Neural regulation and dynamics of prolactin secretion in the rat = Neurale regulatie en dynamiek van de prolactine secretie in de rat

<TT>The subject of this thesis was an investigation of the neural regulation and dynamics of prolactin (Prl) secretion. Experimentation was performed with freely behaving undisturbed male and female rats, chronically fitted with an atrial blood sampling catheter. In some studies rats were also equipped with a chronic intracerebroventricular cannula, or with chronic metal electrodes bilaterally implanted in the medial preoptic area (MPOA) or the median eminence (ME). Stress was always carefully avoided. The animals, therefore, had a post-operative recovery period of at least one week, during which time they were handled daily and fully accustomed to the experimental situation. During experimentation blood samples were collected between 06.00 and 22.00 h. Blood volume reduction was compensated for with blood transfusions.</TT><TT>The study starts with a thorough evaluation of circulating (Prl) levels in cycling and pseudopregnant (PSP) rats (chapter 1). Onehour interval studies show that diestrous (Prl) levels were low, about 15 ng/ml, and showed minor fluctuations. During the afternoon and early night of proestrus a single (Prl) surge was observed with a peak level of 1100 ng/ml at 17.00 h. On the afternoon of estrus there was also a single surge which was of a smaller magnitude and duration, with a peak level of 400 ng/ml at 16.00 h. In PSP rats two daily (Prl) surges were released during successively 11 days, one nocturnal and one diurnal. During the course of PSP these surges gradually declined in magnitude. Short-time sampling interval studies show that (Prl) secretion during PSP occurred occasionally in substantial bursts from baseline levels, whereas during the afternoon of proestrus plasma (Prl) was elevated constantly due to a more or less continuous release of (Prl) Such a difference in actual secretion patterns indicates a separate neural regulation.</TT><TT>These data were obtained in rats chronically fitted with a blood sampling/transfusion catheter. Since (Prl) secretion is extremely susceptible to stress, it was necessary to investigate whether the applied blood sampling/transfusion procedure was free of stress. It appeared that frequent blood sampling for several hours at rates of up to 1 sample/min did not affect normal (Prl) secretion when blood volume reduction was compensated for with blood transfusion of fresh donor blood (chapter 2). However, compensation with preserved blood affected prolactin secretion significantly (chapter 3). In all later studies, therefore, blood transfusions were performed with freshly collected donor blood. The application of high frequency blood sampling permits the assessment of the dynamics of (Prl) secretion satisfactorily. The short-time interval studies presented in chapter 1, 2 and 3 show that during a surge plasma (Prl) always increased in an unpredictable manner, discontinuously, by means of several bursts, with maximum increments of about 600 ng/ml/min. The shortest half-time values, as calculated from the disappearance of (Prl) from the circulation, were about 2.2 min. The individual release patterns indicate that (Prl) release must be the consequence of a very dynamic neural regulatory process.</TT><TT>In chapter 4 the effects of red light and/or surgery upon (Prl) secretion were studied in cycling and PSP rats. Nocturnal (07.00- 11.00 h), prediurnal (14.00-17.00 h) and diurnal (19.00-22.00 h) Prl secretion was differently affected by these "treatments", and the effect was dependent upon the physiological state. The data together demonstrate the existence of different regulatory mechanisms for each of the surges of (Prl) secretion: the proestrous and estrous surge in cycling rats, and the nocturnal and diurnal surge in PSP rats. Moreover, in PSP day 0 rats, on the first day of pseudopregnancy, the occurrence of a prediurnal surge, preceeding the diurnal surge, was evident, which in fact was a reflection of the estrous afternoon surge in cycling rats.</TT><TT>In the last three chapters the involvement of the brain in (Prl) regulation was explored by studying the effects of hormonal and electrical stimulation upon (Prl) secretion. Since (Prl) has no specific target organ, an autofeedback control mechanism was hypothesized. Therefore, the effect of intracerebroventricular infusion of (Prl) on endogenous Prl secretion was investigated. However, as far as the proestrous surge of (Prl) is concerned, there is no evidence for the existence of an autoregulatory mechanism, neither in the expression, nor in the termination of the surge (chapter 5).</TT><TT>In chapter 6 the role of two brain areas in the control of (Prl) was investigated: the MPOA and the ME. The MPOA shows sexual dimorphism and is concerned functionally with several parameters of homeostasis, (sexual) behavior and endocrine function. The ME contains the terminals of the tuberoinfundibular dopaminergic (TIDA) neurons. Electrical stimulation experiments show that the</TT>MPOA<TT>is involved in the control of (Prl) secretion and that this control is different in males and females: electrical stimulation produced an increase in (Prl) secretion in the male, but reduced (Prl) secretion in the proestrous female. ME stimulation data do not provide evidence that this sexually differentiated function of the</TT>MPOA<TT>could be contributed to a sexual dimorphism in prolactin- inhibiting factor or prolactin-releasing factor activity.</TT><TT>The data of chapter 7 show that the</TT>MPOA<TT>is involved in the control of all presently known surges of (Prl) secretion in cycling, pregnant and lactating rats: electrical stimulation consistently suppressed (Prl) secretion at the times of expected surges. So the</TT>MPOA<TT>may be considered as an "anti-surge key-control" centre for (Prl) secretion in female rats. Whether the</TT>MPOA<TT>exerts its control via one final common neural pathway represented by the tuberoinfundibular dopaminergic system, remains to be determined.</TT><TT>In summary: (Prl) is a multi-target and multi-functional hormone. Based on the differences in actual secretion patterns of (Prl) and the differential effects of stress on (Prl) secretion it is concluded that all yet known surges of (Prl) secretion in cycling, (pseudo) pregnant and lactating rats are controlled by different neural regulatory mechanisms. In proestrous rats there is no evidence for an autoregulatory mechanism. Release of (Prl) is the consequence of a very dynamic neural regulatory process. The release of (Prl) is finally controlled by one common neural centre, the</TT>MPOA,<TT>which control is sexually differentiated: stimulatory in the male and inhibitory in the female.</TT>