Stimulatory effect of dopamine derivative, salsolinol, on pulsatile luteinizing hormone secretion in seasonally anestrous sheep: Focus on dopamine, kisspeptin and gonadotropin-releasing hormone.

In the present study, there was testing of the hypothesis that a centrally administered dopamine (DA) derivative, salsolinol, could affect pulsatile luteinizing hormone (LH) secretion in seasonally anestrous sheep by affecting the neuronal components of the estradiol (E2) negative feedback. In two experiments performed during early spring (increasing day length - March/April), salsolinol or Ringer-Locke solution (control) were administered into the third brain ventricle (IIIv): 1) in several injections for three consecutive days; and 2) in several hour-long infusions. In addition to determining the LH concentration (in both experiments), the abundances of gonadotropin-releasing hormone (GnRH) and kisspeptin mRNA were examined in the hypothalamus and LHß subunit mRNA in the pituitary (Experiment 1). In Experiment 2, concentrations of DA and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in perfusates collected from the infundibular nucleus/median eminence (IN/ME) by the push-pull method. In both experiments, salsolinol increased both LH pulse frequency (P < 0.05) and plasma LH concentration (P < 0.001) compared to controls. The injected salsolinol also increased (P < 0.05) the abundance of GnRH mRNA in the mediobasal hypothalamus and kisspeptin mRNA in the arcuate nucleus. The two doses of infused salsolinol decreased DA to undetectable concentrations and DOPAC concentration by 60% in perfusates collected from the IN/ME. In conclusion, exogenous salsolinol functioning centrally stimulates pulsatile LH secretion in sheep during seasonal anestrus. It is suggested that salsolinol may have this effect by reducing the activity of the hypothalamic neuroendocrine dopaminergic system, which results in an increase in both kisspeptin and GnRH neurons activity.

Adaptive Modifications of Maternal Hypothalamic-Pituitary-Adrenal Axis Activity during Lactation and Salsolinol as a New Player in this Phenomenon.

Both basal and stress-induced secretory activities of the hypothalamic-pituitary-adrenal (HPA) axis are distinctly modified in lactating females. On the one hand, it aims to meet the physiological demands of the mother, and on the other hand, the appropriate and stable plasma cortisol level is one of the essential factors for the proper offspring development. Specific adaptations of HPA axis activity to lactation have been extensively studied in several animal species and humans, providing interesting data on the HPA axis plasticity mechanism. However, most of the data related to this phenomenon are derived from studies in rats. The purpose of this review is to highlight these adaptations, with a particular emphasis on stress reaction and differences that occur between species. Existing data on breastfeeding women are also included in several aspects. Finally, data from the experiments in sheep are presented, indicating a new regulatory factor of the HPA axis-salsolinol-which typical role was revealed in lactation. It is suggested that this dopamine derivative is involved in both maintaining basal and suppressing stress-induced HPA axis activities in lactating dams.

ß3-Adrenergic receptors, adipokines and neuroendocrine activation during stress induced by repeated immune challenge in male and female rats.

The main hypothesis of the study is that stress associated with repeated immune challenge has an impact on ß3-adrenergic receptor gene expression in the brain. Sprague-Dawley rats were intraperitoneally injected with increasing doses of lipopolysaccharide (LPS) for five consecutive days. LPS treatment was associated with body weight loss and increased anxiety-like behavior. In LPS-treated animals of both sexes, ß3-receptor gene expression was increased in the prefrontal cortex but not the hippocampus. LPS treatment decreased ß3-receptor gene expression in white adipose tissue with higher values in males compared to females. In the adipose tissue, LPS reduced peroxisome proliferator-activated receptor-gamma, leptin and adiponectin gene expression, but increased interleukin-6 expression, irrespective of sex. Repeated immune challenge resulted in increased concentrations of plasma aldosterone and corticosterone with higher values of corticosterone in females compared to males. Concentrations of dehydroepiandrosterone (DHEA) in plasma were unaffected by LPS, while DHEA levels in the frontal cortex were lower in the LPS-treated animals compared to the controls. Thus, changes of DHEA levels in the brain take place irrespective of the changes of this neurosteroid in plasma. We have provided the first evidence on stress-induced increase in ß3-adrenergic receptor gene expression in the brain. Greater reduction of ß3-adrenergic receptor expression in the adipose tissue and of the body weight gain by repeated immune challenge in male than in female rats suggests sex differences in the role of ß3-adrenergic receptors in the metabolic functions. LPS-induced changes in adipose tissue regulatory factors and hormone concentrations might be important for coping with chronic infections.

Hypothalamic-pituitary GnRH/LH axis activity is affected by salsolinol in sheep during lactation: Effects of intracerebroventricular infusions of salsolinol and its antagonizing analogue.

The aim of the study was to test the hypothesis that salsolinol, a derivative of dopamine, is involved in the regulation of hypothalamic-pituitary gonadotropic (GnRH/LH) axis activity in lactating sheep. In the first experiment performed on sheep during the fifth week of lactation, a structural analogue of salsolinol (1-MeDIQ) was infused into the third brain ventricle (IIIv) to antagonize its action within the central nervous system (CNS). A push-pull perfusion of the infundibular nucleus/median eminence was performed simultaneously, and blood samples were collected from the jugular vein. In the second experiment, sheep received infusions of salsolinol into the IIIv, 48 hours after the weaning of their 8-week-old lambs. Blood samples were collected during the experimental periods, and the anterior pituitary (AP) tissue was dissected immediately after the end of the experiment. Perfusate GnRH concentration (experiment 1), plasma LH concentration (experiments 1 and 2), and relative LHß mRNA levels in the AP tissue (experiment 2) were assayed. Blocking of salsolinol action in the CNS of lactating sheep caused a significant (P < 0.001) decrease in the perfusate GnRH concentrations in comparison with controls. Treatment with 1-MEDIQ also significantly decreased (P < 0.001) the LH concentration in the blood plasma. In turn, salsolinol infused 48 hours after lamb weaning significantly (P < 0.001) increased plasma LH concentration, reflected in the significant (P < 0.05) increase in the amplitude of LH pulses in the treated sheep as compared to the control animals. There was no significant difference in the relative levels of LHß-subunit mRNA in the AP between control and salsolinol-infused sheep. The results lead to a conclusion that salsolinol affects the secretory activity of the GnRH/LH axis in sheep during lactation. Whether salsolinol infused into the IIIv evokes this stimulatory effect by itself or by modulation of other regulatory systems needs to be clarified.

The influence of salsolinol on dopaminergic system activity within the mediobasal hypothalamus of anestrous sheep: a model for studies on the salsolinol-dopamine relationship.

Salsolinol with its derivatives has been considered as a potential neurotoxin for the dopaminergic system in the human and rat brain. Investigating a sheep model for studies on the action of salsolinol within the central nervous system we examined whether this compound is able to affect the hypothalamic neuroendocrine dopaminergic (NEDA) system during its high seasonal activity, when sheep entered to anestrus under the long day conditions. Therefore, salsolinol was infused into the third ventricle of the brain in combination with the in vivo push-pull perfusion of the mediobasal hypothalamus/median eminence (MBH/ME). The effects of this drug on either perfusate noradrenaline (NA) or plasma prolactin concentration were also studied. The infusion of salsolinol resulted in rapid and permanent diminution in dopamine (DA) release into the extracellular spaces of the MBH/ME up to an undetectable level and in the 57% decrease in DA metabolite 3,4-dihydroxyphenylacetic acid concentration, compared to the control. This effect of salsolinol was accompanied by the significant enhancement of the pituitary prolactin release into circulation. The concentration of other DA metabolite, homovanillic acid, as well as NA in the MBH/ME was not affected. Thus, our results in the anestrous sheep underline the role played by salsolinol as a neuromodulator for the hypothalamic NEDA system and as a signal transmitter for the pituitary prolactin release. We suggest that the hypothalamic NEDA system of anestrous sheep during its high secretory activity may be set as a model for studies on the salsolinol-dopamine relationship.