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Objective and Design: Histamine can modulate feeding behaviour and hormone release; therefore we examined the hypothalamic histamine system, the growth pattern and the serum levels of prolactin and growth hormone in rats with portacaval anastomosis (PCA)., Material: The growth rate of 30 PCA- and 30 sham-operated male Han:Wistar rats was monitored for 6 months. Thirteen sham and 9 PCA rats were used for biochemical studies., Methods: Histamine was assayed by HPLC, tele-methylhistamine by GC-MS, prolactin and growth hormone by RIA. Student's t-test was used to compare the groups., Results: Six months after surgery, the PCA rats exhibited marked growth retardation (weight gain of 20 g vs. 140 g for the sham rats; p < 0.001), increased plasma levels of prolactin (9.7 +/- 2.4 vs. 3.6 +/- 0.6; p<0.01) and unaltered growth hormone levels (6.2 +/- 0.5 vs. 8.1 +/- 1.0). A six-fold elevation of histamine concentration (29.5 +/- 3.9 vs. 4.8 +/- 0.4; p<0.001) and a two-fold increase of tele-methylhistamine levels (1.8 +/- 0.1 vs. 0.8 +/- 0.02; p<0.001) were found in hypothalamus., Conclusion: We suggest that increased histaminergic activity in the hypothalamus may be involved in the development of growth retardation and in the enhanced basal secretion of prolactin in male rats with long-term PCA.

In vivo microdialysis was used to study the effects of a potent and selective alpha 2-adrenoceptor antagonist, atipamezole, on histamine and noradrenaline release from the medial hypothalamus in anesthetized rats. Local perfusion with atipamezole via the microdialysis probe increased histamine release significantly and dose-dependently. However, the effect of systemic administration of atipamezole (1 mg/kg) was opposite: it significantly decreased histamine release. Local and systemic administration of atipamezole produced an approx. 2-fold increase in noradrenaline release. To study the modulatory effect of noradrenergic neurons on histamine release, noradrenaline synthesis was inhibited with alpha-methyl-p-tyrosine. In the microdialysis experiment, rats that received alpha-methyl-p-tyrosine exhibited no decrease, but rather a slight increase in histamine release in response to systemic atipamezole administration. These results show clearly that atipamezole enhances noradrenaline release in vivo from rat hypothalamus and its effects on histamine release are dependent on the route of drug administration.

In vivo microdialysis was used to study the effects of serotonergic drugs on histamine release from the suprachiasmatic nuclei region of the anterior hypothalamus in anesthetized rats. Local perfusion with serotonin (5-hydroxytryptamine, 5-HT) increased histamine release significantly and dose dependently. Methysergide (10 mg/kg i.p.), a 5-HT2C/2A receptor antagonist, given 30 min before 5-HT perfusion, blocked the 5-HT-evoked histamine release. Methysergide (10 mg/kg i.p.), given alone, also suppressed basal histamine release by 33%. Dexfenfluramine (10 microM), a 5-HT releaser and uptake blocker, administered via the microdialysis probe, significantly enhanced hypothalamic histamine release. With the same dose of dexfenfluramine, 5-HT release increased 10-fold in the same brain area. These results show for the first time that endogenous 5-HT modulates histamine release in vivo and it has a tonic stimulatory effect on the histaminergic nerve terminals of the rat anterior hypothalamus.

Rats were deprived of REM sleep (REMS) for 72 h with the platform method and decapitated in the morning immediately after the deprivation or in the afternoon after having been allowed 5 hours of rebound sleep. The histamine concentrations of the anterior and posterior hypothalamus, the cortex, the hippocampus and the pineal gland were measured, as well as the tele-methylhistamine concentrations of the anterior and posterior hypothalamus. Histamine concentrations were no different after REMS deprivation compared to large platform or dry cage controls, but in the anterior hypothalamus histamine levels increased during rebound sleep only in the REMS deprived rats. tele-Methylhistamine/histamine ratios were higher after 72 h of both REMS deprivation and the large platform treatment compared to dry cage controls, indicating increased histamine utilization during the platform treatment procedure.

Histaminergic neurones may be involved in the regulation of feed intake. Since TCDD causes anorexia in rats, histamine concentrations were measured in several hypothalamic nuclei involved in feeding regulation. Histamine concentrations were not changed in medial or lateral accumbens, suprachiasmatic, paraventricular, arcuate, ventromedial, dorsomedial or perifornical nuclei, or in lateral hypothalamic area, cortex, or pineal gland. There was, however, an increase in histamine concentration in median eminence 25 h after the administration of TCDD.

Male Long-Evans rats were given 50 micrograms/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intraperitoneally and after 1, 4, 28 or 76 hr, noradrenaline, dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), tryptophan and histamine were measured in the brain (dissected into ten parts) as well as in the pituitary gland. Several slight but significant changes were observed, e.g. in the hypothalamus where HVA and 5-HIAA were decreased after 4 hr, noradrenaline was decreased after 76 hr and histamine increased after 28 hr. Several late changes were also found, conspicuously tryptophan was increased in most brain areas after 76 hr and in some cases earlier; these changes may be due to starvation after hypophagia rather than TCDD directly. The results demonstrate that TCDD causes changes in brain neurotransmitter systems, but the changes are minor and it is not likely that aminergic systems are the key mediators in TCDD-induced hypophagia.

The ontogenetic development of histamine was studied in the diabetes insipidus rat to clarify the possible interference between the lack of vasopressin and the development of histaminergic systems in the hypothalamus. Rat pups were decapitated at different ages between the 2nd and 38th postnatal days. In addition to homozygous Brattleboro (diabetes insipidus) rats, Long Evans controls and heterozygous animals were studied. In all three genotypes hypothalamic histamine was almost equal during the first 6 postnatal days. In homozygous Brattleboro rats the period of most rapid increase occurred between days 14 to 26, which was significantly later than in Long Evans rats. In the remainder of the brain no such difference was seen. On the contrary, histamine values were highest in the youngest animals. It remains to be elucidated whether the delayed ontogenesis is causally related to vasopressin deficiency and what is the underlying mechanism.

The accumulation of [-14C] histamine into slices of rabbit hypothalamus was studied. All areas of hypothalamus took up histamine against a concentration gradient. The highest accumulation was into the infundibular area and the lowest into the mamillary body. The uptake did not correlate with the level of endogenous histamine. The uptake continued for at least two hours and a maximum tissue/medium ratio of about 5.6 was reached. The major part of radioactivity was chromatographically shown to be histamine. The uptake was temperature dependent and required sodium. It was not significantly inhibited by compound 48/80, but it could be inhibited with desipramine and 5-hydroxytryptamine. Therefore, the uptake of histamine shares many characteristics of the uptake of monoamines by brain slices, even if the rate of uptake appeared to be slower.

To evaluate the role of vasopressin in the regulation of atrial natriuretic peptide (ANP) secretion, the plasma, atrial, ventricular, and hypothalamic levels of ANP were measured in Long-Evans (LE) and vasopressin-deficient Brattleboro (DI) rats. Total atrial immunoreactive ANP (IR-ANP) as well as right auricular IR-ANP concentration were higher in the DI than in the LE rats, whereas no significant difference was noted in left auricular IR-ANP concentration. In the left ventricle of DI rats, the IR-ANP concentration was 82% greater than that in the LE rats, while no substantial difference was found in the right ventricular IR-ANP concentration between the strains. Normal LE rats had low levels of left ventricular ANP mRNA and barely detectable ANP mRNA in the right ventricle, DI rats showed a 3-fold greater ANP mRNA concentration in the left ventricle than age-matched LE controls, and ANP mRNA levels were also increased in the left auricle of DI rats. The hypothalamic IR-ANP content, but not the concentration, was significantly increased in the DI compared to the LE rats. Despite increased cardiac IR-ANP and ANP mRNA levels, plasma IR-ANP concentrations were similar in the conscious DI rats (97 +/- 9 pg/ml; n = 13) and the LE rats (95 +/- 8 pg/ml; n = 15). Volume expansion (1.1 ml/100 g BW of 0.9% saline, iv) increased right atrial pressure and caused a significant rise in plasma IR-ANP in both strains (P less than 0.01). Elevations of plasma IR-ANP concentrations caused by volume loading were comparable in LE and DI rats in either the absence or presence of exogenous vasopressin (5 ng/kg.min, iv), which, when infused alone, did not significantly influence the plasma IR-ANP concentration. However, the relation between the change in IR-ANP concentration and the change in right atrial pressure shifted to the left, and thus, for a given increase in right atrial pressure, a greater amount of IR-ANP was released in the vasopressin-treated rats than in the control animals. These results demonstrate that although acute volume expansion does not necessarily require endogenous vasopressin for the ANP secretory response, vasopressin increased the ability of volume expansion to induce ANP release, thus modulating the direct mechanical stimulus-induced ANP secretion. The increased left ventricular levels of immunoreactive ANP and augmentation of ANP mRNA levels in Brattleboro rats despite normal left ventricular weight to body weight ratio show that increased ANP gene expression may occur in the ventricles independently of hypertrophy.

Arginine-vasopressin (AVP) levels and osmolality were measured in the CSF of rats during 5 days of osmotic stimulation. Dehydration increased AVP levels about 3-fold but did not affect the circadian rhythm of AVP. During dehydration, AVP levels in CSF increased as osmolality increased. Neither AVP levels nor osmolality changed significantly in the CSF of rats receiving 2% NaCl as drinking water. The increased AVP values in CSF may reflect activated release of AVP in the central nervous system during dehydration. Our data also suggest that the AVP release connected with the regulation of osmotic changes may be separate from the mechanism that regulates the circadian rhythm of AVP in the CSF of rats.