Systemic administration of diarylpropionitrile (DPN) or phytoestrogens does not affect anxiety-related behaviors in gonadally intact male rats

Abstract

The development of highly selective agonists for the two major subforms of the estrogen receptor (ERa and ERϐ) has produced new experimental methodologies for delineating the distinct functional role each plays in neurobehavioral biology. It has also been suggested that these compounds might have the potential to treat estrogen influenced behavioral disorders, such as anxiety and depression. Prior work has established that the ERϐ agonist, diarylpropionitrile (DPN) is anxiolytic in gonadectomized animals of both sexes, but whether or not this effect persists in gonadally intact individuals is unknown. Isoflavone phytoestrogens, also potent but less selective ERϐ agonists, have also been shown to influence anxiety in multiple species and are becoming more readily available to humans as health supplements. Here we determined the effects of 0.5, 1 or 2 mg/kg DPN, 1 mg/kg of the ERa agonist propyl-pyrazole-triol (PPT), 3 or 20 mg/kg of the isoflavone equol (EQ) and 3 or 20 mg/kg of the isoflavone polyphenol resveratrol (RES) on anxiety behavior in the gonadally intact male rat using the light/dark box and the elevated plus maze. We first determined that DPN can be successfully administered either orally or by subcutaneous injection, although plasma DPN levels are significantly lower if given orally. Once injected, plasma levels peak rapidly and then decline to baseline levels within 3 hours of administration. For the behavioral studies, all compounds were injected and the animals were tested within 3 hours of treatment. None of the compounds, at any of the doses, significantly altered anxiety-related behavior. Plasma testosterone levels were also not significantly altered suggesting that these compounds do not interfere with endogenous androgen levels. The results suggest that the efficacy of ERϐ agonists may depend on gonadal status. Therefore the therapeutic potential of ERϐ selective agonists to treat mood disorders may be limited.

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

“…Previous behavioral studies reported its beneficial effects on depressive-like symptoms (Samardzic et al, 2013;Wang et al, 2013;Xu et al, 2010;Yu et al, 2012). Except when evaluating the effects of resveratrol on the consequences of prenatal stress (Sahu et al, 2013), studies showed no effects of resveratrol on anxiety-like behavior in lightedark box or open field locomotor data (Patisaul et al, 2009;Samardzic et al, 2013;Wang et al, 2013;Xu et al, 2010). This finding is in agreement with the absence of an effect on object exploration in our study, instead showing a selective effect on social investigation.…”

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

“…These observations fuel the current interest in ER␤ ligands as promising CNS-active compounds that lack ER␣ actions and are known to mediate some unwanted peripheral actions of estradiol, including proliferative effects in breast tissue (Patchev et al, 2008). It is noteworthy that although ER␤ ligands may have anxiolytic actions in gonadectomized males and females, a recent study has shown that they do not affect anxiety-related behavior in gonadintact male rats, indicating that efficacy may be dependent on gonadal hormone status and different in males and females (Patisaul et al, 2009). …”

Use of Phytoestrogens for the Treatment of Psychiatric Symptoms Associated with Menopause Transition

“…In contrast, no efect or anxiogenic efect was reported after a rich isolavone diet administration [66,67]. It is important to mention that these data were generated in male rats instead of female rats where more information is needed.…”

“…The later is an important issue since Harley et al [66] used intact male rats, and Lund and Lephard [64] used intact male and female rats inding positive results in anxiety in females but impaired the anxious-like state in males. Further, Patisaul et al [67] showed that the administration of a soy-rich (600 µg/g) diet to gonadally intact male rats produced anxiogenic efects. Furthermore, authors tested high (20 mg/kg) and low (3 mg/ kg) doses of equol and resveratrol (3 and 20 mg/kg) in two animal models of anxiety in intact male rats.…”

“…Furthermore, authors tested high (20 mg/kg) and low (3 mg/ kg) doses of equol and resveratrol (3 and 20 mg/kg) in two animal models of anxiety in intact male rats. The authors reported that these compounds did not produce any efect after 3 days of treatment and discussed the possibility that the endocrine condition that prevails in males could be a factor to explain the lack of efect [67].…”