Evaluation of the Effect of Acute Sibutramine in Female Rats in the Elevated T-Maze and Elevated Plus-Maze Tests

Abstract

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...

Effect of Estrous Cycle on Behavior of Females in Rodent Tests of Anxiety

“…The limited comparisons made between male and female rats in this test show no sex-differences for inhibitory avoidance acquisition or escape expression in Wistar rats ( 93 – 95 ). However, female Long-Evans or Sprague-Dawley rats show a deficit in avoidance learning compared to males, indicating a less anxious phenotype ( 96 ).…”

“…Sex and estrous cycle-linked differences in responsiveness to other anxiolytic drugs have also been reported in other behavioral tests. Whereas, no sex difference was observed in the effect of the serotonin and noradrenaline reuptake inhibitor sibutramine in rats tested in the EPM, sibutramine impaired inhibitory avoidance (withdrawal from the enclosed arm) in the ETM in males but not females, but inhibited escape expression (latency to leave the open arm) in both sexes ( 95 ). When the estrous cycle was taken into consideration, the antipanic-like effect of the drug on escape performance was found to be absent in females in diestrus II but preserved in the other cycle phases ( 95 ).…”

“…With regard to the influence of estrous cycle phases, one study reported that female Wistar rats in diestrus II are slightly more reactive to the open-arms than males (i.e., they take longer to leave the enclosed arm but only in the first trial), indicating a higher anxiety level (93). However, this subtle effect was not replicated in a recent study with the same rat strain (95).…”

Interplay Between the Gut-Brain Axis, Obesity and Cognitive Function

“…The connection between obesity and behavioral deficits is further supported by evidence showing that some anti-obesity therapies exert anxiolytic effects. Thus, several drugs used to treat obesity have attenuated behavioral alterations in mice, such as sibutramine (Santos et al, 2014 ), duloxetine (Chudasama and Bhatt, 2009 ), pioglitazone (Kurhe and Mahesh, 2016 ), celecoxib (Kurhe et al, 2014a ), ondansetron (Kurhe and Mahesh, 2015 ), 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) (Kurhe et al, 2014b , 2015 ), GPR120 agonist (Auguste et al, 2016 ). These findings suggest that obesity and emotional disorders, such as anxiety and depression, could share a common base.…”

Effects of Arctium lappa aqueous extract on lipid profile and hepatic enzyme levels of sucrose-induced metabolic syndrome in female rats

“…Ten days before inducing the metabolic syndrome, every morning between 8 a.m. and 9 a.m., vaginal smears were taken for all groups, and then pro-estrus was a selective phase of this investigation (Santos et al, 2014).. The blood glucose level was measured by a glucometer (Elegans) at the end of the fourth and sixth weeks.…”