Involvement Of Serotonergic Pathways Research Articles

Involvement of serotonergic pathways in gastric dysmotility induced by fat burning nutritional supplements in mice

Fat burners are a category of nutritional supplements that are claimed to increase the metabolism and promote greater energy expenditure, leading to weight loss. However, little is known about the side effects on gastrointestinal motility. In this study, we evaluated the effect of ingestion with a fat burner named Thermbuterol® (THERM) on the gastric motility and food behavior of mice. THERM compounds were identified using nuclear magnetic resonance (NMR). Mice received variable doses of THERM (10, 50, 100 or 300 ​mg/kg, p.o.) or NaCl 0.15 ​M (control). Gastric emptying (GE) was assessed using the phenol red technique. Another set of mice was pretreated with intraperitoneal administration of hexamethonium (HEXA, 10 ​mg/kg), prazosin (PRAZ, 0.25 ​mg/kg), propranolol (PROP, 2 ​mg/kg), parachlorophenylalanine (PCPA, 300 ​mg/kg) or ondansetron (ONDA, 50 ​μg/kg) 30 ​min before THERM treatment for evaluation of GE. We assessed the gastrointestinal responsiveness in vitro as well as THERM's effects on food behavior. Caffeine was the major compound of THERM, identified by NMR. THERM 100 and 300 ​mg/kg decreased GE compared to the respective controls. Pretreatment with PRAZ or PROP did not prevent gastric dysmotility induced by THERM 100 ​mg/kg. However, the pretreatment with HEXA, ONDA or PCPA prevented GE delay induced by THERM. In vitro, THERM relaxed contractions in strips of longitudinal gastric fundus and duodenum. THERM also increased food intake, which was prevented by PCPA and ONDA treatments. THERM decreased GE of a liquid and increased food intake in mice, a phenomenon mediated by the autonomic nicotinic receptors and serotoninergic receptor.

Anticonvulsant and Depressant Activity of Methanol Leaf Extract of Croton zambesicus

Aims: To study anticonvulsant and central nervous system depressant activity of methanol leaf extract of Croton zambesicus (MECZ) in Swiss albino mice and investigate the role of serotonin in these activities. Methodology: Anticonvulsant activity of graded doses (200, 300 and 400 mg/kg p.o) of MECZ was assessed through seizures induced by picrotoxin and pentylenetetrazole (PTZ). Effects of the extract on pentobarbitone-induced sleep and amphetamine-induced stereotype behavior were also evaluated. Possible involvement of serotonergic pathways was studied using cyproheptadine (4mg/kg i.p), a non-selective serotonin antagonist (5HT1/5HT2). Results: In both picrotoxin and PTZ-induced seizures, the extract significantly delayed onset of seizure (p<0.05) in a dose-dependent manner and provided significant protection against death. There was a dose-dependent increase of pentobarbitone sleeping time and a significant reduction (p<0.05) in the sleep latency. The extract also produced a significant reduction in amphetamine-induced stereotype behavior. Pretreatment with cyproheptadine abolished the anticonvulsant effect of the extract. The inhibitory effect of the extract on amphetamine-induced hyperactivity and its potentiation of pentobarbitoneinduced sleep were also reversed by cyproheptadine. Conclusion: The results of this study showed that methanol extract of Croton zambesicus leaf possesses anticonvulsant activity and other CNS depressant activities and these activities are possibly mediated through interaction between serotonergic and GABAergic transmissions. Research Article

Anti-amnesic effect of Ficus religiosa in scopolamine-induced anterograde and retrograde amnesia

Context: Ficus religiosa Linn (Moraceae) is a variety of fig tree. Its figs are known to contain a high serotonergic content, and modulation of serotonergic neurotransmission plays a crucial role in the pathogenesis of amnesia. Thus, the present study was envisaged.Objective: To investigate the effect of the methanol extract of figs of Ficus religiosa (FRFE) on scopolamine-induced anterograde and retrograde amnesia in mice.Materials and methods: Transfer latency (TL) to the preferred niche in the elevated plus-maze (EPM) and learning avoidance of passive behavior to avoid punishment in the modified passive avoidance paradigm (MPA) served as behavioral models for the assessment of memory. Scopolamine (1 mg/kg, i.p.) was administered before training for induction of anterograde amnesia and before retrieval for induction of retrograde amnesia in both models. TL in the EPM, step down latency (SDL), number of trials, and number of mistakes in the MPA were determined in vehicle control, FRFE treated (10, 50, and 100 mg/kg, i.p.), and standard groups (piracetam 200 mg/kg, i.p.). Cyproheptadine, a non-selective 5-HT1/2 blocker (4 mg/kg, i.p.), was administered along with the FRFE to investigate the involvement of serotonergic pathways in the anti-amnesic effect of FRFE.Results and discussion: FRFE resulted in a significant improvement of memory, as its treatment attenuated the scopolamine-induced anterograde and retrograde amnesia dose-dependently. Further, cyproheptadine pretreatment significantly reversed the anti-amnesic effect of FRFE.Conclusion: FRFE has anti-amnesic activity against scopolamine-induced amnesia, in a dose-dependent manner. Inhibition of the anti-amnesic effect of FRFE by cyproheptadine substantiates the involvement of serotonergic pathways for its activity.

Synergistic effect of [1H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one] and antidepressant drugs in the mouse forced swimming test: Possible involvement of serotonergic pathway

To augment the effects of classical antidepressant drugs by combination therapies in drug-resistant patients has been an emerging treatment strategy. In the present study, the potential synergistic effect of [1H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one] (ODQ) and antidepressant drugs in the forced swimming test was evaluated. While 5mg/kg intraperitoneal administration of imipramine, fluoxetine or desipramine caused no effect in the duration of immobility in the forced swimming test (sub-effective doses), higher doses (20, 10 and 10mg/kg, respectively) reduced the immobility period (effective doses). When sub-effective doses of ODQ (15mg/kg) and imipramine (5mg/kg) were applied, there was a significant reduction in the immobility time compared with those of each drug alone. Similarly the reduction seen with the effective dose of imipramine (20mg/kg) was also augmented by the co-administration of ODQ (15mg/kg). By its sub-effective dose, ODQ exerted statistically significant augmentations in the responses to either sub-effective (5mg/kg) or effective dose (10mg/kg) of fluoxetine. By contrast, desipramine was not influenced by the co-administration of ODQ (15mg/kg). None of the drugs used in the present study had any effects on the locomotor activity test over the dose range applied. The results show that co-administration of imipramine/fluoxetine and ODQ exhibits a supra-additive effect and that serotonergic rather than noradrenergic pathway may be involved in the synergistic effect of ODQ.

Serotonergic function, two-mode models of self-regulation, and vulnerability to depression: What depression has in common with impulsive aggression.

Evidence from diverse literatures supports the viewpoint that two modes of self-regulation exist, a lower-order system that responds quickly to associative cues of the moment and a higher-order system that responds more reflectively and planfully; that low serotonergic function is linked to relative dominance of the lower-order system; that how dominance of the lower-order system is manifested depends on additional variables; and that low serotonergic function therefore can promote behavioral patterns as divergent as impulsive aggression and lethargic depression. Literatures reviewed include work on two-mode models; studies of brain function supporting the biological plausibility of the two-mode view and the involvement of serotonergic pathways in functions pertaining to it; and studies relating low serotonergic function to impulsiveness, aggression (including extreme violence), aspects of personality, and depression vulnerability. Substantial differences between depression and other phenomena reviewed are interpreted by proposing that depression reflects both low serotonergic function and low reward sensitivity. The article closes with brief consideration of the idea that low serotonergic function relates to even more diverse phenomena, whose natures depend in part on sensitivities of other systems.

Gastric relaxation induced by hyperglycemia is mediated by vagal afferent pathways in the rat

Hyperglycemia has a profound effect on gastric motility. However, little is known about the site and mechanism that sense alteration in blood glucose level. The identification of glucose-sensing neurons in the nodose ganglia led us to hypothesize that hyperglycemia acts through vagal afferent pathways to inhibit gastric motility. With the use of a glucose-clamp rat model, we showed that glucose decreased intragastric pressure in a dose-dependent manner. In contrast to intravenous infusion of glucose, intracisternal injection of glucose at 250 and 500 mg/dl had little effect on intragastric pressure. Pretreatment with hexamethonium, as well as truncal vagotomy, abolished the gastric motor responses to hyperglycemia (250 mg/dl), and perivagal and gastroduodenal applications of capsaicin significantly reduced the gastric responses to hyperglycemia. In contrast, hyperglycemia had no effect on the gastric contraction induced by electrical field stimulation or carbachol (10(-5) M). To rule out involvement of serotonergic pathways, we showed that neither granisetron (5-HT(3) antagonist, 0.5 g/kg) nor pharmacological depletion of 5-HT using p-chlorophenylalanine (5-HT synthesis inhibitor) affected gastric relaxation induced by hyperglycemia. Lastly, N(G)-nitro-L-arginine methyl ester (L-NAME) and a VIP antagonist each partially reduced gastric relaxation induced by hyperglycemia and, in combination, completely abolished gastric responses. In conclusion, hyperglycemia inhibits gastric motility through a capsaicin-sensitive vagal afferent pathway originating from the gastroduodenal mucosa. Hyperglycemia stimulates vagal afferents, which, in turn, activate vagal efferent cholinergic pathways synapsing with intragastric nitric oxide- and VIP-containing neurons to mediate gastric relaxation.

Effect of Chromium Picolinate on Modified Forced Swimming Test in Diabetic Rats: Involvement of Serotonergic Pathways and Potassium Channels

Depression occurs frequently in patients with diabetes mellitus. Chromium picolinate, an essential trace element is recommended for diabetes and also has been reported to benefit depression, but its mechanism is still debated. To investigate the mechanism, we studied its effects on serum insulin, serum glucose and on modified forced swimming test, a behavioural paradigm for depression in rats. The study involving co-administration of sub-active doses of glimepiride, a K(+) channel blocker and chromium picolinate on blood glucose levels and modified forced swimming test was also performed to probe any role of K(+) channels in its antidiabetic and antidepressants effects. Streptozotocin (55 mg/kg, intraperitoneally) was injected in rats to induce diabetes (Type 1). After a week, chromium picolinate (8 microg/ml in drinking water) was administered for 4 weeks. Normal rats received similar drug treatment. The sub-active doses of chromium picolinate (4 microg/ml in drinking water) and glimeperide (2.5 mg/kg, orally) were co-administered and their effects on modified forced swimming test and on glucose levels were measured. Chromium picolinate (8 microg/ml in drinking water) produced hypoglycaemia in diabetic and normal rats. It had no effects on the streptozotocin-induced reduction in insulin levels. Chromium picolinate (8 microg/ml in drinking water) increased swimming with subsequent decrease in immobility. The sub-active doses of chromium picolinate and glimeperide showed significant additive effects in modified forced swimming test and reduction in serum glucose concentrations, though statistically insignificant. In conclusion chromium picolinate shows antidepressant action on modified forced swimming test affecting only swimming that suggests serotonergic pathways involvement. The additive effects on swimming in modified forced swimming test and reduction in serum glucose levels shows involvement of K(+) channels in antidiabetic and antidepressant actions of chromium picolinate.

Evidence indicating participation of the serotonergic system in controlling feeding behavior in Coturnix japonica (Galliformes: Aves)

We investigated participation of the brain serotonergic system in food intake control by using oral and systemic administration of serotonin precursors in quails (Coturnix japonica). Dietary supplemental tryptophan (0.1-50.0 g/kg) provoked a dose-dependent inhibition of food intake during a 5-h observation period, which persisted up to 24 h for doses of 30.0 and 50.0 g/kg. Normally fed and fasted animals treated with hydroxytryptophan (12.5-50.0 mg/kg) by the intracoelomic route showed an acute inhibition of food intake. Hypophagia in fasted birds was only effective when the precursor was administered immediately before food presentation. A similar response was obtained by administering serotonin (0.125-2.5 mg/kg, sc), with animals showing a hypnogenic response within the first ten minutes after administration, suggesting that, in contrast to mammals, the amine crosses the blood-brain barrier in quails. Administration of hydroxytryptophan at all doses tested induced significant dipsogenic behavior despite the concomitant hypnogenic response. The results suggest the involvement of serotonergic pathways in food intake control in quails and also show, for the first time, hypnogenic action induced by serotonin and a hyperdipsic effect elicited by hydroxytryptophan.

Involvement of serotonergic pathways in postanaesthetic cold defence: dolasetron prevents shivering

Serotonin is regarded as an essential neurotransmitter in thermoregulation. We evaluated the influence of the serotonergic antagonist dolasetron on thermoregulation and postanaesthetic shivering in mildly hypothermic patients in a randomised placebo-controlled study. The incidence of shivering was 24% after dolasetron compared to 69% after placebo ( p<0.01). During the first 80 min postoperatively, core temperature remained lower in the treatment group ( p<0.05). After dolasetron, 20% of the patients experienced thermal discomfort compared to 54% after placebo ( p<0.05). Serotonin antagonism seems to lower the human thermal set-range thereby reducing metabolic cold defence and discomfort associated with postoperative hypothermia.

Serotonin Blockade Does Not Affect Nonarticular Tenderness in Healthy Volunteers

Objectives: To investigate the role of serotonergic pathways as a potential factor modulating pain in general and nonarticular tenderness in particular.Methods: Twenty healthy volunteers were given metergoline [a nonspecific serotonin blocker] once and placebo once, in a double blind, placebo-controlled, randomized cross over design. The administrations were separated by atleast one week. In each session a count of 18 tender points was conducted by thumb palpation just before and 90 minutes after capsule ingestion. Tenderness of nine of the tender points as well as four control points was further assessed with a Chatillon dolorimeter.Results: There was no significant difference in the point count or in tenderness in the presence or absence of serotonin blockade.Conclusions: Serotonin blockade in healthy individuals has no effect on the point count or on tender point sensitivity. This suggests that involvement of serotonergic path ways does not contribute to pain syndromes associated with nonarticular tenderness, or, alternatively, that studies of nonarticular tenderness in healthy volunteers are not relevant to the same phenomenon in clinical syndromes.

Involvement of serotonergic pathways in mediating the neuronal activity and genetic transcription of neuroendocrine corticotropin-releasing factor in the brain of systemically endotoxin-challenged rats

The present study investigated the effect of serotonin depletion on the neuronal activity and transcription of corticotropin-releasing factor in the rat brain during the acute-phase response. Conscious male rats received an intraperitoneal (i.p.) injection with the immune activator lipopolysaccaride (25 μg/100 g body wt) after being treated for three consecutive days with para-chlorophenylalanine (30 mg/100 g/day). This irreversible inhibitor of tryptophane-5-hydroxylase decreased hypothalamic serotonin levels by 96%. One, 3 and 6 h after a single i.p. injection of lipopolysaccharide or vehicle solution, rats were killed and their brains cut in 30-μm coronal sections. Messenger RNAs encoding c- fos, nerve-growth factor inducible-B gene, corticotropin-releasing factor and the heteronuclear RNA encoding corticotropin-releasing factor primary transcript were assayed by in situ hybridization using 35S-labeled riboprobes, whereas Fos-immunoreactive nuclei were labeled by immunocytochemistry. Lipopolysaccharide induced a wide neuronal activation indicated by the expression of both immediate- early gene transcripts and Fos protein in numerous structures of the brain. The signal for both immediate- early gene transcripts was low to moderate 1 h after lipopolysaccharide administration, maximal at 3 h and decline at 6 h post-injection, whereas at that time, Fos-immunoreactive nuclei were still detected in most of the c- fos messenger RNA-positive structures. Interestingly, the strong and widespread induction of both immediate- early gene transcripts was almost totally inhibited by para-chlorophenylalanine treatment; in the hypothalamic paraventricular nucleus for example, c- fos messenger RNA signal and the number of Fos-immunoreactive positive cells were reduced by 80 and 48%, respectively, in serotonin-depleted rats treated with the bacterial endotoxin. This blunted neuronal response was also associated with an attenuated stimulation of neuroendocrine corticotropin-releasing factor transcription and plasma corticosterone release. Indeed, lipopolysaccharide caused a selective expression of corticotropin-releasing factor primary transcript in the paraventricular nucleus of the hypothalamus and this effect was significantly reduced by treatment with the serotonin inhibitor. However, basal expression of corticotropin-releasing factor messenger RNA across the brain (bed nucleus of the stria terminalis, medial preoptic area, paraventricular nucleus of the hypothalamus, central nucleus of the amygdala, etc.) was not affected by the para-chlorophenylalanine treatment. These results suggest that the integrity of serotonin pathways plays a role in the neuronal activity triggered by the systemic endotoxin insult. The fact that serotonin depletion largely prevented activation of neurosecretory parvocellular neurons of the paraventricular nucleus of the hypothalamus and neuroendocrine corticotropin-releasing factor gene transcription in response to immunogenic challenge provides the evidence that serotonergic system is part of the brain circuitry involved in the corticotroph axis–immune interface.

45 Involvement of serotonergic pathways in the central cardiovascular effects of substance P in the rat

45 Involvement of serotonergic pathways in the central cardiovascular effects of substance P in the rat

Prolactin suppression by (-) delta-9-tetrahydrocannabinol (THC): involvement of serotonergic and dopaminergic pathways.

(-) delta-9-Tetrahydrocannabinol (THC) was previously shown to suppress serum PRL levels (SPL) in rats. In the present study, various pathways by which THC suppresses PRL secretion were investigated. THC abolished the elevated SPL induced by either 5-hydroxytryptophan or melatonin. The SPL suppression after THC treatment was abolished upon treatment with cyproheptadine. These results suggest on involvement of a serotonergic pathway in the suppressive effect of THC on PRL secretion. Elevated SPL induced by a low dose of the dopaminergic blocker pimozide was suppressed after treatment with THC. However, elevated SPL, induced by a high dose of pimozide or by any dose of perphenazine (a less specific dopaminergic blocker), were not reduced by combined treatment of either of these drugs with THC. It seems that THC also enhances the dopaminergic activity in the pathway that controls PRL secretion. In addition, the pimozide-induced SPL elevation dropped upon combined treatment of cyproheptadine and pimozide. As cyproheptadine alone, and in the dose used, did not affect SPL, it is proposed that the serotonergic and dopaminergic pathways that control PRL secretion do not necessarily act independently of one another.