Benefits of Hormone Therapy Estrogens Depend on Estrogen Type: 17β-Estradiol and Conjugated Equine Estrogens Have Differential Effects on Cognitive, Anxiety-Like, and Depressive-Like Behaviors and Increase Tryptophan Hydroxylase-2 mRNA Levels in Dorsal Raphe Nucleus Subregions

Abstract

Decreased serotonin (5-HT) function is associated with numerous cognitive and affective disorders. Women are more vulnerable to these disorders and have a lower rate of 5-HT synthesis than men. Serotonergic neurons in the dorsal raphe nucleus (DRN) are a major source of 5-HT in the forebrain and play a critical role in regulation of stress-related disorders. In particular, polymorphisms of tryptophan hydroxylase-2 (TpH2, the brain-specific, rate-limiting enzyme for 5-HT biosynthesis) are implicated in cognitive and affective disorders. Administration of 17β-estradiol (E2), the most potent naturally circulating estrogen in women and rats, can have beneficial effects on cognitive, anxiety-like, and depressive-like behaviors. Moreover, E2 increases TpH2 mRNA in specific subregions of the DRN. Although conjugated equine estrogens (CEE) are a commonly prescribed estrogen component of hormone therapy in menopausal women, there is a marked gap in knowledge regarding how CEE affects these behaviors and the brain 5-HT system. Therefore, we compared the effects of CEE and E2 treatments on behavior and TpH2 mRNA. Female Sprague-Dawley rats were ovariectomized, administered either vehicle, CEE, or E2 and tested on a battery of cognitive, anxiety-like, and depressive-like behaviors. The brains of these animals were subsequently analyzed for TpH2 mRNA. Both CEE and E2 exerted beneficial behavioral effects, although efficacy depended on the distinct behavior and for cognition, on the task difficulty. Compared to CEE, E2 generally had more robust anxiolytic and antidepressant effects. E2 increased TpH2 mRNA in the caudal and mid DRN, corroborating previous findings. However, CEE increased TpH2 mRNA in the caudal and rostral, but not the mid, DRN, suggesting that distinct estrogens can have subregion-specific effects on TpH2 gene expression. We also found differential correlations between the level of TpH2 mRNA in specific DRN subregions and behavior, depending on the type of behavior. These distinct associations imply that cognition, anxiety-like, and depressive-like behaviors are modulated by unique serotonergic neurocircuitry, opening the possibility of novel avenues of targeted treatment for different types of cognitive and affective disorders.

Influence of ovarian hormones on value-based decision-making systems: Contribution to sexual dimorphisms in mental disorders

“…Although not directly assessed in the decision-making domain, evidence suggests a positive effect of estradiol on the serotonergic neurotransmission in the DRN as well: estradiol treatment, unopposed by progesterone, of ovariectomized female rats increased serotonin synthesis in caudal DRN and correlated with decreased anxiety-like behaviors (Hiroi et al, 2006(Hiroi et al, , 2016. Felton and Auerbach (2004) found higher extracellular serotonin level during the proestrus as compared to the estrus phase.…”

Tamoxifen Blocks the Development of Motivational Features of an Addiction-Like Phenotype in Female Rats

“…Additionally, while 100% of non-treated controls showed a 15% or more increase in motivation for cocaine following protracted abstinence, only 44% of the vehicle-treated group displayed this phenotype. We selected sesame oil for the vehicle in this study as it is commonly used to dissolve fat-soluble hormones in not only addiction studies (Perrotti et al, 2000; Roth-Deri et al, 2006; Silverman and Koenig, 2007; Russo et al, 2008; Mello et al, 2011; Van Swearingen et al, 2013; Ghazvini et al, 2016; Rauhut and Curran-Rauhut, 2018), but also in general biomedical studies (Dubal et al, 2001; Babaei et al, 2010; Asarian et al, 2012; McClure et al, 2013; Hiroi et al, 2016; González-Garcia et al, 2018; Khariv et al, 2018; Matsumoto et al, 2018). Given its widespread use, we were reluctant to attribute effects in the vehicle group to sesame oil.…”

New Insights for Hormone Therapy in Perimenopausal Women Neuroprotection

“…There are comparisons regarding the subregion-specific effects on tryptophan hydroxylase-2 (TpH2, the brain-specific, rate-limiting enzyme for 5-HT biosynthesis, a serotonin precursor). The comparison of CEE and E2 treatments on behavior and TpH2 mRNA on female ovariectomized Sprague Dawley rats [43]. Both CEE and E2 exert beneficial behavioral effects, although efficacy depended on the distinct behavior and for cognition, on the task difficulty.…”