Maysie J. Hughes

Chronic vitamin D deficiency in the weanling rat alters catecholamine metabolism in the cortex

The effect of a vitamin D deficient (--D), vitamin D replete (150 I.U. D3 twice weekly) and normal rat diets for 4 weeks in weanling male rats on the steady-state concentration in several brain sites of dopamine (DA), norepinephrine (NE), and dihydroxyphenylacetic acid (DOPAC) was investigated. The areas of the central nervous system assayed were the brainstem, cerebellum, cerebral cortex, hypothalamus-median eminence, and striatum. The results indicate that DA content of cortex and hypothalamus significantly increased in the --D group compared to the normal diet or D replete groups. The concentrations of DOPAC and NE in the cortex of both --D and D replete rats increased significantly compared to normal diet group. Plasma calcium level was significantly lower in --D group compared to the normal diet or vitamin D replete groups.

Alteration of dopamine metabolism in different brain regions of the rabbit by estradiol and tamoxifen

Tamoxifen citrate, a mixed estrogen agonist-antagonist, and estradiol 17-beta administered separately for 14 days significantly reduced dopamine and dihydroxyphenylacetic acid in the cortex and hypothalamus regions of the brain in immature female rabbits. In addition to these areas, estradiol also reduced dopamine and dihydroxyphenylacetic acid in the striatum but tamoxifen treatment significantly reduced only dihydroxyphenylacetic acid concentration in the striatum. When estradiol and tamoxifen were injected together, dopamine and dihydroxyphenylacetic acid concentrations were reduced only in the cortex. Specific binding of [3H]spiperone to dopamine receptors was significantly increased by both estradiol and tamoxifen in the hypothalamus but only tamoxifen increased dopamine binding in the striatum. A low dose of tamoxifen, either alone or in combination with estradiol, increased uterine weight, but a higher dose of tamoxifen was neither an estrogen agonist nor antagonist. These studies indicate that estradiol and tamoxifen alter dopamine metabolism in the various regions of brain differentially. The estrogen agonist activity of tamoxifen does not correspond to antidopaminergic action of estradiol in the striatum.

Antiestrogen-induced alterations of hypothalamic dopamine and norepinephrine levels in the female rat.

The influence of antiestrogen (tamoxifen) administration in vivo on the steady state concentration of dopamine (DA) and norepinephrine (NE) in the hypothalamus-median eminence area of mature female rats was investigated. Rats were treated with tamoxifen at 3 different dose levels (0.1, 1.0 and 10.0 mg/kg, s.c.) daily for 7 or 21 days. Control groups were injected with vehicle only (10% ethanol; 1.0 ml/kg). In a separate experiment, mature female rats were ovariectomized or sham operated and killed either 7 or 21 days after operation. Dopamine and NE were estimated by high pressure liquid chromatography with electro-chemical detection. Seven days of tamoxifen treatment at 3 different dose levels did not alter DA and NE concentrations compared to the control. The chronic (21 days) tamoxifen treatment in the smallest dose (0.1 mg) significantly increased the DA concentration. The concentration of NE was reduced only at the 1.0 mg/kg dose. There was no significant difference in the NE concentration 7 or 21 days after ovariectomy or sham operation, but the DA concentration was significantly increased 21 days after ovariectomy. The uterine weights were reduced significantly after 21 days of treatment with tamoxifen in the two larger doses, but were increased with the smallest dose of tamoxifen. Uterine weight after ovariectomy both after 7 and 21 days was significantly reduced. These results suggest that chronic low-dose antiestrogen treatment may affect the hypothalamic-median eminence DA and NE concentrations. The data also suggests that antiestrogenic action (uterine growth inhibition) of tamoxifen is not related to the alterations of DA and NE in the hypothalamus-median eminence.

Alterations in norepinephrine and dopamine content in selected brain areas of guinea pigs adapted to simulated high altitude.

Abstract: The alterations in brain content of norepinephrine (NE) and dopamine (DA) were studied in guinea pigs adapted to simulated high altitude (hypobaric hypoxia) equivalent to 5500 meters. The animals were adapted for 46 days over a period of 82 days to a pressure of 375 mm Hg. The animals were then killed and the following brain parts dissected: cerebellum, neocortex, caudate head/basal forebrain, diencephalons/rhinencephalon, and brain stem. NE and DA content were analyzed by high pressure liquid chromatography with electrochemical detection by a technique described. Results showed a significant increase of NE and DA in neocortex; a significant increase of DA but not NE in caudate/basal forebrain, and a significant decrease of NE and not DA in diencephalons/rhinencephalon.

Regional alterations of brain catecholamines by lead ingestion in adult rats

The alterations in steady-state dopamine (DA) and norepinephrine (NE) content of hypothalamus-median eminence (HME) and striatum (STR) were measured in adult female rats fed normal calcium (1.2%) or low calcium (0.005%) diets for 4 weeks and exposed to lead via drinking water containing lead acetate (0.032, 0.32, and 3.2 mg Pb/ml) for the last 3 weeks of a 4-week diet period. Control lead-free groups of both dietary regimens received equimolar acetate as sodium acetate. The eight groups (six rats/group) were divided equally between the two diet regimens. Three weeks treatment with lead significantly reduced DA and NE in HME but DA only in STR (0.32 and 3.2 mg Pb/ml) of both dietary groups. Low dietary calcium alone reduced DA and NE in HME. In contrast with the HME low calcium diet alone had no significant effect on DA and NE in STR. No additive effect of low calcium diet and lead ingestion in catecholamine reduction was found in the brain parts studied.

Alterations in CNS amine levels by acclimatization to hypobaric hypoxia.

Rabbits were acclimatized to simulated high altitude (SHA) (hypobaric hypoxia) at 6000 M (350 torr) on alternate days for 70 days. The norepinephrine levels of the midbrain were lower in the acclimatized animal compared to the controls (p less than 0.06) and 3,4 dihydroxyphenylacetic acid (DOPAC) was significantly higher (p less than 0.04) in the striatum of control than in the test animals. The mean dopamine (DA) levels in the striatum of the test animals were higher than the controls. The ratio of DOPAC/DA was 2.0 for the controls and 0.4 for the SHA brains which suggests reduced dopamine turnover in the striatum of the SHA rabbits. Rats acclimatized in the same manner did not show any difference in the NE or DA levels between the control and SHA animals, possibly the result of species differences.

Liberation of histamine by compound 48/80, tolazoline, betahistine and burimamide from isolated spontaneously beating guinea pig and rabbit atrial pairs

Tolazoline, betahistine, burimamide and compound 48/80 release histamine from isolated guinea pig atria resulting in histamine concentrations that will stimulate H2-receptors. Tolazoline, burimamide and 48/80 also release histamine from rabbit atria but do not result in histamine concentrations that will stimulate either H1- or H2-receptors. However, betahistine (which does not release histamine from rabbit atria) and tolazoline stimulate the rabbit atrial chronotropic response by releasing catecholamines.

A question of the specificity of rabbit atrial chronotropic histamine receptors and agents which affect their activity.

The histamine chronotropic response of rabbit atria appears to be controlled by both H1 and H2 receptors and can be blocked in part by either metiamide (an H2 antagonist) or diphenhydramine (an H1 antagonist), while both 2- and 4-methylhistamine (H1 and H2 agonists, respectively) stimulated the chronotropic response. At low agonist concentrations, the simultaneous presence of both H1 and H2 blockers results in considerably less inhibition than could be expected from calculations of individual inhibition data, suggesting that some sites behave as if they have both H1 and H2 properties. Additional compounds were tested for specific action on H1 and H2 receptors: 2-(2-pyridyl) ethylamine, reported to be an H1 agonist, appears to stimulate rabbit atria by releasing norepinephrine and guinea pig atria by releasing both norepinephrine and histamine; while dimaprit, reported to be an H2 agonist, may stimulate histamine receptors directly but has a nonspecific depressant action on rabbit atria which interferes with its use as an agonist in this species.

Chronic administration of naltrexone alters central catecholamine levels but not the development of hypertension in spontaneously hypertensive rats

The effect of chronic administration of the opiate antagonist naltrexone on the genesis and development of hypertension and correlated changes in central norepinephrine levels was evaluated in spontaneously hypertensive rats and Wistar-Kyoto controls. Capsules of poly-epsilon-caprolactone containing naltrexone in ethyl oleate or ethyl oleate alone were implanted in 4 week old SHR and WKY rats. Naltrexone failed to alter the genesis or magnitude of hypertension developed by the SHR and did not alter heart rates. Blood pressure and heart rate of WKY rats were also unaffected. A significant decrease in midbrain and hippocampal NE levels was observed in SHRs but not in WKYs following naltrexone.

Central and peripheral receptors in guinea-pigs exposed to simulated high altitude

Guinea-pigs, chronically exposed to simulated high altitude of 6000 m, showed alterations in some, but not all, neurotransmitter-receptor systems. Thus, peripheral (cardiac) beta-adrenergic receptors were decreased in numbers (Bmax) with an increased affinity although no alterations in endogenous cardiac norepinephrine content were found. In contrast, H1-histamine receptors in the guinea-pig ventricle and brain showed no changes in Bmax or affinity. Dopamine receptors of the caudate nucleus showed no differences between control and altitude-exposed guinea-pigs, although previous reports demonstrated a significant increase (19%) in the content of endogenous dopamine of the caudate. Thus, chronic exposure to simulated high altitude altered beta-adrenergic receptors so that they were more sensitive to small ligand concentrations and less sensitive to large ligand concentrations.