Drug-induced changes of epinephrine turnover in the rat hypothalamus

The effects of various psychotropic agents on the steady state levels and on the FLA 63-induced disappearance of hypothalamic epinephrine have been investigated in the rat. Desipramine retarded the utilization without affecting the basal levels of epinephrine while mianserin accelerated epinephrine utilization and reduced the steady state concentrations of the transmitter. In contrast, chlorimipramine, iprindole and trazodone were without effect. An acceleration of epinephrine utilization and a reduction of basal epinephrine levels were also observed after administration of (α-adrenolytic doses of) neuroleptic agents (chlorpromazine, haloperidol, clozapine, thioridazine) or (+)-amphetamine and cocaǐne but sulpiride or the dopamine receptor agonists apomorphine and bromocriptine were without effect. The clonidine-induced retardation of epinephrine utilization was antagonized by yohimbine, phenoxybenzamine, mianserin, haloperidol and chlorpromazine but not by desipramine or trazodone. These data indicate that α-adrenoceptors are involved in the regulation of epinephrine release and mediate the action of psychotropic agents. The cholinomimetic agent oxotremorine increased epinephrine utilization; this effect was abolished by atropine. In contrast, diazepam or GABAmimetic agents failed to affect epinephrine utilization. These results suggest cholinergic but not GABAergic regulation of epinephrine turnover.     

Cholinergic effect on the dopamine turnover in the rat corpus striatum]

The peripheral administration of oxotremorine caused a significant increase in dihydroxyphenylacetic acid (DOPAC) in the striatum of rats, dopamine (DA) level was unaffected. Injection of oxotremorine into the substantia nigra failed to change the content of dopamine and its acid metabolites homovanillic acid (HVA) and DOPAC in striatum. Injection of oxotremorine or carbachol into the substantia nigra or into the caudate nucleus did not significantly influence the DA-turnover. The partly inconsistent results are discussed in connection with literature data in regard to the existence of excitatory as well as inhibitory cholinergic systems, which are located differently and are involved in the regulation of DA-turnover.     

Inhibition of polyphosphoinositide turnover in rat cerebral cortex by clonidine

In the rat brain, a number of receptors are linked to phospholipase C which catalyzes the hydrolysis of membrane inositol phospholipids; stimulation of alpha 1-adrenergic receptors, for example, increases polyphosphoinositide turnover, but stimulation of alpha 2-receptors does not. The hydrolysis of inositol phospholipids in rat cortical slices was investigated using a direct assay involving prelabeling these lipids with 3H-inositol and then measuring the formation of 3H-inositol phosphates in the presence of lithium ions. As expected, clonidine, an alpha 2-agonist, did not stimulate the formation of 3H-inositol phosphates; however, clonidine antagonized the ability of noradrenaline to stimulate 3H-inositol phosphate formation. This effect was not blocked by antagonists of alpha 2, 5HT2, H2, or muscarinic receptors. Clonidine did not affect carbachol-stimulated 3H-inositol phosphate formation.     

Atrial natriuretic factor inhibits norepinephrine biosynthesis and turnover in the rat hypothalamus

We have previously reported that atrial natriuretic factor (ANF) increased neuronal norepinephrine (NE) uptake and reduced basal and evoked neuronal NE release. Changes in NE uptake and release are generally associated to modifications in the synthesis and/or turnover of the amine. On this basis, the aim of the present work was to study ANF effects in the rat hypothalamus on the following processes: endogenous content, utilization and turn-over of NE; tyrosine hydroxylase (TH) activity; cAMP and cGMP accumulation and phosphatidylinositol hydrolysis. Results showed that centrally applied ANF (100 ng/microl/min) increased the endogenous content of NE (45%) and diminished NE utilization. Ten nM ANF reduced the turnover of NE (53%). In addition, ANF (10 nM) inhibited basal and evoked (with 25 mM KCl) TH activity (30 and 64%, respectively). Cyclic GMP levels were increased by 10 nM ANF (100%). However, neither cAMP accumulation nor phosphatidylinositol breakdown were affected in the presence of 10 nM ANF. The results further support the role of ANF in the regulation of NE metabolism in the rat hypothalamus. ANF is likely to act as a negative putative neuromodulator inhibiting noradrenergic neurotransmission by signaling through the activation of guanylate cyclase. Thus, ANF may be involved in the regulation of several central as well as peripheral physiological processes such as cardiovascular function, electrolyte and fluid homeostasis, endocrine and neuroendocrine synthesis and secretion, behavior, thirst, appetite and anxiety that are mediated by central noradrenergic activity.     

Somatostatin concentration and binding in the rat hypothalamus and striatum during severe insulin-induced hypoglycemia

Hypoglycemia was induced by administration of insulin (40 I.U./kg) to 24 h fasted rats. Somatostatinlike immunoreactivity (SLI) and¹²⁵I-Tyr¹¹-somatostatin binding were measured in the striatum and hypothalamus at the onset of hypoglycemic coma (5–10 min). No significant changes in SLI concentration were detected in either site although the total number of specific somatostatin receptors in the striatum membranes, but not in the hypothalamus, decreased in insulin-injected rats when compared with the control group.     

Effect of aging on 24-hour changes in dopamine and serotonin turnover and amino acid and somatostatin contents of rat corpus striatum

This study examined the 24-hour changes in a number of transmitters in the corpus striatum of young and middle-aged male Wistar rats. The contents of excitatory amino acids (glutamate, aspartate) and inhibitory amino acids (gamma-aminobutyric acid, GABA; taurine, glycine) and of somatostatin were measured in 2-month- and 18- to 20-month-old rats killed at six different time points along the 24-hour cycle. The striatal serotonin and dopamine turnover was also measured. Both young and middle-aged rats showed significant 24-hour variations in striatal glutamate and aspartate contents; only in young rats these variations fitted a cosine function, with acrophase during the first part of rest span. Mesor values of striatal excitatory amino acid contents were lowest in middle-aged rats. Significant 24-hour variations in striatal contents of GABA, taurine, and glycine occurred in young rats, while only striatal GABA exhibited 24-hour changes in middle- aged rats (acrophases during the first part of rest span). For every inhibitory transmitter, the mesor values in middle-aged rats were significantly lower than in young rats. The 24-hour variation of the striatal somatostatin content showed acrophase during the first part of rest span, mesor values and amplitude being lowest in middle-aged rats. Aging rats exhibited significantly higher mesor values of striatal serotonin turnover (34% increase) and lower mesor values of dopamine turnover (69% decrease) than their younger counterparts. Some of the circadian modifications of motor function seen in aging rats could be related to the striatal transmitter changes reported herein.     

Effect of beta-endorphin on catecholamine levels in the rat hypothalamus and cerebral cortex

The present paper deals with the effect of beta-endorphin on catecholamine content in the hypothalamus and cerebral cortex of male rats. beta-endorphin was found to decrease catecholamine content in the rat brain, with the degree of reduction depending on the brain topography and the time following the peptide administration. 5 min later no changes in catecholamine content were observed either in the hypothalamus or in the cerebral cortex. 20 min later beta-endorphin induced a statistically significant fall of catecholamine concentration in the hypothalamus. A tendency towards its decrease was also observed in the cerebral cortex. 60 min later beta-endorphin produced an insignificant decrease in catecholamine level in both brain areas under study. It may be therefore suggested that beta-endorphin-induced decrease of catecholamine content in the hypothalamus and cerebral cortex represents one of the mechanisms underlying beta-endorphin stimulating action on a number of trophic functions of the hypophysis.     

Effect of insulin and glucagon on aldolase turnover in rat liver

The effects of exogenous and endogenous insulin and glucagon on aldolase turnover in rat liver and blood were studied. Some effects of these hormones on the biosynthesis and degradation of hepatic aldolase were specified. The rate of the "de novo" synthesis of aldolase was investigated in hepatocyte mitochondria and in blood plasma. The exogenous and endogenous hormones were shown to produce different effects on the biosynthesis and spontaneous degradation of rat liver aldolase.     

Effect of cocaine on the tyrosine hydroxylase of rat hypothalamus]

The influence of cocaine on tyrosine hydroxilase of rat brain hypothalamus was investigated in vivo (0.5 mg/kg) and in vitro (10(--6)--10(--5)M). Cocaine was used as a substance with a known adrenergic type of action. It was shown that under standard conditions cocaine in vitro increased the enzyme activity and decreased the Km for DMPH4 cofactor without changing Vmax of the reaction analyzed by the membrane enzyme. Cocaine in vitro decreased the tyrosine hydroxylase activity, especially that of the membrane enzyme. In this case there occurred a decrease of Km for DMPH4 and a decrease of Vmax of the reaction. The decrease of Vmax is considered to be the result of the secondary effect of cocaine.     

Effect of lanthanum on the turnover of calcium in rat uterus.

Previous investigations suggest that lanthanum might enter uterine smooth muscle cells and work as intracellular calcium displacing agent. The present investigation had been carried out in order to confirm if lanthanum develops an intracellular effect. Experiments show that lanthanum brings about a marked increase of the intracellular calcium; the comparison of the uptake and of the wash-out curve of 45Ca shows that lanthanum induces a lowering of the rapid phase of 45Ca release from rat uterus, while the uptake of the labelled ion is not modified or is even enhanced. The present data demonstrate that the action of lanthanum in rat uterus is limited to the cell membrane, whose calcium extruding properties are inhibited.     

Effect of clonidine on second messenger systems in rat adrenal gland.

Clonidine, an alpha 2-adrenergic agonist, also binds to non-adrenergic imidazole receptors in brain and peripheral tissues. In adrenal medulla, however, clonidine appears to bind only to imidazole receptors. To assess whether the signal transduction mechanism of imidazole receptors differs from alpha 2-adrenergic receptors, we studied the actions of clonidine on the turnover of phosphoinositide and the production of cAMP and cGMP in slices of rat adrenal gland. Clonidine did not modify basal or carbachol mediated increases in phosphoinositide turnover or production of cAMP, however it increased the production of cGMP. The increase in cGMP was slow and unaffected by the addition of the phosphodiesterase inhibitor, IBMX. We conclude that the second messenger response triggered by clonidine in adrenal differs from that usually coupled to alpha 2-adrenergic receptors. Whether the effect is mediated by cell surface imidazole receptors remains to be established.     

Effect of reserpine on adenylate cyclase system of rat striatum

We have investigated the properties of dopamine-dependent adenylate cyclase in rat striatal homogenates, 20 h after reserpine treatment. In this experimental condition, we have found that the affinity of the enzyme for dopamine is greatly enhanced. On the other hand, the concentration of apomorphine required to produced half-maximal activation of the enzyme in striatal homogenates of controls and reserpine-treated rats is not changed. The unchanged affinity of adenylate cyclase for the substrate (ATP:Mg⁺⁺) indicates that reserpine probably affects the receptor component of the enzyme.     

Effect of streptozotocin-induced diabetes on the turnover of hexokinase II in the rat

Skeletal muscle hexokinase II activity and turnover rates were measured in the normal and streptozotocin-induced diabetic rat. Enzyme activity decreases in the diabetic animal relative to the normal rat; however, the specific activity of hexokinase II is essentially the same for the two conditions. No alteration is observed in the relative rate of hexokinase II synthesis in the normal or diabetic rats, but there is a 3-fold increase in the rate of hexokinase II degradation in the latter group of animals. These results suggest that the primary cause of the well-established decrease in hexokinase II activity in skeletal muscle of the diabetic is an increase in the rate of enzyme degradation.     

Age differences in neurokinin A and substance P from the hypothalamus,pituitary, pineal gland,and striatum of the rat. Effect of exogenous melatonin

Previous data showed that aging of the central nervous system (CNS) is associated with widespread changes in tachykinin gene expression. However, there are no data about the possible role of exogenous melatonin in modulating the tachykinergic system during aging. The aim of this work was to analyze the age-dependent changes on neurokinin A (NKA) and substance P (SP) levels in hypothalamus, pituitary, pineal gland and striatum and the role of exogenous melatonin on these changes. We studied female rats at three different ages: 5-month-old (cyclic), 15-month-old (preacyclic) and 25-month-old (acyclic). Hypothalamic tachykinin levels increase when female rats reached acyclicity, this increase was blunted in acyclic-melatonin-treated rats. However, melatonin treatment in young cyclic rats resulted in significantly increased values as compared to controls. Pituitary NKA concentrations did no show age-dependent changes in control rats, however, in both, preacyclic and acyclic-melatonin-treated rats significantly increased values of pituitary NKA were found compared to controls. In the pineal gland, a marked decrease of NKA levels was observed in acyclic-control rats. Melatonin treatment did not alter this decrease. In the striatum, NKA and SP concentrations were significantly reduced in preacyclic- and acyclic-control rats compared to young cyclic rats, melatonin had no effect on striatal tachykinins. Our results indicate that melatonin may regulate tachykinin stores during aging mainly on structures of the neuroendocrine-reproductive axis.     

Noradrenaline turnover rate in the mediobasal and anterior hypothalamus of the rabbit

Noradrenaline turnover rate in the mediobasal and anterior hypothalamus of the rabbit. Acta Physiol. Pol., 1977, 28 (1): 39-43. The rate of noradrenaline (NA) turnover in mediobasal hypothalamus (MBH) and anterior hypothalamus (AH) of the rabbit was estimated by steady-state isotopic method with a tritiated noradrenaline (3H-NA) as a tracer. The disappearance rate of 3H-NA both in MBH and in AH was found to be biphasic; the first rapid phase of the NA half-life of about 30 min, followed by the second phase of slower decay of the half-life of 2.4 h and 10 h for MBH and AH respectively. The results suggest an existence of more than one metabolic pool of endogenous noradrenaline in MBH and AH and indicate regional difference in the metabolism of NA stores in the hypothalamus.     

Effect of amantadine on the rate of dopamine synthesis in rat corpus striatum.

Abstract— The effect of amantadine on the rate of dopamine synthesis in rat corpus striatum was determined by three methods. (1) Measuring the rate of decline of endogenous dopamine following inhibition of synthesis with a-methyltyrosine (α-MT); (2) Measuring the rate of conversion of [3,5-³H]tyrosine to ³H-labelled catechols under conditions of an initial rate; and (3) measuring the levels of homovanillic acid (HVA), the principal metabolite of brain dopamine. Endogenous dopamine levels were 68-1 n-mole/g with a control synthesis rate of about 21 n-mole/g/h as determined using either α-MT or [3,5-³H]tyrosine. Amantadine had no effect on synthesis at doses up to 100 mg/kg using α-MT and [3,5-³H]tyrosine. HVA levels were unaffected after 30 mg/kg drug, but were elevated 48%(P < 005) after 100 mg/kg of drug. By contrast apomorphine reduced and haloperidol increased synthesis as determined by all three methods. It is concluded that amantadine has no marked effect on dopamine synthesis in rat corpus striatum.