Inhibitory effects of desvenlafaxine on gastric slow waves, antral contractions, and gastric accommodation mediated via the sympathetic mechanism in dogs

Desvenlafaxine succinate (DVS; Pristiq) is a new antidepressant, serotonin-norepinephrine reuptake inhibitor. Antidepressants have been widely used for the treatment of functional gastrointestinal disorders. Possible roles of DVS on gastrointestinal motility have not been studied. The aim of this study was to investigate the effects of DVS on gastric slow waves (GSW), antral contractions, and gastric accommodation in dogs. Fifteen healthy dogs implanted with gastric serosal electrodes and a gastric cannula were studied in four separate sessions: control, DVS (50 mg), propranolol (1 mg·kg(-1)·h(-1)), and propranolol + DVS. GSW were measured via the gastric serosal electrodes. Antral contractions were assessed via an intraluminal manometric catheter inserted via the gastric cannula. The sympathovagal activity was assessed from the spectral analysis of the heart rate variability signal. Gastric tone was measured by barostat via an intragastric balloon inserted into the fundus via the gastric cannula. In the postprandial period, in comparison with the control, DVS reduced the percentage of normal GSW (P=0.001) and increased the percentage of tachygastria (P=0.005) and bradygastria (P=0.002). Simultaneously, DVS increased the sympathetic activity (P=0.006) and the sympathovagal ratio (low frequency/high frequency; P=0.044). These effects were blocked by propranolol. DVS attenuated postprandial antral contractions and gastric accommodation. The postprandial antral contractile index (area under the curve) was decreased by 26% with DVS (P=0.013), and gastric accommodation was decreased by about 50% with DVS (P < 0.001). The inhibitory effect of DVS on gastric accommodation was blocked by propranolol. DVS inhibits gastric contractions, slow waves, and accommodation in the fed state. These inhibitory effects are associated with an increased sympathetic modulation in the gastrointestinal system. Cautions should be made when DVS is used for treating patients with depression and gastric motility disorders.     

Mechanisms of synergism of the autonomic nervous system compartments

The realization mechanisms of phenomena of sympathetic nerve potentiation of vagal stimulation of motor activity of duodenal and jejunal intestine, urinary bladder and ureters, uterus and tubes, vas deference and mechanism of sympathetic nerve potentiation of vagal cardioinhibitory action were studied. There were demonstrated that these phenomena were realized with participation of preganglionic serotoninergic nerve fibers transmitting an excitation on ganglionary serotoninergic neurons. It was found an existence of increasing cranio-caudal and decreasing ventro-dorsal gradients of serotoninergic innervation of visceral organs.     

Neurochemical approaches to the prevention of ventricular fibrillation

Current evidence indicates that susceptibility to ventricular fibrillation (VF) can be reduced by decreasing cardiac sympathetic activity and by increasing vagal tone. Pharmacological agents that favor such a pattern of autonomic outflow protect the heart against fibrillation. These include morphine sulfate, clonidine, digitalis drugs, and bromocriptine. An intriguing new approach involves changing the serum concentration of amino acid precursors of the central neurotransmitters that modulate autonomic traffic. Considerable evidence indicates that accumulation of serotonin in the brain reduces sympathetic neural activity. When L-tryptophan or 5-hydroxytryptophan is administered with phenelzine (a monoamine oxidase inhibitor) and carbidopa (a selective peripheral L-amino acid decarboxylase inhibitor) to raise brain serotonin, a significant increase in myocardial electrical stability is observed. This effect results from a decrease in cardiac sympathetic tone as indicated by selective denervation and nerve recording studies. Enhancing serotoninergic neurotransmission can also significantly reduce vulnerability to VF during acute coronary artery occlusion. The effect of augmenting serotoninergic activity without the use of enzyme inhibitors has been investigated by administering agents such as melatonin, 5-methoxytryptophol, and 6-chloro-2-(1-piperazinyl) pyrazine (MK-212). Each of these substances increases cardiac electrical stability. The protective influence is unaffected by bilateral vagotomy but is blocked by the specific serotonin antagonist methergoline. Diminution of cardiac sympathetic drive appears to be the main mechanism of action. Thus, neurochemical interventions can exert a profound effect on cardiac electrical stability. Recent advances in neurochemistry and psychopharmacology promise new insights into the problem of sudden death and suggest a fresh approach for the management of life-threatening arrhythmias.     

Mechanism of the intracardiac interactions of the vagus and sympathetic nerves: is a serotoninergic mechanism possible?

A study was made of the conditions of the occurrence and mechanisms of the enhancement by the sympathetic nerve of the vagus-induced inhibition of rabbit heart work. It was discovered that to obtain such a phenomenon, it is necessary that stimulation of the stellate ganglion be made in the presence of perithreshold stimulation of the vagus after blockade of beta-adrenoreceptors. The inhibitory effect was not abolished by dihydroergotoxin but was blocked by promedol, aminazine and diprazine. It is suggested that the serotoninergic component is involved in the mechanism of the enhancement of the vagus-induced inhibition that occurs during stimulation of the sympathetic nerve.     

Characterization of the muscarinic and serotoninergic receptors of the intestine of the rainbow trout (Salmo gairdneri)

The ability of carbachol and 5-hydroxytryptamine (5-HT) to contract isolated segments of rainbow trout intestine in a concentration-dependent manner indicates the presence of muscarinic and serotoninergic receptors in this tissue. The activity of these agonists appears to be directly on the smooth muscle, since ganglionic blockers and inhibitors of neurotransmission did not inhibit contractions. The carbachol-induced contractions were selectively inhibited by atropine and (+-)-3-quinuclidinyl xanthene-9-carboxylate hemioxalate hydrate, an M-2 muscarinic receptor antagonist. However, the inhibition was not competitive. McN-A-343, an M-1 muscarinic agonist had no effect on intrinsic tone. The 5-HT-induced contractions were selectively inhibited by methysergide and the 5-HT2 receptor blockers, ketanserin and 1-(1-naphthyl)piperazine. Again, the inhibition by these agents was not competitive. 5-HT1 and 5-HT3 receptor antagonists did not inhibit contractions. The results thus suggest that the smooth muscle of the rainbow trout intestine contains M-2 muscarinic and 5-HT2 receptors.     

Possible Participation of Serotonin in the Peripheral Link of the Defensive Reflex in the Mollusc Lymnaea stagnalis

The contractions of the dorsal longitudinal muscle of the mollusc Lymnaea stagnalis L., which are evoked by electric stimulation of n. cervicalis inferior were studied. It has been shown that an increase of magnesium ion concentration in saline to 10–15 mM decreases reversibly amplitude of the evoked contractions. Application of serotonin produced a dual effect: at concentrations of 2 × 10^–5–10^–6 M, it enhanced muscle contractions, whereas at concentrations above 10-5 M, on the contrary, decreased them. The inhibitory effect of the serotonin antagonist mianserin on the evoked contraction amplitude increased with elevation of its concentrations in the studied range (from 10^–5 to 10^–3 M). The enhancing effect of serotonin on muscle contractions was blocked either by previous mianserin application or its application on the background of the already acting serotonin. A participation of serotoninergic mechanisms in the control of the contractile function of the studied muscle is suggested.     

The effect of leukotriene D4 on the isolated stomach and colon of the rat

The effect of synthetic leukotriene D4 (LTD4) was evaluated on isolated gastric longitudinal or circular smooth muscle and distal colon of the rat. The concentrations of LTD4, 2.5 X 10(-10)M to 5 X 10(-7)M, evoked minimal to maximal contractile responses. In addition, selected prostaglandins were used to identify the mediator of LTD4-induced contraction of gastric smooth muscle. FPL 55712 inhibited LTD4-induced contractions of gastric longitudinal or circular muscle. Indomethacin inhibited only LTD4-induced contractions of the longitudinal muscle. A combination of FPL 55712 and indomethacin produced greater inhibition of LTD4-induced contractions of longitudinal muscle than either agent alone. However, the same combination of inhibitors showed no greater effect than FPL 55712 alone on LTD4-induced contractions of circular smooth muscle. Unlike PGI2, PGF2, PGA2, or PGD2, PGE2 evoked contraction of the longitudinal muscle and relaxation of the circular muscle of the stomach. The dissimilar effect of PGE2 in the two smooth muscle layers of the rat stomach may signify that PGE2 is the prostaglandin released by LTD4 from the longitudinal and circular gastric muscle. However, the opposing pharmacologic effects following LTD4-induced release of prostaglandins in the circular muscle of the stomach would preclude the appearance of an inhibitory effect of indomethacin in this tissue. In contrast, PGE2 and other prostaglandins contract gastric longitudinal muscle in response to LTD4. Thus, these studies clearly suggest that LTD4 has both a direct and indirect effect on gastric smooth muscle of the rat. Unlike the stomach, LTD4-induced contraction of the distal colon was not inhibited by indomethacin while FPL 55712 antagonized contractions. Thus, these findings indicate a differential mechanism of stimulation of rat gastrointestinal tissue by LTD4.     

Functional and morphologic organization of stomach vegetative innervation

The functional and morphological organization of stomach vegetative innervation was studied. It is shown, that the sympathetic nerve strengthens vagal stimulation of motor activity of various departments of a stomach. In realization of the phenomenon participate preganglionic serotoninergic fibres transmitting excitation on ganglionic serotoninergic neurons. It is established, that stimulation of a wandering nerve results to degranulation of serotoninergic EC-cells carrying on the surface ganglionic 5-HT3,4-receptors. The irritation of a wandering nerve results in reduction of volume of EC-cells in older age.     

Therapeutic potential of synchronized gastric electrical stimulation for gastroparesis: enhanced gastric motility in dogs

The aim of this study was to determine the effects and mechanism of synchronized gastric electrical stimulation (SGES) on gastric contractions and gastric emptying. The first experiment was designed to study the effects of SGES on antral contractions in four randomized sessions. Sessions 1 (control) and 2 (atropine) were performed in the fasting state, composed of three 30-min periods (baseline, stimulation, and recovery). Sessions 3 (control) and 4 (SGES performed during 2nd 20-min period) were performed in the fed state, consisting of two 20-min periods; glucagon was injected after the first 20-min recording. The second experiment was designed to study the effect of SGES on gastric emptying and consisted of two sessions (control and SGES). SGES was delivered with train duration of 0.5-0.8s, pulse frequency of 40 Hz, width of 2 ms, and amplitude of 4 mA. We found that 1) SGES induced gastric antral contractions in the fasting state. The motility index was 1.3 +/- 0.5 at baseline and 6.1 +/- 0.7 (P = 0.001) during SGES. This excitatory effect was completely blocked by atropine. 2) SGES enhanced postprandial antral contractions impaired by glucagon. 3) SGES significantly accelerated glucagon-induced delayed gastric emptying. Gastric emptying was 25.5 +/- 11.3% without SGES and 38.3 +/- 10.7% with SGES (P = 0.006 vs. control). This novel method of SGES induces gastric antral contractions in the fasting state, enhances glucagon-induced antral hypomotility in the fed state, and accelerates glucagon-induced delayed gastric emptying. The effect of SGES on antral contractions is mediated via the cholinergic pathway.     

Fixed feeding potentiates interdigestive gastric motor activity in rats: importance of eating habits for maintaining interdigestive MMC

Endogenous ghrelin regulates the occurrence of interdigestive gastric phase III-like contractions in rats. However, the fasted motor pattern is not as regular and potent in humans and dogs. We hypothesize that eating habits play an important role in maintaining a regular interdigestive gastric contractions. We studied the effect of fixed-feeding regimen on interdigestive gastric contractions and plasma acyl ghrelin levels. The fixed-fed rats were trained to the assigned meal feeding regimen, once daily at 12:00 PM to 4:00 PM for 14 days. Free-fed rats were maintained with free access to food. As ghrelin regulates gastric emptying as well, solid gastric emptying was also studied in fixed-fed rats and free-fed rats. In free-fed rats, two of six rats did not show interdigestive gastric phase III-like contractions. In contrast, phase III-like contractions were observed in all rats 14 days after starting the fixed-feeding regimen. The maximal amplitude of phase III-like contractions significantly increased from 8.4 +/- 0.6 to 16.3 +/- 1.8 g (n = 6, P < 0.05) 14 days after the start of the fixed feeding. Fasted and postprandial plasma ghrelin levels were significantly increased after 14 days of fixed feeding. Solid gastric emptying was significantly accelerated in fixed-fed rats (72.1 +/- 4.2%) compared with that of free-fed rats (58.7 +/- 2.7%, n = 6, P < 0.05). Our present findings suggest that fixed feeding increases plasma ghrelin levels, potent interdigestive contractions, and acceleration of gastric emptying.     

Risperidone potentiates the sympathetic and hyperthermic reactions induced by orexin A in the rat

This experiment tested the effect of risperidone on the sympathetic and thermogenic effects induced by orexin A. The firing rates of sympathetic nerves to interscapular brown adipose tissue (IBAT), along with IBAT and colon temperatures and heart rate were monitored in urethane-anesthetized male Sprague-Dawley rats before an injection of orexin A (1.5 nmol) into the lateral cerebral ventricle and over a period of 2 hours after the injection. The same variables were monitored in rats with an intraperitoneal administration of risperidone (50 mg/kg bw), injected 30 min before the orexin administration. The results show that orexin A increases the sympathetic firing rate, IBAT, colonic temperatures and heart rate. This increase is enhanced by the injection of risperidone. These findings suggest that risperidone elevates the responses due to orexin, probably through an involvement of serotoninergic and dopaminergic pathways, which are affected by risperidone. Furthermore, we suggested the name "hyperthermine A" as additional denomination of "orexin A" by considering the strong influence of this neuropeptide on body temperature.     

Autonomic nervous control of gastric somatostatin secretion from the perfused rat stomach

The effect of parasympathetic and sympathetic nerve stimulation on the secretion of gastric somatostatin and gastrin has been studied in an isolated perfused rat stomach preparation. Stimulation of the vagus nerve inhibited somatostatin secretion and increased gastrin release. Splanchnic nerve stimulation increased somatostatin release during simultaneous atropine perfusion, but not in its absence, whereas gastrin secretion was unchanged. The secretory activity of the gastric D-cell was therefore reciprocally influenced by the sympathetic and parasympathetic nerves but sympathetic stimulation was only effective during muscarinic blockade.     

Role of Potassium Channels in the Effects of Hydrogen Sulfide on Contractility of Gastric Smooth Muscle Cells in Rats

The effect of sodium hydrosulfide (NaHS), a hydrogen sulfide (H₂S) donor, on spontaneous contractile activity of rat gastric smooth muscle cells was analyzed. Experiments were conducted on gastric stripes under conditions of isometric contraction. It was shown that NaHS has a biphasic effect on spontaneous contractile activity, increasing tonic tension and the amplitude of phasic contractions within the first minutes since application. This initial phase is followed by a decrease in amplitude, basal tone, and frequency of spontaneous contractions. The inhibitory effect of NaHS was dose-dependent at concentrations from 10 to 600 μM. Preliminary application of tetraethylammonium and 4-aminopirydine, inhibitors of voltage-gated and calciumactivated potassium channels, prevented a NaHS-induced initial increase in basal tone and phasic contraction amplitude. Activation of ATP-dependent potassium channels (KATP-channels) by diazoxide prevented in part a NaHS-induced decrease in basal tone and amplitude of spontaneous contractions. Glibenclamide, an inhibitor of K_ATP-channels, decreased the inhibitory effect of NaHS on amplitude, basal tone and frequency of spontaneous contractions. It was concluded that in rat gastric smooth muscles the excitatory effect of H₂S is mediated by the inhibition of voltagegated and calcium-activated potassium channels, while its inhibitory effect involves the activation of K_ATP-channels.     

Roles of neuropeptide Y and noradrenaline in sympathetic neurotransmission to the thoracic vena cava and aorta of guinea-pigs.

The roles of neuropeptide Y (NPY) and noradrenaline (NA) in sympathetic neurotransmission to large arteries and veins were studied in vitro using the thoracic portions of the aorta and inferior vena cava from guinea-pigs. Both vessels are densely innervated by axons containing NA and NPY. Repetitive transmural stimulation at 2-30 Hz produced contractions of the aorta, which were abolished by prazosin. NPY did not have significant postsynaptic or presynaptic effects on vascular tone of the aorta. Transmural stimulation of the vena cava produced long-lasting contractions which were enhanced by alpha- and beta-adrenoceptor antagonists, and were blocked by guanethidine. Precontracted venae cavae responded to sympathetic stimulation with beta-adrenoceptor-mediated relaxation, followed by contraction. alpha-Adrenoceptor blockade delayed the onset of neurogenic contractions. NPY was a potent contractile agent of the vena cava (EC50 approximately 1.5 x 10(-8) M). A high concentration (3 x 10(-6) M) of NPY, or the specific NPY Y1 receptor agonist, [Leu31, Pro34]NPY, caused parallel, and reversible, desensitization of contractions produced by sympathetic nerve stimulation, and by low concentrations of exogenous NPY. This provides good evidence that NPY is the mediator of the non-adrenergic sympathetic contractions of the vena cava. Furthermore, these results demonstrate that differential location or coupling of postsynaptic receptors for NA and NPY in the aorta and vena cava, leads to differential participation by these substances in sympathetic vasomotor responses. This is likely to be related to the different functions of these two parts of the systemic circulation.     

Coordination of motilin and ghrelin regulates the migrating motor complex of gastrointestinal motility in Suncus murinus

Motilin and ghrelin are the gastrointestinal (GI) hormones released in a fasting state to stimulate the GI motility of the migrating motor complex (MMC). We focused on coordination of the ghrelin/motilin family in gastric contraction in vivo and in vitro using the house musk shrew (Suncus murinus), a ghrelin- and motilin-producing mammal. To measure the contractile activity of the stomach in vivo, we recorded GI contractions either in the free-moving conscious or anesthetized S. murinus and examined the effects of administration of motilin and/or ghrelin on spontaneous MMC in the fasting state. In the in vitro study, we also studied the coordinative effect of these hormones on the isolated stomach using an organ bath. In the fasting state, phase I, II, and III contractions were clearly recorded in the gastric body (as observed in humans and dogs). Intravenous infusion of ghrelin stimulated gastric contraction in the latter half of phase I and in the phase II in a dose-dependent manner. Continuous intravenous infusion of ghrelin antagonist (d-Lys3-GHRP6) significantly suppressed spontaneous phase II contractions and prolonged the time of occurrence of the peak of phase III contractions. However, intravenous infusion of motilin antagonist (MA-2029) did not inhibit phase II contractions but delayed the occurrence of phase III contractions of the MMC. In the in vitro study, even though a high dose of ghrelin did not stimulate contraction of stomach preparations, ghrelin administration (10(-10)-10(-7) M) with pretreatment of a low dose of motilin (10(-10) M) induced gastric contraction in a dose-dependent manner. Pretreatment with 10(-8) M ghrelin enhanced motilin-stimulated gastric contractions by 10 times. The interrelation of these peptides was also demonstrated in the anesthetized S. murinus. The results suggest that ghrelin is important for the phase II contraction and that coordination of motilin and ghrelin are necessary to initiate phase III contraction of the MMC.     

Bombesin-induced changes in membrane potential-dependent phasic contractions of cat gastric muscle

Electrical and contractile activities of smooth muscle strips isolated from the circular muscle layer of cat gastric antrum were studied using the sucrose gap technique. Bombesin (10(-8) mol/l) depolarized the gastric muscle; this was accompanied by an increase in the strip tone, in the plateau action potential frequency and in both the frequency and the amplitude of the spike potentials as well as by a shortening of the plateau action potential duration. Both the frequency and the amplitude of the phasic contractions increased thereafter. The changes in the frequency of the plateau action potentials and contractions were not influenced either by antagonists of cholinergic and adrenergic receptors or by TTX. In the presence of the Ca antagonists D600 (10(-6) mol/l) and nifedipine (10(-7) mol/l) or in Ca-free medium containing EGTA the effect of bombesin on the frequency of the plateau action potentials and phasic contractions remained unchanged; however, spike potentials were not observed and no increase in the amplitude of phasic contractions occurred. UV-light inactivation of nifedipine restored the typical bombesin effect on the electrical and contractile activities of the gastric smooth muscle. The present data suggest that the effect of bombesin on the frequency of both plateau action potentials and phasic contractions is not linked with Ca2+ influx.     

Inhibitory effects and mechanisms of intestinal electrical stimulation on gastric tone, antral contractions, pyloric tone, and gastric emptying in dogs

The aim of this study was to investigate the effects and mechanisms of intestinal electrical stimulation (IES) on gastric tone, antral and pyloric contractions, and gastric emptying in dogs. Female hound dogs were equipped with a duodenal or gastric cannula, and one pair of serosal electrodes was implanted in the small intestine. The study consisted of five different experiments. Liquid gastric emptying was assessed by collection of chyme from the duodenal cannula in a number of sessions with and without IES and with and without N-nitro-l-arginine (l-NNA). Postprandial antral and pyloric contractions were measured with and without IES and in the absence and presence of l-NNA or phentolamine by placement of a manometric catheter into the antrum and pylorus via the duodenal cannula. Gastric tone was assessed by measurement of gastric volume at a constant pressure. Gastric emptying was substantially and significantly delayed by IES or l-NNA compared with the control session. IES-induced delay of gastric emptying became normal with addition of l-NNA. IES reduced gastric tone, which was blocked by l-NNA. IES also inhibited antral contractions (frequency and amplitude), and this inhibitory effect was not blocked by l-NNA but was blocked by phentolamine. IES alone did not affect pyloric tone or resistance, but IES + l-NNA decreased pyloric tone. In conclusion, IES reduces gastric tone via the nitrergic pathway, inhibits antral contractions via the adrenergic pathway, does not affect pyloric tone, and delays liquid gastric emptying. IES-induced delay of gastric emptying is attributed to its inhibitory effects on gastric motility.     

Effect of fasting on small intestinal antiperistalsis in the Nicholas turkey (Meleagris gallopavo)

Small intestinal refluxes (SIRs) were monitored in the gastrointestinal tract of Nicholas turkeys via implanted strain gage transducers and radiographic observations. It was determined that reflux of ingesta from the small intestine into the gizzard was a result of a single antiperistaltic contraction. Radiographic observation indicated that the antiperistaltic contraction originated in the ileum 88% of the time and the duodenum 12% of the time. Each antiperistaltic contraction was preceded by a single peristaltic contraction. No gastric contractions occurred during SIRs. Fasting for 12 to 24 hr significantly increased the frequency of occurrence of SIRs in the Nicholas turkey (P < 0.0001) but had no significant effect on the velocity of the peristaltic and antiperistaltic contractions or on recovery time to pre-SIR gastric contractile frequency. The pooled mean velocity of peristaltic contractions was determined to be 10.55 +/- 3.68 cm/sec, and that of antiperistaltic contractions was determined to be 12.12 +/- 3.69 cm/sec. The pooled mean recovery time to pre-SIR gastric contraction frequency was 28.31 +/- 8.25 sec. It has been suggested that the SIR may be a mechanism of maximizing nutrient utilization by the turkey.     

Restraint stress delays solid gastric emptying via a central CRF and peripheral sympathetic neuron in rats

Central corticotropin-releasing factor (CRF) delays gastric emptying through the autonomic nervous system. CRF plays an important role in mediating delayed gastric emptying induced by stress. However, it is not clear whether a sympathetic or parasympathetic pathway is involved in the mechanism of central CRF-induced inhibition of solid gastric emptying. The purpose of this study was to investigate whether 1) CRF inhibits solid gastric emptying via a peripheral sympathetic pathway and 2) stress-induced inhibition of solid gastric emptying is mediated via a central CRF and peripheral sympathetic pathways. Using male Sprague-Dawley rats, CRF was injected intracisternally with or without various adrenergic-blocking agents. To investigate whether central CRF-induced inhibition of solid gastric emptying is mediated via a peripheral sympathetic pathway, rats underwent celiac ganglionectomy 1 wk before the gastric emptying study. After solid meal ingestion (90 min), gastric emptying was calculated. To investigate the role of endogenous CRF in stress-induced delayed gastric emptying, a CRF type2 receptor antagonist, astressin2-B, was intracisternally administered. Rats were subjected to a restraint stress immediately after the feeding. Intracisternal injection of CRF (0.1-1.0 microg) dose-dependently inhibited solid gastric emptying. The inhibitory effect of CRF on solid gastric emptying was significantly blocked by guanethidine, propranolol, and celiac ganglionectomy but not by phentolamine. Restraint stress significantly delayed solid gastric emptying, which was improved by astressin2-B, guanethidine, and celiac ganglionectomy. Our research suggests that restraint stress inhibits solid gastric emptying via a central CRF type2 receptor and peripheral sympathetic neural pathway in rats.     

Role of the serotoninergic neuron system of the brain stem on the release of thyrotrophic and luteinizing hormone

1. Decrease of brain serotonin concentration, elicited by either parachlorophenylalanine treatment, surgical interruption of the ascending serotoninergic fibres, or by pinealectomy provokes an enhanced release both of TSH and LH. 2. Increased serotonin content of the brain, produced by intraventricular, intrahypothalamic or systemic administration of serotonin, results in a significant inhibition of the release of these two trophic hormones. 3. It is concluded that the serotoninergic neuron system of the brain stem represents an inhibitory mechanism in the neuroendocrine circuit regulating pituitary trophic hormone release.