Wim B.J. Mens

Penetration of neurohypophyseal hormones from plasma into cerebrospinal fluid (CSF): Half-times of disappearance of these neuropeptides from CSF

The penetration of neurohypophyseal peptides after peripheral administration into the cerebrospinal fluid (CSF) was studied in freely moving rats. In addition, the clearance of these peptides from CSF was investigated. Increased concentrations of vasopressin (AVP) in CSF were detectable 2 min after s.c. injection of 5.0 micrograms of this peptide. Peak concentration was reached at 5 min after administration and this level declined slowly over the next hour. Administration of 5.0 micrograms oxytocin (OXT) s.c. or i.v. resulted in increased OXT levels in CSF within 10 min after application. After 60 min a significant elevation of OXT in CSF was no longer present. These data reveal that approximately 0.002% of the peripherally applied amount of AVP or OXT reached the central nervous system at 10 min after injection. AVP (2.5 ng) and OXT (5.0 ng) applied into one of the lateral brain ventricles reached the cisternal cavity within 2 min after administration. Both neuropeptides were cleared from the CSF with terminal half-times of 26 and 19 min for AVP and OXT, respectively. The present data demonstrate that neurohypophyseal hormones do cross the blood-brain barrier in amounts obviously sufficient to induce central actions.

Differential effects of various stimuli on AVP levels in blood and cerebrospinal fluid

Water deprivation, drinking water containing 2% NaCl, or systemic injection with histamine or nicotine markedly increased plasma levels of vasopressin in rats. In contrast, none of the applied stimuli changed vasopressin levels in the CSF collected simultaneously from the same animal. These data suggest that the blood levels of vasopressin are controlled quite differently from CSF levels of this hormone.

Changes in cerebrospinal fluid levels of vasopressin and oxytocin of the rat during various light-dark regimes

Levels of arginine-vasopressin (AVP) and oxytocin (OXT) in cerebrospinal fluid (CSF) of rats were determined at various times of the day and the night under normal and changed light-dark conditions. During a regular daily 14 h light and 10 h dark cycle (lights on 06.00 h, off 20.00 h), AVP in CSF reached a peak at 13.00 h, while the lowest levels were found at 19.00 h. Reversal of the normal light-dark cycle into a 14 h dark and 10 h light cycle (lights on 20.00 h, off 06.00 h) did not change the normal AVP rhythm. These lighting conditions elevated the OXT levels in the CSF as compared to those found during a normal light-dark regime, but again no differences were observed between the OXT levels determined at the various time-points. A shift of 6 h of the light-dark cycle (lights on 12.00 h, lights off 02.00 h), completely disrupted the AVP rhythm. However, after 3 weeks of adaptation to this new light-dark regime a high level of AVP in CSF was again observed at 13.00 h, and a low level at 19.00 h. The present data suggest that changes in the normal light-dark conditions affect the levels of neurohypophyseal peptides in the CSF. The results are of interest because of reported changes in memory function induced by alterations in the light-dark cycle.

Vasopressin and oxytocin content in cerebrospinal fluid and in various brain areas after administration of histamine and pentylenetetrazol

The content of vasopressin (AVP) and oxytocin (OXT) in the septum, hippocampus, hypothalamus and cortex was determined at 5 min and 24 hr after peripheral (intraperitoneal) administration of histamine (20.0 mg/kg) and pentylenetetrazol (45.0 mg/kg) and in the cerebrospinal fluid at 24 hr after pentylenetetrazol treatment. At 5 min after administration of histamine the AVP content in the septum was increased whereas the OXT level in the various areas was not changed. At 24 hr, neurohypophyseal peptide contents were unaffected in the brain regions analyzed. Pentylenetetrazol did not alter AVP content at 5 min after its administration, however, the OXT level in the septum and the cortex was diminished. At 24 hr after administration of pentylenetetrazol a decreased AVP content in the hippocampus and in the cortex was observed. In contrast, OXT content in the cortex was increased at this time. AVP and OXT levels in CSF were not changed at 24 hr following pentylenetetrazol treatment. The present results suggest that the levels of neurohypophyseal hormones can be differentially altered in particular brain regions at short- (5 min) and long- (24 hr) term intervals after treatment with histamine or pentylenetetrazol. Long-term changes in AVP and OXT levels after pentylenetetrazol may be implicated in the amnesic properties of this convulsive drug. Furthermore, the present findings point to a possible relationship with previously reported pentylenetetrazol-induced changes in peptide levels in the CSF.

Hypophyseal hormone levels in blood and cerebrospinal fluid in response to histamine and pentylenetetrazol.

Histamine administered intraperitoneally increased, in a dose-dependent manner, AVP, OXT and PRL levels in plasma of rats, whereas alpha-MSH levels were not affected. Levels of AVP in plasma after histamine 20.0 mg/kg treatment were approximately 100-fold higher than those of controls, while OXT and PRL levels were approximately 7-fold higher after this treatment. CSF content of AVP, OXT, PRL and alpha-MSH was not influenced by histamine, indicating that a stimulated release of hormones from the pituitary into the blood is not accompanied by a concomitant increase of secretion of these hormones into the CSF. Convulsions induced by pentylenetetrazol were accompanied by a temporary increase in AVP levels and by strongly and consistently elevated OXT levels in plasma. PRL and alpha-MSH plasma levels were affected in a biphasic manner. A convulsion type 1 induced elevated PRL levels and diminished alpha-MSH levels, while a convulsion type 2 had no effect on plasma PRL concentration, but increased the concentration of alpha-MSH. Only the level of OXT in CSF was increased after a pentylenetetrazol-induced convulsion type 1. The present data suggest that histamine affects the release of AVP, while pentylenetetrazol might act more specifically on the OXT-releasing system. Furthermore, a possible relationship between the pentylenetetrazol-induced increase of OXT levels in the CSF and amnesia is suggested.

Influence of histamine and pentobarbitone on plasma and CSF vasopressin levels of hypophysectomized rats

Histamine increased vasopressin levels, as measured by radioimmunoassay (RIA), in both cerebrospinal fluid (CSF) and plasma of hypophysectomized rats, while histamine enhanced plasma but not CSF levels of vasopressin in sham operated rats. Pentobarbitone increased CSF vasopressin levels in hypophysectomized rats and in sham operated animals. The present data demonstrate that the histamine induced elevation of vasopressin levels in the blood is only temporarily disturbed after hypophysectomy, while the effect of histamine on CSF vasopressin levels of hypophysectomized rats is of a more permanent nature.

Influence of β-lipotropin fragments on responsiveness of rats to electric footshock

Subcutaneous administration of graded doses of neuropeptides related to lipotropin (beta LPH) changed responsiveness of rats to electric footshock. gamma-Endorphin and related peptides increased the susceptibility of rats, whereas beta-endorphin induced a reversed effect. The enhanced responsiveness induced by DT gamma E, persisted for more than 24 hr and appeared to be of a central origin. Structure-activity relationship studies revealed that the sequence LPH 65-69 may contain the active core in this respect. An increased sensitivity to electric shock within one test procedure was observed with DT gamma E and alpha-endorphin. Prior experience with the test procedure diminished or abolished this effect of alpha-endorphin. It is suggested that beta-endorphin and its fragments play a physiological role in adaptive behavioral changes induced by peripheral stimuli.

Neurohypophyseal peptide levels in CSF and plasma during passive avoidance behavior in rats

Levels of vasopressin (AVP), oxytocin (OXT), and neurophysin (NP) in CSF and plasma of rats were determined during acquisition and retention of passive avoidance behavior. None of the levels of neurohypophyseal peptides in CSF were changed either during the adaptation period, or during acquisition or the retention of this behavior. Moreover, no differences were found in hormone levels in CSF of the various groups of rats subjected to different shock intensities during the acquisition trial. The marked differences in individual latencies of nonavoiding rats, and the differences in latencies due to a different shock intensity applied during the learning trial were not reflected by changes in CSF hormone levels. Neither AVP nor NP levels in plasma were affected by the different shock intensities applied, when measured at 20 min after the learning trial. In contrast, a decrease in plasma OXT levels was observed after application of a shock intensity of 0.25 mA during the learning trial. During retention of the passive avoidance response plasma levels of AVP, OXT and NP were not different from the levels found in the nonshocked groups. It is suggested that under the conditions used in this study the CSF is apparently not involved in the distribution of neurohypophyseal peptides to their possible sites of behavioral action in the brain.

DEPRESSOR ACTIVITY OF INTRACEREBROVENTRICULARLY ADMINISTERED PEPSTATIN IN YOUNG SPONTANEOUSLY HYPERTENSIVE RATS

The effect of prolonged intracerebroventricular (i.c.v.) infusion of N-acetyl-pepstatin in young and adult spontaneously hypertensive rats was studied. In young animals, pepstatin infusion resulted in a decrease in blood pressure and heart rate. Water intake and body weight were not affected. The depressor effect was accompanied by a slight increase in plasma renin activity and decreases in plasma vasopressin and plasma catecholamines. The blood pressure of adult rats with already established hypertension was not significantly affected. In addition, changes in plasma renin or catecholamines were not observed in these animals while vasopressin levels were slightly increased. The involvement of a possibly decreased sympathetic activity in the depressor effect of pepstatin is suggested. It is concluded that increased brain renin activity contributes to the development of hypertension of spontaneously hypertensive rats.