabolite allopregnanolone. Progesterone is metabolised to allopregnanolone by the actions of two reducing enzymes: 5␣-reductase (5␣-R) type I, which transforms progesterone into 5␣-DHP, and 3␣-hydroxysteroid dehydrogenase (3␣-HSD), which transforms 5␣-DHP into allopregnanolone and vice versa (Ebner et al., 2006). Over expression or mutations of the genes controlling these enzymes could dramatically affect the kinetics of progesterone metabolism. Whether abrupt or gradual withdrawal of progesterone has a differential effect on GABAA receptor upregulation in panic-related circuits has yet to be investigated. If it does, this could open new therapeutic opportunities for developing short-term neurosteroid replacement (Lovick, 2013) as a treatment for panic in women.

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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 ...
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