Brain-derived neurotrophic factor (BDNF) Val(66)Met polymorphism differentially predicts hippocampal function in medication-free patients with schizophrenia.

A Val(66)Met single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene impairs activity-dependent BDNF release in cultured hippocampal neurons and predicts impaired memory and exaggerated basal hippocampal activity in healthy humans. Several clinical genetic association studies along with multi-modal evidence for hippocampal dysfunction in schizophrenia indirectly suggest a relationship between schizophrenia and genetically determined BDNF function in the hippocampus. To directly test this hypothesized relationship, we studied 47 medication-free patients with schizophrenia or schizoaffective disorder and 74 healthy comparison individuals with genotyping for the Val(66)Met SNP and [(15)O]H(2)O positron emission tomography (PET) to measure resting and working memory-related hippocampal regional cerebral blood flow (rCBF). In patients, harboring a Met allele was associated with significantly less hippocampal rCBF. This finding was opposite to the genotype effect seen in healthy participants, resulting in a significant diagnosis-by-genotype interaction. Exploratory analyses of interregional resting rCBF covariation revealed a specific and significant diagnosis-by-genotype interaction effect on hippocampal-prefrontal coupling. A diagnosis-by-genotype interaction was also found for working memory-related hippocampal rCBF change, which was uniquely attenuated in Met allele-carrying patients. Thus, both task-independent and task-dependent hippocampal neurophysiology accommodates a Met allelic background differently in patients with schizophrenia than in control subjects. Potentially consistent with the hypothesis that cellular sequelae of the BDNF Val(66)Met SNP interface with aspects of schizophrenic hippocampal and frontotemporal dysfunction, these results warrant future investigation to understand the contributions of unique patient trait or state variables to these robust interactions.

Epistatic interactions of AKT1 on human medial temporal lobe biology and pharmacogenetic implications.

AKT1 controls important processes in medial temporal lobe (MTL) development and plasticity, but the impact of human genetic variation in AKT1 on these processes is not known in healthy or disease states. Here, we report that an AKT1 variant (rs1130233) previously associated with AKT1 protein expression, prefrontal function and schizophrenia, affects human MTL structure and memory function. Further, supporting AKT1's role in transducing hippocampal neuroplasticity and dopaminergic processes, we found epistasis with functional polymorphisms in BDNF and COMT--genes also implicated in MTL biology related to AKT1. Consistent with prior predictions that these biologic processes relate to schizophrenia, we found epistasis between the same AKT1, BDNF and COMT functional variants on schizophrenia risk, and pharmacogenetic interactions of AKT1 with the effects on cognition and brain volume measures by AKT1 activators in common clinical use--lithium and sodium valproate. Our findings suggest that AKT1 affects risk for schizophrenia and accompanying cognitive deficits, at least in part through specific genetic interactions related to brain neuroplasticity and development, and that these AKT1 effects may be pharmacologically modulated in patients.

DRD2 co-expression network and a related polygenic index predict imaging, behavioral and clinical phenotypes linked to schizophrenia.

Genetic risk for schizophrenia (SCZ) is determined by many genetic loci whose compound biological effects are difficult to determine. We hypothesized that co-expression pathways of SCZ risk genes are associated with system-level brain function and clinical phenotypes of SCZ. We examined genetic variants related to the dopamine D2 receptor gene DRD2 co-expression pathway and associated them with working memory (WM) behavior, the related brain activity and treatment response. Using two independent post-mortem prefrontal messenger RNA (mRNA) data sets (total N=249), we identified a DRD2 co-expression pathway enriched for SCZ risk genes. Next, we identified non-coding single-nucleotide polymorphisms (SNPs) associated with co-expression of this pathway. These SNPs were associated with regulatory genetic loci in the dorsolateral prefrontal cortex (P<0.05). We summarized their compound effect on co-expression into a Polygenic Co-expression Index (PCI), which predicted DRD2 pathway co-expression in both mRNA data sets (all P<0.05). We associated the PCI with brain activity during WM performance in two independent samples of healthy individuals (total N=368) and 29 patients with SCZ who performed the n-back task. Greater predicted DRD2 pathway prefrontal co-expression was associated with greater prefrontal activity and longer WM reaction times (all corrected P<0.05), thus indicating inefficient WM processing. Blind prediction of treatment response to antipsychotics in two independent samples of patients with SCZ suggested better clinical course of patientswith greater PCI (total N=87; P<0.05). The findings on this DRD2 co-expression pathway are a proof of concept that gene co-expression can parse SCZ risk genes into biological pathways associated with intermediate phenotypes as well as with clinically meaningful information.

Endocrine modulation of gamma-aminobutyric acidergic innervation in the rat fallopian tube.

The present study investigates the effect of different endocrine manipulations on the gamma-aminobutyric acid (GABA)-ergic system in the rat fallopian tube. Either hypophysectomy or ovariectomy induced a significant decrease of glutamic acid decarboxylase (GAD) activity and of GABA levels in in situ tubes. This effect was completely reversed by either gonadotropins or combined estrogen-progesterone administration, respectively. Estrogen or progesterone alone proved less effective than the administration of both steroids in counteracting the effect of ovariectomy on GAD activity. The in vitro incubation of ovariectomized rat fallopian tubes with estrogen-progesterone for 1 h failed to counteract the reduction of the GAd activity induced by surgical manipulation. The in vivo effect of estrogen-progesterone administration on the GABA-ergic system seems to be specific since steroid treatment induced the synthesis of an enzyme which was immunologically identical to the GAD present in the fallopian tube and brain of normal diestrous rat. Autotransplantation of the fallopian tube under the skin brought about a decrease of GAD activity similar to that obtained after ovariectomy. In this situation, however, estrogen-progesterone administration did not counteract the decrease of GAD activity induced by fallopian tube deafferentation. The present results demonstrate that an interaction between the GABA-ergic system and the hypothalamo-pituitary-gonadal axis seems to be operative at the level of the rat fallopian tube. However, the physiological meaning of this interrelationship between the endocrine and the peripheral nervous systems remains to be clarified.

Role of central nervous system-derived or circulating gamma-aminobutyric acid on prolactin secretion in the rat.

To investigate the respective role in PRL secretion of gamma-aminobutyric acid (GABA), either derived from the central nervous system or circulating in plasma, experiments were performed using ethanolamine-O-sulfate (EOS), a specific inhibitor of GABA catabolism. Intracerebroventricular injection of EOS (2 mg/kg) induced in unanesthetized male rats 2-8 h post injection a clear-cut rise in hypothalamic, anterior pituitary (AP), and plasma GABA concentrations. Rises in GABA titers occurred earlier in the hypothalamus and AP (2 h) than in the plasma (4 h). Concomitant to alterations of GABA, there was a striking lowering of plasma PRL evident at 2 h and still present 24 h after EOS administration. In contrast, systemic administration of graded doses of EOS (200-400 mg/kg, iv) did not induce significant changes in plasma GABA concentrations 4 h post injection; only the 600 mg/kg dose of EOS increased GABA concentrations 4 h post injection in the hypothalamo-AP system and decreased plasma PRL concentrations. Finally, in hypophysectomized rats bearing ecotopic pituitaries, despite the occurrence of rises in the hypothalamic GABA after intracerebroventricular or systemic (600 mg/kg) administration of EOS, AP, plasma GABA, and plasma PRL concentrations were not altered. In all these findings indicate that: 1) changes in plasma PRL are best correlated to variations in the amino acid titers occurring in the hypothalamo-AP systems; and 2) circulating GABA does not play a functional role in the control of PRL secretion. Finally, since alterations in blood GABA levels after central or systemic administration of EOS appear to reflect primary changes occurring in the brain concentration of the amino acid, circulating GABA may be a reliable indicator of central nervous system GABAergic function.

Possible involvement of ovarian mechanisms other than estrogen-progesterone secretion in the regulation of glutamic acid decarboxylase activity of the rat fallopian tubes.

This study was performed to clarify the physiological role of the ovary in regulating the glutamic acid decarboxylase (GAD) activity in rat Fallopian tubes. To this purpose, GAD activity of the oviduct was evaluated in the following experimental conditions: immature or adult castrated (CX) rats; immature or adult CX rats treated with graded doses of estradiol benzoate (EB) or a fixed dose of EB and progesterone; adult CX rats bearing Silastic implants able to produce steady state estradiol plasma levels in the range of diestrous values; and prepubertal rats treated with ovulatory or anovulatory doses of exogenous gonadotropins (PMS and hCG). Moreover, the possible fluctuations of both gamma-aminobutyric acid (GABA) concentrations and GAD activity in the Fallopian tubes were studied during the estrous cycle. The results show that the prepubertal rat oviduct possesses a GABA content and a GAD activity analogous to those of normal diestrous rats. The GAD activity measured with the CO2 formation method was well correlated with the formation of labeled GABA, indicating that tubes of prepubertal rats are able to form the neurotransmitter by means of specific decarboxylation of glutamate. GAD activity, but not GABA levels, was increased over control values by the administration of exogenous gonadotropins. The role of the ovary in both adult and prepubertal rats to regulate this enzymatic activity is further stressed by the results of the experiments performed in CX animals which showed that ovariectomy produced a 4- to 5-fold decrease in GAD activity independent of the age of the animals. However, implantation of Silastic estradiol-containing capsules in adult CX animals or the administration of EB for 5 days in a dose range from 0.001-6.4 micrograms/day to adult ovariectomized animals and from 0.001-0.2 microgram/day to prepubertal animals did not modify GAD activity in spite of marked peripheral estrogenization of the animals evidenced by increases in uterine weight. Moreover, no variation of the enzymatic activity was observed at puberty (assessed by the age at vaginal opening). The administration of progesterone (0.2 mg) plus EB (0.01 microgram) did not produce any significant variation in GAD activity. GABA content and GAD activity of the tubes did not change during the estrous cycle. We, therefore, believe that other ovarian, still unidentified, secretions might be involved in the regulation of GAD activity in rat Fallopian tubes.

Pharmacological characterization of regulation of phosphoinositide metabolism by recombinant 5-HT2 receptors of the rat.

Transfection of 5-HT2 receptor cDNA in 293 cells induced the expression of a protein binding domain, exhibiting the classical 5-HT2 receptor transduction mechanism. Both [3H]DOB and [3H]spiperone high affinity binding sites were present in membranes of sense but not of antisense, 5-HT2 receptor cDNA transfected cells. Addition of 1 microM 5-HT induced a time-dependent increase of phosphoinositide (PI) metabolism in sense but not in antisense, 5-HT2 receptor cDNA transfected cells. Graded concentrations of 5-HT and of different serotonergic agonists showed different potencies (DOI greater than 5-HT greater than quipazine greater than DOM greater than alpha-methyl-5-HT greater than 8-OH-DPAT greater than 2-methyl-5-HT greater than CGS-12066B) in stimulating turnover of PI in cells transfected with cDNA encoding for 5-HT2 receptors of the rat. The ability of different antagonists to inhibit 5-HT-stimulated turnover of PI bore a direct relationship with their potency to inhibit 5-HT2 receptor binding in cells transfected with 5-HT2 receptor cDNA (spiperone greater than ketanserin greater than ritanserin greater than mianserin greater than haloperidol). Preincubation of transfected 293 cells with pertussis toxin failed to modify either 5-HT- or DOI-induced activation of metabolism of PI. Pretreatment of transfected 293 cells with DOI (100 nM) for 2 hr or more, significantly reduced activation of turnover of PI elicited by graded doses of 5-HT. When the transfected 293 cells were exposed to DOI (100 nM) for 12 hr and the challenge was performed after a 2-hr wash-out period, the desensitization of the response to 5-HT was virtually abolished.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Biochemical and functional aspects on the control of prolactin release by the hypothalamo-pituitary GABAergic system.

A growing body of biochemical, immunohistochemical, and autoradiographic evidence indicates the presence of two different GABAergic systems in the mediobasal hypothalamus: one intrinsic, the tuberoinfundibular GABAergic system, and the other extrinsic, whose cell bodies are located outside the mediobasal hypothalamus and which projects to this area and establishes synaptic contacts with aminergic and peptidergic neurons involved in endocrine function. This particular anatomical configuration provides a rational basis to explain the dual action of GABA (inhibitory and stimulatory) on prolactin release. Different studies aimed at identifying the precise role of GABA on prolactin function have demonstrated that this system can be modulated, at the pre- and/or post-synaptic level, by different experimental maneuvers in which prolactin secretion is physiologically and pharmacologically altered. GABA mainly appears to be involved in feedback mechanisms preventing an exaggerated prolactin output during specific physiological situations. The ability of clinically tested, direct GABAmimetic compounds to lower prolactin secretion in the rat points towards a clinical usefulness of these drugs in particular spontaneous or induced neuroendocrine disorders. However, the possibility of a widespread use of this type of compounds is hampered by the lack of potent, specific and non-toxic GABA agonists suitable for clinical purposes.

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.

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.

Effects of smoking during antipsychotic withdrawal in patients with chronic schizophrenia.

A number of studies have shown that patients with schizophrenia smoke more than other psychiatric patients and more than the general population. Also, medicated schizophrenics who smoke present more positive symptoms of schizophrenia than non-smokers. The objective of the present study was to assess the effect of smoking on ratings of psychopathology for 30 days following discontinuation of antipsychotic medication. The subjects were 101 treatment-resistant patients with schizophrenia who had been admitted to the inpatient service of Neuroscience Research Hospital (NRH), National Institute of Mental Health, between 1982 and 1994 to undergo studies involving discontinuation of antipsychotic medication. Patients were rated independently on a daily basis on the 22-item Psychiatric Symptom Assessment Scale (PSAS), an extended version of the Brief Psychiatric Rating Scale (BPRS). At baseline, ratings for Verbal Positive, Paranoia and Loss of Function were higher in smokers (n=65) than non-smokers (n=36), but a statistically significant difference was observed only for the Verbal Positive cluster. Analysis by gender revealed that male non-smokers had the lowest psychopathology ratings at baseline. There were no differences in Anxiety/depression, Behavior Positive, Deficit Symptoms or Mannerisms (a measure for abnormal involuntary movements). Following medication discontinuation, repeated-measure analysis demonstrated a 'time' effect for all the variables studied and a 'group' (smokers vs. non-smokers) effect for Verbal Positive, Paranoia, and Loss of Function. Post-hoc comparisons at individual time points showed significantly higher ratings for smokers at week 1 for Paranoia. No differences were observed at later time points. In conclusion, at baseline, smokers had more positive symptoms and were apparently more functionally impaired than non-smokers. This difference was no longer evident after a 30 day medication discontinuation period.

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.

Acetylcholine modulates the effect of ovarian steroids on glutamic acid decarboxylase activity in the rat fallopian tube.

Glutamic acid decarboxylase (GAD) activity was measured in the oviduct of normal rats in diestrous and in rats ovariectomized (OVX) seven days before. OVX induced a significant decrease of GAD activity in the Fallopian tube. This effect was completely reversed by coadministration of estradiol benzoate + progesterone (E + P). Simultaneous injection of atropine, but not of alpha-methyl-para-tyrosine or labetalol, completely prevented the activation of GAD induced by ovarian sterois. Moreover, prostigmin significantly potentiated the action of E + P on GAD activity in the rat oviduct. These data clearly suggest the participation of acetylcholine in the mechanisms whereby ovarian steroids regulate GAD activity in the rat Fallopian tube.

GABAergic mechanism involved in sinoaortic denervation in rats.

GABAergic neurotransmission in sinoaortic denervated (SAD) rats with that in sham-operated animals 15 days after operation. In sham-operated rats, glutamic acid decarboxylase (GAD) and 4-amino-butyrate-2-oxoglutarate aminotransferase (GABA-T) activities were higher in dorsal than in ventral regions of pons and medulla oblongata and a higher GAD activity was observed in anterior than in posterior hypothalamus. Fifteen days after SAD, GAD and GABA-T activities were significantly reduced in dorsal pons and in anterior hypothalamus whereas GABA-T activity was increased in ventral medulla oblongata. The results indicate the involvement of GABAergic neurotransmission in the deafferentation of the nucleus tractus solitarii by sinoaortic denervation. GABA hypothalamic inputs could be involved in the baroreflexes.

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)

Treatment of tardive dyskinesia.

Although the new generation of atypical antipsychotic agents could some day eliminate concerns about tardive dyskinesia (TD), this disorder remains a significant clinical problem for both patients and physicians. Fortunately, many, if not most, cases of TD are mild. For patients with mild to moderate TD, therapeutic efforts are primarily directed at minimizing neuroleptic exposure or, when possible, changing to atypical agents. Most cases of TD do not seem to progress, suggesting that the risk of remaining on typical neuroleptics is probably small. Patients with moderate to severe forms of TD present greater challenges. These patients frequently require medication to suppress their dyskinesias. A variety of suppressive agents have been tried with limited success. No treatment strategy has emerged that is clearly superior or even successful in most patients. Increasing doses of typical neuroleptics may be useful for short-term suppression; however, the long-term efficacy and risk of this strategy have not been studied carefully. Data on atypical neuroleptics are scant. Clozapine's short-term suppressive effects seem, at best, weak, but patients may improve with long-term treatment. Medications with relatively few side effects that may have suppressive efficacy for some patients include calcium channel blockers, adrenergic antagonists, and vitamin E. Gamma-amino-butyric acid agonists agents and dopamine depleters are frequently useful, but have troubling side effects of their own. A variety of other medications have been employed, but are not well studied. For patients with tardive dystonia, anticholinergic agents or botulinum toxin has been particularly effective. Efforts to understand the neurobiology of TD may shed light on this persistent clinical conundrum.

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.

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.