Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the roles of the vagus nerve and the serotonin3 (5-HT3) receptor in mediating the food intake depression associated with amino acid deficiency. The food intake of sham-operated (sham) rats given an isoleucine-imbalanced (IMB) diet was reduced to < 40% of control basal (BAS) diet intake (P = 0.0009), and pretreatment with the 5-HT3 antagonist tropisetron (Trop) increased IMB intake by twofold over the vehicle (VEH)-treated group (P < or = 0.0001), as we have reported before. However, after subdiaphragmatic vagotomy (VAGX), IMB intake was increased to a level intermediate between the sham-VEH and sham-Trop groups, while administration of Trop did not increase IMB intake over VAGX alone. By the end of day 1, the VAGX-Trop group had eaten only 1 g more of IMB than the VAGX-VEH group (NS). We conclude that 1) the vagus is among the physiological systems involved in the anorectic responses to IMB and 2) intact vagal function is necessary for the full effect of 5-HT3 antagonists in alleviating the anorectic responses to IMB.
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PMID:Anorectic responses to dietary amino acid imbalance: effects of vagotomy and tropisetron. 802 48

The relationship between serotonin neurotransmission and alcohol consumption (AC) was first determined in preclinical studies. AC generally increases following treatments which decrease serotonin activity, and levels of 5-HT and metabolites are low in some brain regions of alcohol-preferring rats. Pharmacological treatments which enhance serotonergic neurotransmission (uptake inhibitors, releasers, agonists) consistently reduce AC in rats. Serotonin uptake inhibitors (SUI; e.g., citalopram, fluoxetine) have been studied extensively in humans. In several double-blind randomized, placebo-controlled trials, SUI consistently decreased short-term (2-4 weeks) AC by averages of 15% to 20% in nondepressed mildly/moderately dependent alcoholics who received no other treatment. Some subjects decreased AC by up to 60%. The effects of SUI on AC were dose-dependent and not related to side effects (few and mild) or changes in anxiety or depression (not observed). SUI decreased desire to drink and liking for alcohol, suggesting a mechanism of action, to be considered in the development of treatments to reduce AC and prevent relapse. However, while an adjunctive brief psychosocial intervention enhanced the short-term effect of a SUI, the long-term (12-week) effects of SUI and placebo were similar. Other drugs acting on the 5-HT system have been tested in humans, but results are inconclusive. For example, buspirone, a 5-HT1A receptor partial agonist, reduced anxiety and alcohol craving, but not AC; a 5-HT partial agonist, m-CPP, increased craving in abstinent alcoholics; modest reductions in AC were observed with a 5-HT3 antagonist, ondansetron (0.5 mg/day, but not 4 mg/day). Ritanserin, a 5-HT2 antagonist, reduced desire to drink and prevented relapse in a small (n = 5) study, and there was some indication that it reduced desire to drink and enhanced alcohol effects without reducing AC, in another study. The therapeutic potential of these medications is being studied. SUI and other serotonin-altering medications are promising new neuropharmacological treatments for AC.
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PMID:Serotonin-altering medications and desire, consumption and effects of alcohol-treatment implications. 803 52

1. We have previously found that the P2x-purinoceptor agonist, alpha, beta-methylene adenosine 5'-triphosphate (alpha, beta-methylene ATP), depolarizes the rat cervical vagus nerve, measured with a 'grease-gap' extracellular recording technique. This effect was attenuated by the P2 purinoceptor antagonist, suramin. In the present study we have investigated in more detail the antagonism produced by suramin and have also investigated the actions of two other putative P2 purinoceptor antagonists, cibacron blue and pyridoxal-phosphate-6-azophenyl-2', 5'-disulphonic acid (iso-PPADS). Furthermore, we have studied the interactions between suramin and cibacron blue or iso-PPADS in an attempt to determine whether these antagonists act at a common receptor site. 2. Suramin (1 x 10(-5)-1 x 10(-4) M) produced reversible, concentration-related rightward displacements of the concentration-effect curve to alpha, beta-methylene ATP. Schild analysis of this antagonism yielded a pA2 value of 5.90 with a slope value of 0.47. 3. Cibacron blue (3 x 10(-5)-1 x 10(-4) M) also antagonized depolarizations induced by alpha, beta-methylene ATP. The antagonistic effects of cibacron blue were slow to reach equilibrium but could be readily reversed on washout. At low concentrations for antagonism, cibacron blue (1 x 10(-5) M and 3 x 10(-5) M) produced enhancement of the maximal response to alpha, beta-methylene ATP. At the highest concentration tested (1 x 10(-4) M) the concentration-effect curve to alpha, beta-methylene ATP was shifted to the right in a parallel manner, yielding a pKB estimate of 4.96. 4. Iso-PPADS (1 X 10-6 1 X 10-5- M) produced a concentration-related depression in the maxima ofthe concentration-effect curves to alpha,beta-methylene ATP. Analysis of these data by a double reciprocal plot yielded a pKB estimate of 6.02. This profile of insurmountable antagonism could not be attributed to irreversible binding of iso-PPADS to the receptor since the effect of iso-PPADS could be reversed on washing, albeit slowly.5. In the presence of suramin (1 x 10-4 M), cibacron blue (1 x 10-4 M) produced no further rightward displacement of the alpha,beta-methylene ATP concentration-effect curve. The mean agonist concentration ratios in the presence of suramin or cibacron blue alone (11.7 and 10.3, respectively) were not significantly different from the mean concentration-ratio in the presence of both antagonists (11.8). This finding suggests that high concentrations of alpha,beta-methylene ATP activate a receptor population which is resistant to blockade by either antagonist.6. The antagonistic effect of iso-PPADS (1 x 10-5 M) was partially attenuated by suramin (1I x 10-4 M).It is possible that this interaction reflects a slow dissociation of iso-PPADS from the receptor with which suramin and alpha,beta-methylene ATP interact.7. Suramin, cibacron blue or iso-PPADS had no marked effect on depolarization produced by 5-hydroxytryptamine (5-HT, 1 x 10-7-3 x 10-5 M), indicating their specificity in antagonizing responses to alpha, beta-methylene ATP.8. Responses to alpha,beta-methylene ATP were not antagonized by 8-para-sulphophenyltheophylline (3 x 10-5M), ondansetron (1 x 10-7 M), bicuculline (1 x I0-5 M), phentolamine (1 X 10-6 M) or hexamethonium(1 X 10-4 M), which are antagonists at P1-purinoceptors, 5-HT3 receptors, GABAA receptors, a-adrenoceptors and nicotinic cholinoceptors, respectively, thereby excluding the involvement of these receptors.Indomethacin (3 X 10-6 M) had no effect on responses to alpha,beta-methylene ATP.9. The results obtained with three purinoceptor antagonists confirm and extend our original supposition that alpha,beta-methylene ATP-induced depolarization of the rat vagus nerve is mediated predominantly via P2 purinoceptors, thought to be of the P2,X subtype. The finding that responses induced by high concentrations of agonist were resistant to blockade by suramin and cibacron blue, but could be attenuated by iso-PPADS, adds further weight to our speculation that the purinoceptor population in the rat vagus nerve is heterogeneous.
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PMID:The use of antagonists to characterize the receptors mediating depolarization of the rat isolated vagus nerve by alpha, beta-methylene adenosine 5'-triphosphate. 803 52

There has been tremendous interest in 5-HT3 receptor antagonists since their discovery and the subsequent identification of 5-HT3 receptors in the CNS. Based on the results of early behavioural tests with these compounds, there has been substantial interest in their potential use for the treatment of various CNS disorders. In this review, Andrew Greenshaw attempts to clarify the status of the therapeutic potential of these drugs, discussing inconsistencies in preclinical findings and identifying areas in need of clarification through future research. 5-HT3 receptor antagonists are claimed to be potentially useful in the treatment of nausea, inflammatory pain (migraine and irritable bowel syndrome), anxiety, depression, schizophrenia, dementia and drug abuse!
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PMID:Behavioural pharmacology of 5-HT3 receptor antagonists: a critical update on therapeutic potential. 810 96

Bilateral infusion of 5-hydroxytryptamine (5-HT) agonists into the substantia nigra pars reticulata (SNr) of awake rats was shown to influence oral behavior. The 5-HT1A agonist (R)-8-hydroxy-2-(di-propylamino)- tetralin (8-OH-DPAT) (1.3-13 nmol on each side) produced a dose-dependent depression of vacuous chewing movements (VCMs) that lasted about 20 min. The (R)-8-OH-DPAT-induced depression of VCMs was blocked by the simultaneous intranigral infusion of a specific 5-HT1A antagonist [(-)-(S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin HCl (UH-301)], which had no effect when given alone. Another 5-HT1A agonist [(5-methoxy-N,N-dimethyltryptamine hydrogen oxalate (5-MeO-DMT)] also reduced VCM frequencies. Intranigral infusion of the nonspecific 5-HT-agonists 1-(3-triflouro-methylphenyl) piperazine (TFMPP) and 1(m-chlorophenyl)-piperazine (mCPP) and a 5-HT3 agonist [2-methyl-5-hydroxytryptamine (2-Me-5-HT)] increased VCM after 5- to 10-nmol doses. Another 5-HT3 agonist (1-phenylbiguanide) and a 5-HT2 agonist [1-(4-bromophenyl-2,5-dimethoxy)-2-aminopropane (DOB)] had no significant effect. As most 5-HT receptors in the SNr are of the 5-HT1B subtype, these results suggest that the increased VCM frequency was mediated via nigral 5-HT1B receptors. The importance of 5-HTergic mechanisms in the development of drug-induced dyskinesias is discussed.
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PMID:Modulation of oral movements by intranigral 5-hydroxytryptamine receptor agonists in the rat. 826 98

Twenty-four norbornane analogues of tryptamine and 5-methoxytryptamine were investigated for affinity at 5-HT2 receptors of the rat tail artery and proved to be weak non-competitive antagonists of 5-HT. Compound 12 which displayed a marked depression of the concentration-effect curves, was examined for potential interaction with the allosteric binding site of the 5-HT2 receptor. The effects elicited by 12, in the presence and absence of the allosteric activator ketanserin, were atypical and must be attributed to a mechanism, unknown up to now. In radioligand displacement experiments binding data for a set of nine compounds were determined at 5-HT1-like, 5-HT2 and 5-HT3 receptors, indicating subtype selectivity for some analogues. The binding affinity of 8 at 5-HT3 receptors which was comparable with the affinity of the selective 5-HT3 agonist 2-methyl-5-HT, could not be demonstrated on the longitudinal muscle strip of the guinea-pig ileum, partially due to the M3 antimuscarinic activity of 8. Functional studies on the rat oesophageal tunica muscularis mucosae did not reveal 5-HT4 agonist properties for two analogues of 5-methoxytryptamine (8, 16).
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PMID:Selectivity of sterically fixed tryptamine and 5-methoxytryptamine derivatives for serotonin receptor subtypes, II: Structure-activity relationships and in vitro pharmacology of N-alkyl- and N,N-dialkyl-3- indolylbicyclo-[2.2.1]-heptane-2-amines. 827 71

5-HT3 receptors are abundant in central dopamine (DA) terminal areas. They do not affect basal DA turnover but appear to modulate DA release by e.g. morphine and nicotine. The interpretation of these findings is uncertain, and it is unclear whether 5-HT3 receptors also influence the activity of compounds such as amphetamine and cocaine, which act more directly on the DA synapse. Variable-interval (VI), threshold-current hypothalamic self-stimulation can provide a continuous index of central dopaminergic activity, but is relatively insensitive to changes in 5-HT and thus offers a means of investigating this question. In the present study, a selective 5-HT3 receptor antagonist, ondansetron (GR 38032F) (1.0 to 1000 micrograms/kg sc), had no effect on VI self-stimulation, nor did a 100 micrograms/kg dose affect facilitation of responding by d-amphetamine (500 micrograms/kg ip). Ondansetron (100 micrograms/kg) reduced the initial depression of self-stimulation by high-dose nicotine (400 micrograms/kg), but not the ensuing facilitation. Similar results were obtained in rats "sensitized" to nicotine by prior chronic exposure. These results support the proposal that 5-HT3 receptors, normally quiescent under basal conditions, mediate the excitatory effect of compounds acting upstream from the DA neuron, such as nicotine, but do not affect the dopaminergic synapse directly.
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PMID:The effect of a 5-HT3 receptor antagonist, ondansetron, on brain stimulation reward, and its interaction with direct and indirect stimulants of central dopaminergic transmission. 838 82

This study was aimed to prove the pharmacological characteristics of 5-hydroxytryptamine (5-HT)-induced respiratory depression, especially apnea. Effects of 5-HT-receptor agonists and antagonists on respiratory parameters were examined using anesthetized and spontaneously breathing rats. A bolus intravenous administration of 5-HT (3.125-25 micrograms/kg) immediately produced an apnea, the duration of which increased in a dose-related manner. This response was antagonized by a selective 5-HT3-receptor antagonist, GR38032F (10 and 100 micrograms/kg). Ketanserin, a 5-HT2-receptor antagonist, 100 micrograms/kg also inhibited the 5-HT-induced apnea. In addition, the effect of 5-HT-induced apnea mimicked by 2-methyl-5-HT (3.125-50 micrograms/kg), a 5-HT3-receptor agonist, and by alpha-methyl-5-HT (3.125-25 micrograms/kg), a 5-HT2-receptor agonist. On the other hand, 5-HT produced a decrease in lung compliance and an increase in lung resistance in a dose-related manner. The 5-HT-induced changes in lung compliance and lung resistance were antagonized by ketanserin (100 micrograms/kg), but not by GR38032F (100 micrograms/kg). Furthermore, alpha-methyl-5-HT caused bronchoconstriction as did 5-HT, but 2-methyl-5-HT did not. Although bilateral vagotomy at the supra-nodose ganglia completely prevented 5-HT-induced apnea, cervical vagotomy below the superior laryngeal nerve did not prevent this change. On the other hand, cervical vagotomy almost prevented bronchoconstrictive responses, and completely blocked alpha-methyl-5-HT-induced apnea. These results suggest that 5-HT-induced apnea might be mediated through 5-HT3-receptor mechanisms of the vagal afferent system including the nodose ganglia, and that 5-HT2-receptor mechanisms also contribute to the apnea via the afferent cervical vagus nerves. Direct and indirect bronchoconstriction might also be partly involved in 5-HT-induced apnea.
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PMID:[Ventilatory mechanical analysis of respiratory depression induced by serotonin]. 844 2

Serotonin neurons in the rostral and caudal brainstem raphe nuclear groups give rise to collateralized ascending and descending projections which provide modulatory input into most networks throughout the entire neuraxis. The rostral raphe system is interconnected with target forebrain areas through reciprocal limbic-midbrain loops, which suggests that serotonin has a role in the regulation of complex intelligent adaptive behavior. Serotonergic pathways sensitize brainstem and spinal cord central rhythmic pattern generators which organize repetitive autonomic and motor activities, e.g. oral-buccal and nutritive behaviors, facilitate tonically active motor neurons innervating antigravity muscles, and disfacilitate somatosensory information processing. Serotonin effects are mediated by multiple receptor subtypes with distinct pre- and postsynaptic localization and regional distribution pattern. They belong to the G protein superfamily, coupling to adenylate cyclase (5-HT1,4,5,6,7) or phospholipase C (5-HT2), and to the ligand-gated ion channel superfamily (5-HT3). Drugs acting at these receptors are known to modulate various aspects of cooperative social behavior and responding latency, i.e. impulsivity, in a variety of experimental models of anxiety and depression. The clinical efficacy of the so-called selective serotonin reuptake inhibitors (SSRIs) in disorders characterized by poor impulse control, e.g. bulimia nervosa, obsessive-compulsive disorder (OCD) and violent suicidal or homicidal behavior, may likewise be due to improved responding latency.
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PMID:Psychopharmacology of central serotonergic systems. 861 4

Modifications in serotonin (5-HT) neurotransmission have been associated with the physiopathology of anxiety and depression. Among the numerous 5-HT receptor subtypes, several (5-HT1A, 5-HT1B, 5-HT2 and 5-HT3) could be involved in these etiologies. By using a murine genetic model, we attempted to correlate variations in the density of receptor subtypes with modifications of anxiety-related behaviors. From a classic inbred strain (C57BL/6ByJ) and a linkage-testing inbred strain (ABP/Le), segregated F(2) populations for 3 loci located in the 4th, 7th and 9th chromosomes have been selected for their different responses in anxiety-related behavioral tests. The regional density of 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2B receptors has been measured in the brains of parental strains, F(1) and F(2) populations by quantitative autoradiography. The results suggest that chromosomal fragments containing the brown, pink-eyed dilution and the short-ear loci, previously shown to be involved in anxiogenic processes, are mainly associated with a variation in the density of the 5-HT1B receptors.
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PMID:An autoradiographic study of serotonergic receptors in a murine genetic model of anxiety-related behaviors. 883 59


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