Biomedical subjects

K Gerozissis

Publications and source records attributed to K Gerozissis.

At least 19 recordsLinked to original sources

PubMed2004

Brain insulin and feeding: a bi-directional communication.

Insulin and specific insulin receptors are found widely distributed in the central nervous system (CNS) networks related in particular to energy homeostasis. This review highlights the complex regulatory loop between dietary nutrients, brain insulin and feeding. It is well documented that brain insulin has a negative, anorexigenic effect on food intake. At present, a specific role for brain insulin on cognitive functions related to feeding is emerging. The balance between orexigenic and anorexigenic pathways in the hypothalamus is crucial for the maintenance of energy homeostasis in animals and humans. The ingestion of nutrients triggers neurochemical events that signal nutrient and energy availability in the CNS, down regulate stimulators, activate anorexigenic factors, including brain insulin, and result in reduced eating. The effects of insulin in the CNS are under a multilevel control of food-intake peripherally and in the CNS, via the metabolic, endocrine and neural modifications induced by nutrients. Single meals as well as glucose and serotonin are able to regulate insulin release directly in the hypothalamus and may be of importance for its biological effects. Central mechanisms operating in glucose-induced insulin release show some analogy with the mechanisms operating in the pancreas. Leptin and melanocortins, peptides that down regulate food intake and are largely affected by nutrients, are highly interactive with insulin in the CNS probably via the neurotransmitter serotonin. In the hypothalamus, insulin and leptin share a common signaling pathway involved in food intake, namely the insulin receptor substrate, phosphatidylinositol 3-kinase pathway. Over or under-feeding, unbalanced single meals or diets, in particular diets enriched in fat, modify the amount of insulin actively transported into the brain, the release of brain insulin, the expression of insulin messenger RNA and potentially disrupt insulin signaling in the CNS. This impairment may result in disorders related to feeding behavior and energy homeostasis leading to profound dysregulations, obesity or diabetes.

Animals↗

PubMed2002

Sex differences in the effects of neonatal handling on the animal's response to stress and the vulnerability for depressive behaviour.

Neonatal handling is known to affect the programming of the hypothalamic-pituitary-adrenal axis and, as a result, the ability of the organism to respond to stress. We determined the effect of neonatal handling on the animal's response in three animal models of depression, as well as to either (a) acute or (b) chronic forced swimming stress. Neonatal handling resulted in a significant increase in the immobility time in the Porsolt forced swimming test in both sexes, and in the 8-hydroxy-2-(di-n-propylamino) tetralin-induced hypothermia in the males. On the other hand, handling had sex-dependent effects when animals were exposed to a chronic stressor. After exposure to chronic restraint stress, statistically more handled than non-handled females failed to adapt, while no such difference was found in the males. In the chronic forced swimming stress, handled males had shorter immobility times, and higher plasma corticosterone levels, while the opposite held true in the females. Furthermore, neonatal handling significantly decreased basal plasma corticosterone levels in both pre- and post-pubertal animals. Thus, the early experience of handling provides males with a greater capacity to actively face chronic stressors, while in the females it increases their susceptibility to express 'depressive' behaviour since they are unable to cope and adopt a 'passive, despaired' behaviour.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2001

Macronutrient-induced cascade of events leading to parallel changes in hypothalamic serotonin and insulin.

Extracellular serotonin (5-HT) and insulin from hypothalamic PVN-VMH region follow parallel changes in response to specific macronutrient ingestion. Possible independent or causal mechanisms have been investigated. A common primary event might be pancreatic insulin secretion for both insulin entry into the brain and 5-HT synthesis through variations in the ratio of tryptophan over competitor amino acids. The steps of this cascade were found to account only partly for the changes in hypothalamic 5-HT and insulin. The central consequences of these metabolic effects may be modulated directly at the hypothalamic level. For instance, we observed a positive relation between the changes in insulin and 5-HT and the satiating potency of each nutrient. In addition, a direct action of dexfenfluramine on insulin has been found at the hypothalamic level showing that an activation of the serotonergic system immediately enhances insulin levels. This central event may be an important step in a cascade of events triggered by macronutrient ingestion leading to common hypothalamic insulin and 5-HT changes involved in feeding regulation.

Animals↗

PubMed2001

A potential role of central insulin in learning and memory related to feeding.

1. Hypothalamic insulin (HI) is well known for its role in feeding regulation. In addition, its concentration is modified in response to meals. Recent studies suggest that brain insulin participates in memory processes, possibly through stimulation by glucose. 2. The present microdialysis study focused on local in vivo regulation of HI by glucose and on the effects of aging on HI, since aging is characterized by deterioration of memory, body weight regulation, and central glucose utilization. Glucose (8 mM) infused for 5 min increased extracellular HI levels rapidly, by 4.6-fold, and cerebellar insulin levels by 0.4-fold only, suggesting a specific area-dependent regulation of HI by glucose. Neither insulinemia nor glycemia were affected, suggesting a central mechanism. The same dose of glucose induced a modest (0.4-fold), delayed (45 min) increase in hypothalamic serotonin, suggesting that the effect of glucose on HI is independent of a previously defined local serotonin-induced insulin release. HI levels in old normal weight rats were half the levels of young rats. In genetically old obese (fa/fa) Zucker rats, HI concentration was 30% of that in young normal rats, suggesting a deterioration of HI availability when aging and obesity are combined. 3. The above results, in line with recent considerations on a potential role of central insulin in learning and memory, suggest particular effects of HI on feeding and memory and probably on a specific "memory for food."

Age Factors↗

PubMed2001

Plasma Trp/LNAA ratio increases during chronic ingestion of an alpha-lactalbumin diet in rats.

Brain serotonin synthesis depends on the uptake of its precursor, tryptophan (Trp), and is correlated to the plasma ratio of Trp to large neutral amino acids (LNAA) which compete for the same transporter system in the brain. As the plasma Trp/LNAA ratio decreases when the dietary protein content exceeds 5%, we tested whether a diet containing 17% of a Trp-rich protein, namely alpha-lactalbumin (LAC), might increase the plasma Trp/LNAA ratio over a long period. Blood samples were obtained at different days (-1, 3, 6 and 9) from rats receiving either a LAC or casein (CAS) diet, and plasma amino acids and insulin concentrations were determined. The increase in plasma Trp concentration was much higher during the LAC diet (49 vs 26%; P<0.001), while the plasma LNAA concentration remained fairly constant. Consequently, the plasma Trp/LNAA ratio increased by 40% during the LAC diet while it decreased by 15% during the CAS diet (P<0.001). The above results were not related to plasma insulin concentration differences during these diets. These data suggest that a balanced diet containing a natural Trp rich-protein increases the plasma Trp/LNAA ratio over a long period, leading to a probable increase in brain serotonin activity.

Amino Acids↗

PubMed2001

[Variations of hypothalamic and cortical prostaglandins and monoamines reveal transitions in arousal states: microdialysis study in the rat].

Brain microdialysis coupled with EEG recording allowed us to track dynamic neurochemical changes every 3 or 6 minutes in relation to sleep/wake cycles. We chose to investigate prostaglandins (PG) and monoamines (catecholamines, serotonin and metabolites) because of their respective role in the states of vigilance, mainly suggested by pharmacological approaches, and because of the known interactions between PGs and monoamines. We focused on the paraventricular and ventromedial nuclei of the hypothalamus for their involvement in the relationships between feeding, metabolic rate and sleep, and the prefrontal cortex for its role in vigilance. These studies revealed a few changes in prostaglandin or monoamine levels as a function of a given state of vigilance. In particular, serotonin levels were higher during wakefulness than during sleep in both hypothalamus and cortex. Both hypothalamic and cortical PGE2 levels were higher during wakefulness than during slow wave sleep and still higher during paradoxical sleep in the cortex. Cortical PGD2 showed an exactly reverse profile of PGE2. These changes are in agreement with the described awaking action of PGE2 and with the hypnogenic action of PGD2. Our most informative findings were the sequential changes around transitions from one state to another that allow to predict the moment of onset of both sleep and wakefulness. Both in hypothalamus and in cortex, ondulatory patterns of PGE2 were encountered around the transitions between states. PGE2 was high in the middle of wakefulness, then regularly dropped announcing the occurrence of sleep, where the drop persisted before giving place to a rise in prediction to the next period of wakefulness. A similar profile was also observed for cortical serotonin, but its low levels reached a plateau during sleep. Cortical dopamine levels showed sudden and dramatic drops during short periods of wakefulness closely surrounding slow wave sleep. In some instances, as in the case of PGE2, similar profiles of variations could be found both in the hypothalamus and cortex. But in most cases, different and even opposite profiles were encountered in those two structures. Interestingly, in some instances, the pattern of changes in both prostaglandins and monoamines were similar, as for example between hypothalamic PGE2 and dopamine as well as between cortical PGE2 and serotonin. These similarities support the idea of the suggested interaction between prostaglandins and monoamines, in particular concerning their involvement in the regulation of sleep/wake cycles.

Animals↗

PubMed2000

Activation of hypothalamic insulin by serotonin is the primary event of the insulin-serotonin interaction involved in the control of feeding.

In previous experiments, we reported a close parallelism in the responses of both serotonin (5-HT) and insulin in the hypothalamic PVN-VMH region of freely-moving rats during feeding. Thus, hypothalamic 5-HT and insulin may participate, independently or in interaction, in the control of carbohydrate and fat ingestion. The precedence of the activation of one or the other substance remained to be investigated. In adult male Wistar rats, (a) dexfenfluramine was administered to the PVN-VMH region by reverse microdialysis (80 microM for 10 min) while local insulin was assessed; (b) insulin was locally infused (400 mU for 10 min) through the tip of the dialysis probe while 5-HT was measured. Dexfenfluramine immediately increased 5-HT release, and also extracellular insulin levels (+102%). This activation of insulin by serotonin is actually a central effect since neither insulinemia nor glycemia were affected. Conversely, insulin enhanced 5-HT release (+81%), but only 45 min after the beginning of its infusion. Noradrenaline, dopamine and metabolites were slightly or not at all modified by insulin. These data demonstrate that an interaction does exist between insulin and 5-HT in the VMH-PVN area. Because of the delay of 5-HT response to insulin, an activation of the serotonergic system would be the causal event acting immediately on insulin, and not the contrary. Whatever the exact mechanism of this interaction, it seems to be a link in a larger cascade of events involving numerous neurotransmitters and peptides leading to the regulation of feeding.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Synergistic effect of arcuate and raphe nuclei graft to alleviate insulinemia and obesity in Zucker rats.

The arcuate nucleus (AN) of the hypothalamus is a key area in which endocrine messages are relayed to the brain, while midbrain raphe nucleus (RN) is the source of brain serotonin. Both nuclei contribute to the central mechanism of energy homeostasis. This experiment aimed to determine the impact of AN and RN grafts on insulinemia and obesity in diabetic rats. AN and RN were dissected from 15-day (Fa/Fa) lean embryos and grafted separately or together into the third brain ventricle of obese (fa/fa) male Zucker rats. Histological analysis showed the functional maturity of grafts, which were vascularized, contained neurons reinnervating the periventricular hypothalamus and hypophysis, and expressed neuropeptide Y and enzymes for dopamine and serotonin synthesis. Three months after transplantation, the rats grafted with AN or RN had a lower body weight gain compared to sham-operated rats (19% and 17%, respectively). Rats grafted with AN together with RN gained significantly less body weight than rats grafted with AN or RN separately (31% vs. sham-operated rats), and showed a decreased plasma insulin concentration (132 +/- 33 microU/ml) vs. sham-operated rats (459 +/- 108 microU/ml, p < 0.05). A synergistic effect on alleviating obesity and insulinemia by double AN and RN grafts suggests that both these nuclei are functionally interrelated in maintaining energy homeostasis, and normal functioning of both nuclei is altered during obesity.

Animals↗

PubMed2000

Is the early increase in leptinemia one of the anorectic signals induced by an essential amino acid-deficient diet in the rat?

Rats start decreasing their food intake as early as 70 min after the first ingestion of a food deficient in threonine. A decrease of the limiting essential amino acid (EAA) in the plasma was proposed to be the first anorectic signal. Because many hormones regulate feeding behavior, we studied the effect of a meal (46 kJ) that was either devoid of threonine or was corrected for the deficiency, on plasma leptin, insulin and glucagon levels using a radio-immunoassay, at 0 to 180 min after the meal. One hour after ingestion of the threonine-devoid meal, a larger increase in insulinemia (22+/-1 vs. 15+/-1 microU/ml) and leptinemia (7.8+/-0.5 vs. 4.4+/-0.6 ng/ml; p<0.001) was observed than after ingestion of the corrected meal. The area under the curve of the threonine-devoid meal group was 3 and 1.34 fold larger than for the corrected meal group for insulin and leptin respectively. Glucagonemia was not different between the two groups. We propose that the rise in leptinemia, perhaps in synergy with rise in plasma insulin, might serve as one early signal to brain structures, participating in the anorectic mechanism following ingestion of an EAA-deficient diet.

Amino Acids, Essential↗

PubMed1999

Brain insulin response to feeding in the rat is both macronutrient and area specific.

Using microdialysis, we showed recently that hypothalamic immuno-reactive insulin (IRI) levels increased after a meal of chow and decreased in response to a fat meal. In the present study, we have compared extracellular hypothalamic and extrahypothalamic basal IRI levels and investigated the effect of meals composed exclusively of either carbohydrates (85% starch, 15% sucrose) or casein on both plasma and medial hypothalamic (PVN-VMH) insulin. The response of IRI to a carbohydrate meal was also investigated in the cerebellum. Basal hypothalamic IRI was twofold higher in the hypothalamus as compared to the cerebellum (33 +/- 4 and 15 +/- 2 pg/mL, respectively). Hypothalamic IRI increased twofold in response to the carbohydrate meal (72 +/- 15 pg/mL) but remained unchanged during the casein meal. No IRI change was found in the cerebellum after a meal of carbohydrates (16 +/- 2 pg/mL). Insulinemia was increased by both the carbohydrate and the casein meal. However, the protein-induced increase was less pronounced (maximum + 359% compared to 1650% for carbohydrates). The present data show a dual specificity of brain insulin response to feeding; in addition to the macronutrient specific variations, a regional specificity was also observed. Taken together with previous observations, the present data are in favor of an involvement of PVN-VMH insulin in the control of feeding and macronutrient-specific appetites.

Animals↗

PubMed1998

Brain insulin response to feeding in the rat is both macronutrient and area specific.

Using microdialysis, we showed recently that hypothalamic immunoreactive insulin (IRI) levels increased after a meal of chow and decreased in response to a fat meal. In the present study, we have compared extracellular hypothalamic and extrahypothalamic basal IRI levels and investigated the effect of meals composed exclusively of either carbohydrates (85% starch, 15% sucrose) or casein on both plasma and medial hypothalamic (PVN-VMH) insulin. The response of IRI to a carbohydrate meal was also investigated in the cerebellum. Basal hypothalamic IRI was twofold higher in the hypothalamus as compared to the cerebellum (33 +/- 4 and 15 +/- 2 pg/mL, respectively). Hypothalamic IRI increased twofold in response to the carbohydrate meal (72 +/- 15 pg/mL) but remained unchanged during the casein meal. No IRI change was found in the cerebellum after a meal of carbohydrates (16 +/- 2 pg/mL). Insulinemia was increased by both the carbohydrate and the casein meal. However, the protein-induced increase was less pronounced (maximum + 359% compared to 1650% for carbohydrates). The present data show a dual specificity of brain insulin response to feeding; in addition to the macronutrient specific variations, a regional specificity was also observed. Taken together with previous observations, the present data are in favor of an involvement of PVN-VMH insulin in the control of feeding and macronutrient-specific appetites.

Animals↗

PubMed1998

Microdialysis and EEG in rats reveal cortical PGE2 changes during sleep and wakefulness.

Prostaglandin (PG) E2 production was assessed in freely moving rats using the technique of microdialysis in the prefrontal cortex associated with parallel cortical EEG recordings. PGE2 concentrations were 40% higher during wakefulness than during slow wave sleep. PGE2 values varied during wakefulness with a maximal increase in the middle of the stage and a drop towards lower values before the occurrence of slow wave sleep. These variations were similar to those observed previously in the rostromedial hypothalamus, where PGE2 concentration was 2.6 times lower than that in the cortex. These data document a positive correlation between cortical EEG activation and PGE2 levels. Taken together with pharmacological data on the awakening effect of centrally administered PGE2, these observations are in favor of an involvement of PGE2 in the generation of wakefulness.

Animals↗

PubMed1997

Insulin responses to a fat meal in hypothalamic microdialysates and plasma.

In a recent microdialysis study in freely-behaving rats, we observed changes in immunoreactive insulin (IRI) in hypothalamic dialysates after a meal of standard laboratory chow. These changes did not always parallel plasma insulin variations, suggesting a partial independence from peripheral insulin. In the present study, we have attempted to assess the profile of medial hypothalamus (VMPH-PVN) extracellular insulin and peripheral insulin before and after a fat meal (lard). In contrast to the increase we previously observed with chow meals, hypothalamic extracellular IRI decreased during the fat meal and fell to 60% 30 min after the meal. Plasma insulin levels did not change. The intake of the lard meal, provided in unlimited amounts, was much larger in calories than the intake of a chow meal under the same conditions. However, when rats were offered a meal of chow after they had eaten a meal averaging 6.7 g of fat (61 calories), they immediately began eating the chow. Thus, the meal of fat produced no general satiation. On the contrary, the rats consumed a second chow meal only after a delay of approximately 40 min after the first one. The present data, in conjunction with our previous observations with chow fed rats, suggest that the level of extracellular hypothalamic IRI may decrease independently of plasma insulin levels and may, at least partially, account for the observed lack of satiation.

Animals↗

PubMed1995

Changes in hypothalamic prostaglandin E2 may predict the occurrence of sleep or wakefulness as assessed by parallel EEG and microdialysis in the rat.

Prostaglandin (PG) E2 is produced by mammalian hypothalamus and when administered exogenously prolongs wakefulness. In order to study the relation of endogenous hypothalamic PGE2 to sleep and wakefulness, we have used microdialysis in freely moving rats associated with EEG recording. Male Wistar rats were implanted with three cortical electrodes and with a guide cannula for microdialysis in the space between the paraventricular nucleus (PVN) and the ventromedial hypothalamus (VMH). PGE2 was measured by RIA in 3- or 6-min dialysates 15 days after surgery, when sleep patterns were normal again and PGE2 production stabilised. PGE2 levels were significantly higher during wakefulness (601 +/- 35 pg/ml, 5 experiments, 35 samples) than during slow-wave sleep (487 +/- 24 pg/ml, 5 experiments, 49 samples). Samples corresponding to paradoxical sleep showed a tendency towards higher PGE2 values compared to slow-wave sleep but lower compared to wakefulness. In epochs of wakefulness or sleep lasting at least 12 min, high PGE2 levels in the middle of wakefulness regularly dropped, thus announcing the occurrence of sleep. During sleep, PGE2 first went on dropping and then reincreased towards the values that characterize early periods of wakefulness. In its turn, this reincrease in PGE2 announced the end of sleep and the imminent occurrence of wakefulness. It is the first study to our knowledge showing that the evolvement in endogenous PG profile may predict the occurrence of sleep or wakefulness.

Animals↗

PubMed1995

Feeding-related immunoreactive insulin changes in the PVN-VMH revealed by microdialysis.

The presence of insulin in the brain and its anorectic effect when centrally infused are well-established today. The question of physiological and dynamic changes in brain insulin in relation to meals is still unanswered and addressed here. Immunoreactive insulin (IRI) was measured using a sensitized RIA in 30-min microdialysates from VMH and PVN nuclei during and after a scheduled meal in male Wistar rats. We indeed observed elevations in hypothalamic IRI during the first 30 min of 1-h meals with a progressive return towards premeal levels in spite of a robust satiety. When the rats were accustomed to the scheduled meals, an anticipatory rise in IRI was found in the hypothalamus, but not in the plasma, during the 30 min preceding the due time of the meal whether the meal was presented or not. This anticipatory rise was proportional to the number of repeated scheduled meals. These results first suggest that hypothalamic IRI changes reflect in some instances those in the plasma although there are exceptions that cannot be accounted for by a simple plasma-brain tissue delivery. Besides, hypothalamic IRI can hardly be proposed as a satiety signal. The present data suggest a role in satiation rather than in satiety or, perhaps, in the inhibition of the behavioral response of feeding that can include the anticipatory rise.

Animals↗

PubMed1995

Hypothalamic monoamines and insulin in relation to feeding in the genetically obese Zucker rat as revealed by microdialysis.

Dynamic changes in VMH and PVN monoamines and immunoreactive insulin (IRI) were investigated by microdialysis in freely-moving genetically obese Zucker rats in order to relate possible disturbances to the impaired regulation of food intake of this model. Serotonin (5-HT), 5-HIAA and dopamine (DA) increased at the beginning of spontaneous meals while DOPAC decreased. Although similar in normal and obese rats, these changes were much more dramatic in the latter, as if more "signal" for satiety were necessary at the VMH-PVN level. Glucoprivic feeding or satiety are induced in normal rats by intravenous infusions of insulin or insulin+glucose respectively. The Zucker rat is resistant to these treatments. The monoaminergic changes brought about by these infusions were similar in obese and normal rats (decreases in 5-HT and DA and increases in 5-HIAA and DOPAC), but the occurrence of meals, in the obese, showed a superim-position of monoaminergic changes resembling those related to spontaneous feeding. The monoaminergic effects of insulin must therefore be dissociated from its effects on feeding. Hypothalamic insulin itself might be the brain signal. At the beginning of meals presented for the first time, VMH-PVN IRI increased earlier and with a smaller magnitude in the obese. When the rats were accustomed to scheduled meals, a similar anticipatory increase in IRI was found in both obese and lean rats. This suggests that brain insulin is more than a satiety signal. In addition, in response to an i.v. insulin infusion, IRI increased twice as much in obese rats despite lower basal levels. Whatever the origin of hypothalamic insulin, the larger response of the obese Zucker rat, known to be insulin resistant, may reflect the inefficiency of the peptide in reducing feeding and body weight in this pathological model.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Specific delta-opioid antagonists exert an agonist-independent inhibitory effect, similar to the agonist, on the release of GnRH in vitro.

1. In in vitro studies with adult male rats we have recently shown that the delta-opioid agonist DTLET inhibits the release of the Gonadotropin-Releasing Hormone (GnRH) from hypothalamic fragments containing the arcuate nucleus and the median eminence. This effect is receptor mediated and eicosanoid dependent (Gerozissis et al., 1993). 2. In the present study we report that the delta-opioid antagonists with negative intrinsic activity, Diallyl-G and ICI 174864, applied under the same experimental conditions (30 min static incubations at 37 degrees C, in a potassium rich milieu), in the absence of the agonist DTLET, also exert a similar to the agonist inhibitory effect on the release of GnRH. 3. The dose-dependent inhibitory effect of Diallyl-G on GnRH release is reversed by increasing concentrations of DTLET. The mu and delta opioid antagonist, naloxone is without effect in the absence of DTLET. However, naloxone acts as an antagonist on the Diallyl-G-induced inhibition of GnRH release. 4. Diallyl-G also inhibits the release of prostaglandin E2 (PGE2). In the presence of indomethacin or nordihydroguaiaretic acid, Diallyl-G is ineffective to further inhibit the release of GnRH. These latter observations taken together with the results of eicosanoid estimation suggest that PGE2 but not leukotrienes participate in the agonist-independent effects of Diallyl-G on GnRH release. 5. Therefore these results support the hypothesis that delta-opioid antagonists with negative intrinsic activity exert agonist-independent biological responses similar to those of the agonists.

Animals↗

PubMed1995

Opioids modify the release of LH at the pituitary level: in vitro studies with entire rat pituitaries.

It is currently accepted that opioids modify the secretion of LH by affecting the release of GnRH in the hypothalamus. A direct action of opioids at the pituitary level is not yet fully established. To this end, we tested the effects of opioids on the release of LH by the entire pituitary in adult male rats. Opioid agonists with mu (DAGO), delta (DS-LET) and kappa (U-50488H) specificity were tested at 0.01 to 10 microM in static incubations. DAGO inhibited dose-dependently the spontaneous and GnRH-induced release of LH. DSLET inhibited only the GnRH-induced release of LH. On the other hand, U-50488H increased spontaneous LH release dose-dependently. The opioid antagonists naloxone, diallyl-G (delta antagonist) and MR 2266 (kappa antagonist) blocked the effects induced by DAGO, DSLET or U-50488H respectively, implying an opioid receptor-mediated effect. The above results showed that opioids with mu, delta and kappa specificity act on the entire pituitary and modify differentially the release of LH. In this study we also compared spontaneous and GnRH-induced LH release by anterior and entire pituitaries and found that the amount of LH released by the anterior lobe was twofold higher, suggesting that inhibitory factors present in the neurointermediate part may affect the release of LH.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗