The most important and widely studied role of prolactin (PRL) is its modulation of stress responses during pregnancy and lactation. PRL acts as a neuropeptide to support physiological reproductive responses. The effects of PRL on the nervous system contribute to a wide range of changes in the female brain during pregnancy and the inhibition of the hypothalamic–pituitary axis. All these changes contribute to the behavioral and physiological adaptations of a young mother to enable reproductive success. PRL-driven brain adaptations are also crucial for regulating maternal emotionality and well-being. Hyperprolactinemia (elevated PRL levels) is a natural and beneficial phenomenon during pregnancy and lactation. However, in other situations, it is often associated with serious endocrine disorders, such as ovulation suppression, which results in a lack of offspring. This introductory example shows how complex this hormone is. In this review, we focus on the different roles of PRL in the body and emphasize the results obtained from animal models of neuropsychiatric disorders.
The mechanisms of treatment-resistant depression (TRD) are not clear and are difficult to study. An animal model resembling human TRD is the Wistar Kyoto rat strain. In the present study, we focused on selecting miRNAs that differentiate rats of the WKY strain from Wistar Han (WIS) rats in two divisions of the habenula, the lateral and medial (LHb and MHb, respectively). Based on our preliminary study and literature survey, we identified 32 miRNAs that could be potentially regulated in the habenula. Six miRNAs significantly differentiated WKY rats from WIS rats within the MHb, and three significantly differentiated WKY from WIS rats within the LHb. Then, we selected relevant transcripts regulated by those miRNAs, and their expression in the habenular nuclei was investigated. For mRNAs that differentiated WKY rats from WIS rats in the MHb (Cdkn1c, Htr7, Kcnj9, and Slc12a5), their lower expression correlated with a higher level of relevant miRNAs. In the LHb, eight mRNAs significantly differentiated WKY from WIS rats (upregulated Htr4, Drd2, Kcnj5, and Sstr4 and downregulated Htr2a, Htr7, Elk4, and Slc12a5). These data indicate that several important miRNAs are expressed in the habenula, which differentiates WKY rats from WIS rats and in turn correlates with alterations in the expression of target transcripts. Of particular note are two genes whose expression is altered in WKY rats in both LHb and MHb: Slc12a5 and Htr7. Regulation of KCC2 via the 5-HT7 receptor may be a potential target for the treatment of TRD.
Wistar-Kyoto rats (WKY), compared to Wistar rats, are a well-validated animal model for drug-resistant depression. Thanks to this, they can provide information on the potential mechanisms of treatment-resistant depression. Since deep brain stimulation in the prefrontal cortex has been shown to produce rapid antidepressant effects in WKY rats, we focused our study on the prefrontal cortex. Using quantitative autoradiography, we observed a decrease in the binding of [3H] methylspiperone to the dopamine D2 receptor, specifically in that brain region—but not in the striatum, nor the nucleus accumbens—in WKY rats. Further, we focused our studies on the expression level of several components associated with canonical (G proteins), as well as non-canonical, D2-receptor-associated intracellular pathways (e.g., βarrestin2, glycogen synthase kinase 3 beta—Gsk-3β, and β-catenin). As a result, we observed an increase in the expression of mRNA encoding the regulator of G protein signaling 2-RGS2 protein, which is responsible, among other things, for internalizing the D2 dopamine receptor. The increase in RGS2 expression may therefore account for the decreased binding of the radioligand to the D2 receptor. In addition, WKY rats are characterized by the altered signaling of genes associated with the dopamine D2 receptor and the βarrestin2/AKT/Gsk-3β/β-catenin pathway, which may account for certain behavioral traits of this strain and for the treatment-resistant phenotype.
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