Anxiety behavior in female Wistar rats was assessed at different stages of the estrous cycle using the elevated plus maze (EPM). No differences were observed at any cycle stage. Pretreatment with diazepam (1 mg kg(-1) intraperitoneal (i.p.)) 30 min before testing produced an anxiolytic effect (significant increase in percentage of time in the open arms compared to control group in the same cycle phase) in animals in proestrus, estrus, and early diestrus but had no effect in rats in late diestrus. Locomotor activity (total arm entries) was unchanged at any cycle phase. When rats in the late diestrus phase were pretreated with the selective serotonin reuptake inhibitor fluoxetine (1.75 mg kg(-1) i.p. on the afternoon of early diestrus and again in the morning of late diestrus) diazepam produced an anxiolytic effect (increase percentage time in the open arms). This dose is sufficient to raise brain allopregnanolone concentration without affecting 5-hydroxytryptamine (5-HT) systems. We propose that insensitivity to diazepam in late diestrus is due to increased expression of benzodiazepine insensitive α4 subunit-containing gamma-aminobutyric acid A (GABAA) receptors triggered by a sharp decrease in brain allopregnanolone concentration. Pretreatment with fluoxetine to raise brain allopregnanolone concentration during late diestrus prevents the withdrawal effect.
Sibutramine is a serotonin and norepinephrine reuptake inhibitor indicated for the treatment of obesity. A pre-clinical study showed that acute administration of sibutramine promoted anxiolytic-and panicolytic-like effects in male rats. However, in clinical reports, sibutramine favoured the onset of panic attacks in women. In this study, the effect of sibutramine on experimental anxiety in females and the relevance of different oestrous cycle phases for this effect were analysed. In experiment 1, both male and female rats were submitted to acute intraperitoneal injection of sibutramine or vehicle 30 min. before testing in the elevated T-maze (ETM) and in the open-field test (OF). Females in the pro-oestrus (P), oestrus (E), early dioestrus (ED) and late dioestrus (LD) phases were tested in the ETM and OF (experiment 2) or in the elevated plus-maze (EPM) 30 min. after the injection of sibutramine. Sibutramine impaired the escape response in the ETM in both males and females. This effect was observed for P, E and ED, but not for LD females. Sibutramine altered neither the inhibitory avoidance in the ETM nor the behaviour of females in the EPM. Thus, sibutramine promoted a panicolytic-like effect in female rats cycling at P, E and ED, but not in the LD phase and did not alter behaviours related to anxiety in both ETM and EPM. Considering that pre-clinical studies aiming the screening of anxiolytic drugs employ male rodents, data here obtained reinforce the importance of better understanding the effects of drugs in females.Sibutramine is a tertiary amine belonging to the class of derivatives cicloalkylamines that has been shown to reduce food intake in human beings and rodent models and presents clinical efficacy for the treatment of obesity [1][2][3]. Its mechanism of action -similarly to tricyclic antidepressants -involves the blockade of the neuronal reuptake of serotonin and noradrenaline [3,4]. Considering that tricyclic antidepressants, such as imipramine, are employed for the treatment of pathologies such as generalized anxiety disorder and panic disorder in human beings [5,6], it was previously investigated whether sibutramine would alter both anxiety-and panic-related behaviours displayed by male rats submitted to animal tests of anxiety [7,8]. Sibutramine did not affect the behaviour of male rats in the elevated plus-maze (EPM), but it decreased the inhibitory avoidance in both light-dark transition test and elevated T-maze (ETM) and impaired the escape response in the ETM [7,8]. Based on pharmacological validation, inhibitory avoidance generated by light-dark transition test, and ETM has been related to generalized anxiety, whereas the escape response evoked by ETM has been associated with panic [9][10][11][12]. Thus, the authors suggested that sibutramine would have a relevant role in the treatment of generalized anxiety and panic disorders [7].Clinical data have linked sibutramine intake to behavioural alterations, including those suggesting an antidepressant effect [13,14]. Meanwhile, there a...
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