J.A. Apud

GABAergic control of anterior pituitary hormone secretion

Anatomical and biochemical studies have identified a hypothalamic tubero-infundibular GABAergic system, which plays a functional role on anterior pituitary hormone secretion. Experimental and clinical evidence support the presence of a dual component in the action of GABA; one mediated via the central nervous system and the other exerted directly at the anterior pituitary level. The two sites of action may be responsible for the excitatory and inhibitory effects of GABA on pituitary hormone and especially prolactin secretion. The future characterization of this system will provide a better understanding of the involvement of GABA in the physiology of anterior pituitary hormone secretion and will contribute to the development of new pharmacological agents for the therapy of neuroendocrine disorders.

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)

Regulation of prolactin secretion during suckling: involvement of the hypothalamo-pituitary GABAergic system

Previous results demonstrated that GABA exerts a dual control on PRL secretion, one excitatory mediated in part by the impairment of the tubero-infundibular dopaminergic (TIDA) system function, the other inhibitory occurring at the level of the anterior pituitary (AP), where 3H-GABA and 3H-Muscimol (3H-M) recognition sites have been described. This report provides evidence for a physiological role of the tubero-infundibular GABAergic system (TI-GABA) on PRL secretion in the rat. In lactating rats separated for 4 h from their pups reinstitution of suckling for different periods resulted in an increase either in glutamic acid decarboxylase (GAD) activity in the mediobasal hypothalamus (MBH) or in AP-GABA content. Dynamic changes of the GABAergic function in the MBH-AP system seemed to have a certain degree of specificity because suckling did not affect GAD activity in the caudate nucleus. In lactating rats 2, 4, 8 and 24 h after removal of the offsprings AP-GABA concentrations and plasma PRL titers significantly decreased with respect to values present in rats never separated from their pups. Since it has been demonstrated that the PRL lowering effect of GABA is a receptor-mediated event, we have investigated the plasticity of AP-GABA receptors during suckling. The inhibitory action of GABA seems to be mediated mainly by the activation of the high affinity binding sites. This proposition is supported by the fact that in lactating rats, where only the high affinity receptor population is present, M was still able to decrease significantly plasma PRL concentrations. These results indicate that the MBH-AP GABAergic system could play a role on PRL secretion, being involved in mechanisms which dampens PRL output during continuous suckling stimulation.

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 APs 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.

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.

Effect of THIP and SL 76002, two clinically experimented GABA-mimetic compounds, on anterior pituitary GABA receptors and prolactin secretion in the rat

In the present study, the ability of three direct GABA agonists, muscimol, THIP and SL 76002 to displace 3H-GABA binding from anterior pituitary and medio-basal hypothalamus membranes was evaluated. Further, the effect of both THIP and SL 76002 on baseline prolactin levels or after stimulation of hormone release with haloperidol has been also studied. Either muscimol, THIP or SL 76002 have shown to posses 7-, 7- and 3-fold higher affinity, respectively, for the central nervous system than for the anterior pituitary 3H-GABA binding sites. Moreover, THIP and SL 76002 have demonstrated to be respectively, 25- and 1000- fold less potent than muscimol in inhibiting 3H- GABA binding at the level of the anterior pituitary and about 25- and 2700- fold less potent at the level of the medio-basal hypothalamus. Under basal conditions, either THIP or SL 76002 were ineffective to reduce prolactin release. However, after stimulation of prolactin secretion through blockade of the dopaminergic neurotransmission with haloperidol (0.1 mg/kg), both THIP (10 mg/kg) and SL 76002 (200 mg/kg) significantly counteracted the neuroleptic-induced prolactin rise with a potency which is in line with their ability to inhibit 3H-GABA binding in the anterior pituitary. The present results indicate that both compounds inhibit prolactin release under specific experimental situations probably through a GABAergic mechanism. In view of the endocrine effects of these GABA-mimetic compounds, the possibility arises for an application of these type of drugs in clinical neuroendocrinology.

Dopamine reuptake inhibitors and dopamine releasers: differential effect on plasma prolactin in the rat.

Summary Administration of diclofensine (5, 10 and 20 mg/kg ip) and CDCI (25 and 50 mg/kg ip), two potent inhibitors of dopamine (DA) reuptake, with virtually no DA releasing activity at the doses used, failed to alter either baseline plasma prolactin (PRL) or anterior pituitary DA concentrations in unanesthetized male rats. In contrast, nomifensine (5 and 10 mg/kg ip), a drug which induces both DA release and blockade of DA reuptake, lowered plasma PRL levels and increased anterior pituitary DA concentrations. The same effects were shared by diclofensine when administered at doses (45 and 100 mg/kg ip), reportedly capable of also affecting DA release. These data indicate that DA recapture into tuberoinflundibular DA nerve terminals does not play a major role in the removal of DA released into the hypophyseal portal system and that this mechanism is not operative in the inhibitory control of DA over PRL secretion.

Effects of repeated tiapride administration on anterior pituitary dopamine receptors and prolactin release in the rat

The substituted benzamides tiapride and sulpiride, and the classic neuroleptic haloperidol, were studied in the rat to assess their interaction with the anterior pituitary (AP) dopamine (DA) receptors both in vitro ([3H]spiperone binding) and in vivo prolactin-PRL-release). Tiapride weakly inhibited [3H]spiperone binding in both pituitary and striatal membranes with affinity 5-7 times lower than sulpiride and 400-300 times lower than haloperidol. All three drugs were more potent in displacing [3H]spiperone from striatum than from AP. In vivo, tiapride produced weak and transient stimulation of PRL release reaching a full effect at 2 mg/kg i.p. Similar doses of sulpiride produced longer-lasting effects. Haloperidol was more potent than both benzamides. In prolonged treatments (15 or 60 days), tiapride, given twice daily at 0.5 mg/kg i.p., did not modify [3H]spiperone binding in either AP or striatum, nor did it induce significant changes of basal PRL levels. The challenge with a low threshold dose of TIA (0.2 mg/kg ip) produced similar increases of PRL release in the group either treated with TIA or saline. The data indicate that the benzamides examined have low potency for interaction with DA receptors in pituitary and striatum. In particular, tiapride displayed weaker affinity for AP-DA receptors than the other drugs and induced only slight stimulation of PRL levels. Results from repeated tiapride administration indicate that the drug, at a clinically relevant dose, is unable to modify either kinetic characteristics of DA receptors in the pituitary or plasma PRL levels.

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.