GABA and gonadotropin secretion: evidence from in vitro studies on regulation of LHRH secretion.
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Biomedical subjects
C Masotto
Publications and source records attributed to C Masotto.
Effect of single or repeated estrogen administration on tuberoinfundibular GABA neurons and anterior pituitary GABA receptors: biochemical and functional studies.
The effect of single or protracted administration of estradiol valerate on the hypothalamo-pituitary gamma-aminobutyric acid (GABA)ergic system and on plasma prolactin levels has been evaluated in female rats 2 months after the last (chronic treatment) or the single dose of the steroid. In the group of animals receiving one dose of estrogen, no modifications were detected in the activity of the tuberoinfundibular GABAergic neurons as implied by unchanged GABA accumulation either in the median eminence or the anterior pituitary after blockade of GABA catabolism with ethanolamine-O-sulphate. However, a complete disappearance of the low affinity population of GABA receptors in the anterior pituitary was observed. In this experimental condition, where baseline prolactin levels were 3-fold higher than in control rats, muscimol, a potent GABA agonist, was effective in significantly lowering plasma prolactin concentrations. Chronic estradiol valerate administration reduced GABA accumulation in the median eminence and the anterior pituitary at 4, but not at 2 h, after intracerebroventricular injection of ethanolamine-O-sulphate. Moreover, in this instance, a complete disappearance of the high affinity population of GABA receptors in the anterior pituitary was detected. Long-term estrogen administration induced also a 55-fold increase of plasma prolactin titers and muscimol was ineffective in reducing prolactin concentrations in plasma. The ability of muscimol to inhibit prolactin release only in single-estrogen-treated animals strongly suggests that the high affinity population of anterior pituitary GABA receptors is that involved in the mechanisms whereby GABA inhibits prolactin release from anterior pituitary.
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Interaction of SCH 23390, a D-1-selective antagonist, with the anterior pituitary D-2 receptors and prolactin secretion in the rat.
The affinity of the dopamine-1 (D-1) selective antagonist SCH 23390 (SCH) towards the dopamine-2 (D-2) receptor population present in the anterior pituitary (AP) was assessed in vitro and in vivo. [3H]Spiperone binding was used as biochemical marker for D-2 receptors in the rat AP and prolactin (PRL) was determined as a measure of the functional response to AP-D-2 blockade. SCH displayed weak activity in inhibiting [3H]spiperone binding in both AP and striatal membranes. The affinity was similar to that exhibited by sulpiride (mu molar range) but lower than that of haloperidol (HAL) (nmolar range). However inhibition of [3H]spiperone by SCH in the AP occurred in a biphasic manner indicating the existence of two D-2 sites with different affinity for the compound. SCH produced a transient and dose-dependent increase in plasma PRL levels when given by the subcutaneous (s.c.) route. A significant rise of PRL levels was observed only 30 min after the administration of high doses of SCH by the intraperitoneal (i.p.) route. SCH counteracted the inhibiting effect of apomorphine on PRL release and potentiated the stimulation effect of low doses of sulpiride on PRL secretion. The low affinity of SCH towards AP-D-2 receptors could be responsible for the small and short-lived increase in PRL secretion. This effect occurred at doses higher than those active in tests predictive for antipsychotic activity, which may depend directly on interaction with D-1 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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Neurochemical studies on GABAergic and aminergic systems in the rat brain following acute and chronic piracetam administration.
In view of the metabolic and behavioural effects of piracetam (P), a cyclic derivative of gamma-aminobutyric acid (GABA), in experimental animals and in man, it was of interest to investigate the effect of acute or chronic administration of the compound on the function of different brain neurotransmitter systems. P was ineffective in modifying either synthesis release, uptake or post- synaptic binding sites for GABA. Acute P injection decreased dose-dependently cGMP levels in the rat cerebellum. Moreover, this effect was not mediated through a GABAergic mechanism. An acute challenge with Piracetam 15 days after chronic treatment with the compound increased DOPAC levels in the striatum and counteracted haloperidol-induced PRL rise. Furthermore, chronic P administration increased normetanephrine levels in the cerebral cortex, an index of the release of norepinephrine at the synaptic level, and induced a desensitization of beta-adrenoceptors in this same brain area. In conclusion, besides the well documented effect of P on cholinergic neurons, P seems to exert its biological and behavioural effects through activation of catecholaminergic mechanisms.
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Inhibition of spontaneous or angiotensin II-stimulated water intake by atrial natriuretic factor.
A family of peptides, known as atrial natriuretic factors (ANF), have been isolated from atrial muscle tissue and reported to have profound effects on water and salt metabolism. ANF have also been reported to be present in the brain. The primary actions of these peptides lead to a reduction in plasma and extracellular fluid volume by eliciting natriuresis and diuresis, and by opposing the action of other peptidergic systems such as the vasopressin and angiotensin systems that promote water retention and enhance drinking behavior. This study was designed to determine if, in addition to its peripheral actions, ANF would also affect water ingestion, a mechanism that would be consistent with its general actions as a factor regulating extracellular fluid volume. Intraventricular (IVT) administration of an ANF, atriopeptin III (APIII), to intact male rats resulted in a significant inhibition of water intake in animals which were conditioned to drink during a one hour period. The inhibitory effects of APIII were immediate and most effective during the first 15 minute period, when maximal drinking occurred. Most remarkably, APIII given IVT also inhibited the potent dipsogenic action of angiotensin II (AII) on both water and a 2% NaCl solution intake. The results strongly suggest that ANF may have a significant role in central regulation of fluid intake and that its antidipsogenic effects may be mediated, at least in part, by an inhibitory effect on the central action of AII.
Angiotensin II↗
Prolactin in cerebrospinal fluid increases the synthesis and release of hypothalamic gamma-aminobutyric acid.
The effect of intracerebroventricularly (i.v.t.)-injected rat prolactin (2 micrograms/rat) on the function of tuberoinfundibular gamma-aminobutyric acid (GABA)ergic neurones was assessed in adult male rats by measuring the activity of glutamic acid decarboxylase (GAD) in the mediobasal hypothalamus (MBH) and the concentrations of GABA in hypophysial portal plasma and in the anterior pituitary gland. Fourteen hours after i.v.t. injection of rat prolactin the activity of GAD in the MBH was significantly (P less than 0.05) increased and it remained elevated for at least 16 h after injection. The mean concentrations of GABA in hypophysial portal plasma and in the anterior pituitary were twice those found in vehicle-treated controls 16 h after administration of rat prolactin; no significant effects were observed at earlier time-periods. A significant (P less than 0.01) and long-lasting decrease in endogenous plasma prolactin concentrations was detected 2 h after the i.v.t. injection of rat prolactin and the concentrations remained suppressed for up to 16 h. The present results are consistent with the concept that the activity of tuberoinfundibular GABAergic neurones is regulated, at least in part, by circulating prolactin. The ability of prolactin to accelerate the synthesis and release of GABA in the MBH might constitute a short loop feedback system by which the hormone regulates its own secretion.
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Behavioural responsiveness to muscimol and apomorphine 2 months after prolonged treatment with estradiol in rats.
Two months after prolonged administration of estradiol (ES) in female rats the behavioural responsiveness to muscimol, a GABA receptor stimulating agent, and to apomorphine, a dopamine receptor agonist, was significantly altered. In particular, the decrease in locomotor activity induced by a challenge dose of muscimol (0.5-1 mg/kg) was significantly attenuated in ES-pretreated animals. Conversely, the intensity of stereotyped behaviour elicited by a challenge dose of apomorphine (1 mg/kg) was significantly increased in ES-pretreated rats. The behavioural alterations in the response to muscimol and apomorphine presumably result from the production of central GABA receptor subsensitivity and dopamine receptor supersensitivity respectively, induced by the prolonged ES administration.
Animals↗
Prolactin control by the tubero-infundibular GABAergic system: role of anterior pituitary GABA receptors.
Anterior pituitary (AP) GABA receptors have been shown to play a functional role in the inhibitory control of prolactin (PRL) secretion by this amino acid. However, the physiological significance and the pharmacological characteristics of these receptors have yet to be determined. In normal male rat AP's incubated in vitro, GABA (10(-6) M) is effective in decreasing PRL release only when incubated in the presence of ethanolamine-O-sulphate (EOS), a potent GABA-transaminase (GABA-T) blocker. The failure of GABA alone to inhibit PRL release in vitro could be explained by the rapid degradation of the amino acid when added to the medium by AP-GABA-T. Central nervous system (CNS)- and AP-GABA receptors present similar affinity constants when evaluated by Scatchard analysis. However, displacement studies show that AP-GABA receptors have 10- and 100-times less affinity for muscimol (M), a GABA agonist, and for bicuculline, a GABA antagonist, respectively, than have GABA receptors. The low affinity of the agonist towards the AP receptors could also account for the relatively poor sensitivity of lactotrophs to GABA-mimetic compounds. Failure of chronic treatment with aminooxyacetic acid, a GABA-T inhibitor, to modify the PRL-lowering effect of GABA-mimetic compounds, despite the decrease in the number of AP-GABA receptors, indicates that in normal conditions only a reduced number of receptors are operative. These studies of AP-GABA receptors provide insight for a better understanding of the mechanisms involved in the regulation of PRL secretion by the hypothalamic GABAergic system.
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Biochemical and immunochemical studies on the GABAergic system in the rat fallopian tube and ovary.
gamma-Aminobutyric acid (GABA) and glutamic acid decarboxylase (GAD) activities were measured in the ovary and the Fallopian tube of rats and compared with brain values. GABA levels in the Fallopian tube were about twice as high as in the brain, while in the ovary they represented only about 5% of the amino acid content of the CNS. In vitro decarboxylation of glutamate, measured via CO2 formation, occurred both in the Fallopian tube and in the ovary. These two organs contained, respectively, 10% and 1% of brain GAD activity. However, the actual formation of GABA from glutamate in a high-speed supernatant was detectable only in the Fallopian tube, where it represented about 5% of brain GAD activity. In contrast with the enzyme present in ovary, liver, anterior pituitary, and kidney, that in the Fallopian tube was quantitatively precipitated by a specific antiserum directed against rat neuronal GAD. Moreover, subcutaneous transplantation resulted in a quantitative decrease of both GABA levels and GAD activity in the Fallopian tube while no change occurred in the ovary, and vagus nerve section induced a 50% decrease of GAD activity in the Fallopian tube, although GABA levels were not significantly altered. The findings suggest an extrinsic GABAergic innervation in the rat Fallopian tube but not in the ovary.
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Daily fluctuations in the activity of the tuberoinfundibular GABAergic system and plasma prolactin levels.
In view of the role exerted by gamma-aminobutyric acid (GABA) in the control of prolactin (PRL) secretion the circadian periodicity of hypothalamo-pituitary GABAergic activity and PRL secretion was evaluated in adult male rats to ascertain if a meaningful correlation between biochemical and endocrine indices may be evidenced. Anterior pituitary and median eminence GABA concentrations peaked during the late afternoon hours (18.00 h), while the glutamic acid decarboxylase activity reached higher concentrations at 15.00 h. Plasma PRL presented two circadian surges at 15.00 h and at midnight. Although the changes of GABA in the hypothalamo-pituitary complex and the PRL surges did not show a close temporal relation, the possibility may be considered that GABA circadian changes occurred as a delayed response to PRL circadian surges. However, it cannot be excluded that changes in the biochemical indices could be related to other neuroendocrine events.
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Ethanolamine-O-sulfate enhances gamma-aminobutyric acid secretion into hypophysial portal blood and lowers serum prolactin concentrations.
In ovariectomized rats the intraventricular administration of ethanolamine-O-sulfate (EOS, 300 micrograms), a specific, competitive and catalytic inhibitor of gamma-aminobutyric acid (GABA) transaminase, induced 3-4 h later a marked reduction in serum prolactin (PRL) concentrations and a 3- to 4-fold rise in the concentration of GABA in pituitary stalk, but not systemic, plasma. The administration of EOS also resulted in an elevation of GABA concentrations in the hypothalamus. These results demonstrate that GABA in pituitary stalk plasma is derived from the central nervous system and that an abrupt increase in the concentration of GABA in hypophysial portal blood is associated with a suppression of PRL secretion.
Animals↗
The role of dopaminergic agonists in congestive heart failure.
Congestive Heart Failure is a clinical syndrome characterised by myocardial dysfunction and sympathetic activation. Plasma norepinephrine (NE) levels have been related to the poorest survival. Large-scale clinical trials have proved the clinical benefits of Angiotensin Converting Enzyme inhibitors in reducing the risk of death and hospitalisation. However, mortality remains high in the treated group underlining the need to explore new therapeutic approaches. Specific activation of peripheral dopamine receptors exerts profound hemodynamic effects and neurohormonal control such as peripheral and renal vasodilation, diuresis and natriuresis and inhibition of NE release. Z1046, a mixed D1/D2-like agonist, reduces peripheral and renal vascular resistance increasing renal blood flow. In anaesthetised dogs the compound strongly reduces plasma NE without increasing plasma renin activity and plasma aldosterone. The inhibition of NE could be the basis of Z1046 potent cardioprotective effect observed in a dog model of myocardial ischemia and reperfusion, in which the severity of ventricular arrhythmias was markedly reduced, resulting in higher survival. These findings suggest that chronic oral treatment with specific dopaminergic agonists is able to alleviate the hemodynamic burden on the myocardium, and to suppress the sympatho-adrenal activity.
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