==================================BSR08================================== 8. Interaction between serotonergic agonists/antagonists especially 5HT agonist/antagonist and non-adrenergic function. More specifically interaction between mCPP and non-adrenergic function. 1 UI - 87118656 AU - Goodwin GM ; De Souza RJ ; Wood AJ ; Green AR TI - The enhancement by lithium of the 5-HT1A mediated serotonin syndrome produced by 8-OH-DPAT in the rat: evidence for a post-synaptic mechanism. AB - Administration of lithium chloride (10 mmol/kg on day 1 and 3 mmol/kg twice daily on subsequent days, SC) for 3-14 days enhances the components of the serotonin syndrome produced by 8-hydroxy-2-(di-propylamino)tetralin (8-OH-DPAT) in the rat. The hypothermic response produced simultaneously was unaltered. Following lithium administration for 3 days the motor response to 5-methoxy,N,N-dimethyltryptamine was also facilitated. These data suggest that lithium administration enhances post-synaptic 5-HT receptor-mediated behavioural responses. (-)-Propranolol (20 mg/kg, IP) but not (+)-propranolol (20 mg/kg IP) fully antagonised the facilitated response to 8-OH-DPAT seen following lithium administration; ritanserin (200 micrograms/kg, IP) was without effect. These findings favour a mechanism for the action of lithium involving the 5-HT1A receptor. Depletion of 5-hydroxytryptamine (5-HT) with parachlorophenylalanine (PCPA, 300 mg/kg, IP on day 1 and 2 of lithium administration) did not prevent the facilitation by lithium of the response to 8-OH-DPAT. These data strengthen the suggestion that lithium has its effect on 5-HT1A-mediated motor function by a post-synaptic action. By contrast, motor responses to the putative 5-HT1B receptor agonist 5-methoxy-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole (RU 24969) were unaltered by repeated lithium administration. MH - p-Chlorophenylalanine/PHARMACODYNAMICS ; Animal ; Body Temperature/DRUG EFFECTS ; Carbidopa/PHARMACODYNAMICS ; Drug Synergism ; Hydroxytryptophan/ PHARMACODYNAMICS ; Indoles/PHARMACODYNAMICS ; Lithium/*PHARMACODYNAMICS ; Male ; Methoxydimethyltryptamines/ANTAGONISTS & INHIBITORS/ PHARMACODYNAMICS ; Motor Activity/*DRUG EFFECTS ; Naphthalenes/ *PHARMACODYNAMICS ; Propranolol/PHARMACODYNAMICS ; Rats ; Rats, Inbred Strains ; Receptors, Serotonin/*PHYSIOLOGY ; Support, Non-U.S. Gov't ; Tetrahydronaphthalenes/*PHARMACODYNAMICS SO - Psychopharmacology (Berlin) 1986;90(4):488-93 2 UI - 87118428 AU - Young R ; Rosecrans JA ; Glennon RA TI - Further studies on the dose-dependent stimulus properties of 5-methoxy-N,N-dimethyltryptamine. AB - Twenty-two rats were trained to discriminate either 1.5 mg/kg of 5-methoxy-N,N-dimethyltryptamine (5-OMe DMT) from saline in a standard two-lever operant procedure. Once responding was stable, various doses of several serotonin (5-HT) antagonists, i.e., cyproheptadine (CYP), methysergide (UML), cinanserin (CIN), and methergoline (MCE), were administered in combination with 5-OMe DMT, to assess the ability of each antagonist to attenuate each 5-OMe DMT-stimulus. The 5-OMe DMT-stimulus at 1.5 mg/kg was completely antagonized by CYP, and was partially attenuated by CIN and MCE. UML had negligible effects on 5-OMe DMT-appropriate responding. In the 3.0 mg/kg 5-OMe DMT-trained rats, UML and MCE partially blocked the 5-OMe DMT-stimulus; CYP and CIN had no significant effect on 5-OMe DMT-appropriate responding. The results suggest that until the in vivo effects and mechanism of action of 5-OMe DMT and certain 5-HT antagonists are better understood, caution is advised when conclusions are drawn from studies employing these agents. MH - Animal ; Conditioning, Operant/DRUG EFFECTS ; Discrimination Learning/ *DRUG EFFECTS ; Dose-Response Relationship, Drug ; Drug Interactions ; Male ; Methoxydimethyltryptamines/ADMINISTRATION & DOSAGE/ *PHARMACODYNAMICS ; Rats ; Rats, Inbred Strains ; Serotonin Antagonists/ PHARMACODYNAMICS ; Serotonin/*ANALOGS & DERIVATIVES ; Support, U.S. Gov't, P.H.S. SO - Pharmacol Biochem Behav 1986 Dec;25(6):1207-10 3 UI - 87111514 AU - Frances H ; Bulach C ; Simon P ; Fillion M ; Fillion G TI - Chronic beta-adrenergic stimulation increases in mice the sensitivity to methysergide and the number of cerebral high affinity serotonin binding sites (5-HT-1). AB - Reserpine administration in mice causes, among other effects an akinesia which can be reversed by the serotonin agonist-antagonist methysergide. The effect of methysergide is potentiated by clenbuterol, a beta-adrenergic agonist, which itself causes hypomotility. Potentiation is weak after a single injection of clenbuterol, but becomes much stronger after repeated administration for 12 days. This treatment also causes a 50% increase in the number of high affinity 5-HT-1 binding sites in the brain. This increase would explain the increased potency of methysergide against reserpine-induced akinesia. These results show that: a beta-adrenergic drug, clenbuterol modulates the serotoninergic system; this modulation takes its importance after chronic treatment only; this interrelation may be important in depressive illness since it is observed on a test used in the screening of antidepressant drugs. MH - Animal ; Binding Sites/DRUG EFFECTS ; Brain/*DRUG EFFECTS/METABOLISM ; Clenbuterol/*ADMINISTRATION & DOSAGE ; Drug Synergism ; Ethanolamines/ *ADMINISTRATION & DOSAGE ; Male ; Methysergide/*ADMINISTRATION & DOSAGE ; Mice ; Movement Disorders/CHEMICALLY INDUCED ; Receptors, Adrenergic, Beta/*DRUG EFFECTS ; Reserpine/ANTAGONISTS & INHIBITORS ; Serotonin/ *METABOLISM ; Support, Non-U.S. Gov't SO - J Neural Transm 1986;67(3-4):215-24 4 UI - 87101732 AU - Barrett VJ ; Leff P ; Martin GR ; Richardson PJ TI - Pharmacological analysis of the interaction between Bay K 8644 and 5-HT in rabbit aorta. AB - Bay K 8644 potentiated and augmented 5-hydroxytryptamine (5-HT)-induced contractions in the rabbit, isolated aorta preparation, as manifested in leftward shift and increase in the asymptote of 5-HT E/[A] (effect vs concentration) curves. The operational model of agonism (Black & Leff, 1983) was used to analyse this interaction and the concomitant effects of irreversible receptor alkylation by phenoxybenzamine. The competitive effects of spiperone in the presence and absence of Bay K 8644 were also examined. From these analyses it is concluded that Bay K 8644 elicits its potentiating effects by increasing the efficacy of 5-HT at the 5-HT2 receptor with no alteration in affinity. This is consistent with the known effect of Bay K 8644 of causing an increase in the functional concentration of plasmalemmal calcium channels coupled to the 5-HT2 receptors in this preparation. The positively co-operative shape of the 5-HT E/[A] curves obtained in the aorta and the quantitative nature of their potentiation by Bay K 8644 indicated that the coupling of 5-HT2 receptor occupancy to intracellular calcium concentration is linear and that the co-operativity resides in the subsequent relation between intracellular calcium and pharmacological effect. Bay K 8644 may serve as a probe for differentiating between the types of calcium channels that transduce 5-HT receptor-mediated effects in different systems. Such information would be useful in the classification of agonist interactions with 5-HT receptors. MH - Animal ; Aorta, Thoracic/DRUG EFFECTS ; Bay K 8644/*PHARMACODYNAMICS ; Drug Synergism ; In Vitro ; Muscle, Smooth, Vascular/*DRUG EFFECTS ; Phenoxybenzamine/PHARMACODYNAMICS ; Rabbits ; Serotonin Antagonists ; Serotonin/*PHARMACODYNAMICS ; Spiperone/PHARMACODYNAMICS SO - Br J Pharmacol 1986 Mar;87(3):487-94 5 UI - 87099043 AU - van der Laan JW ; Hillen FC TI - The potentiation of morphine-withdrawal jumping by clonidine is antagonized by m-chlorophenylpiperazine and not by haloperidol. AB - Administration of naloxone (0.5 mg/kg i.p.) to morphine-dependent rats induced a strong withdrawal syndrome consisting of body shakes, escape jumping and various autonomic signs. Clonidine (750 micrograms/kg s.c.) had a dual action on naloxone-precipitated withdrawal symptoms in rats: a suppressive action on body shakes and a potentiating action on jumping. Both actions were found to be mediated by alpha 2-receptors which generally are responsible for sedative effects. Therefore, the action of alpha 2-agonists such as clonidine and azepexole was studied more extensively. Since both serotonergic and dopaminergic systems have been suggested to be involved in morphine-withdrawal jumping, the interaction of clonidine and azepexole with serotonergic and dopaminergic drugs was studied. Neither haloperidol (0.3 mg/kg i.p.) nor the benzamides sulpiride (40 mg/kg p.o.) and metoclopramide (8 mg/kg i.p.) affected the jumping potentiated by the alpha 2-agonists. However, the serotonin-agonist m-chlorophenylpiperazine (2.5 mg/kg i.p.) suppressed the effects of clonidine. Precipitation of jumping in morphine-dependent animals was more effective using bremazocine (1.0 mg/kg i.p.). This effect again could be potentiated by clonidine (750 micrograms/kg s.c.). A low dose of m-chlorophenylpiperazine (0.03 mg/kg i.p.) antagonized the clonidine-effect without affecting the basal jumping response. The data suggest that clonidine potentiates naloxone-precipitated jumping by decreasing serotonergic output while the administration of m-chlorophenylpiperazine can counteract this lack of serotonergic activity. MH - Adrenergic Alpha Receptor Blockaders/PHARMACODYNAMICS ; Animal ; Azepines/ PHARMACODYNAMICS ; Behavior, Animal/DRUG EFFECTS ; Clonidine/*ANTAGONISTS & INHIBITORS/PHARMACODYNAMICS ; Dopamine/ANTAGONISTS & INHIBITORS ; Drug Synergism ; Haloperidol/*PHARMACODYNAMICS ; Male ; Morphine/ *PHARMACODYNAMICS ; Piperazines/*PHARMACODYNAMICS ; Rats ; Rats, Inbred Strains ; Substance Dependence/PHYSIOPATHOLOGY ; Substance Withdrawal Syndrome/*PHYSIOPATHOLOGY SO - Arch Int Pharmacodyn Ther 1986 Sep;283(1):45-55 6 UI - 87096518 AU - R:enyi L TI - Long lasting supersensitivity to 5-HT mediated behaviour following monoamine depletion in the rat brain. AB - The effects of the depletion of 5-hydroxytryptamine (5-HT) in the rat brain upon the 5-HT behavioural syndrome (ejaculatory response, abduction of hind-limbs, forepaw treading, and Straub tail) induced by 5-methoxy-N,N-dimethyltryptamine (1 mg/kg intraperitoneally) were investigated. The 5-HT depletion was produced by p-chlorophenylalanine (PCPA 2 X 200 mg/kg intraperitoneally) or by reserpine (5 mg/kg subcutaneously). It resulted in rapidly developing and long-lasting supersensitivity of the behavioural responses which were enhanced between 2 and 14 days after the PCPA injections and between 1 and 42 days after a single dose of reserpine. The depletion of catecholamines by alpha-methyltyrosine (250 + 125 mg/kg intraperitoneally) had no effect. These results underline the usefulness of the 5-HT mediated behavioural models for studies of changes in 5-HT receptor activity. MH - p-Chlorophenylalanine/PHARMACODYNAMICS ; Animal ; Behavior, Animal/*DRUG EFFECTS ; Biogenic Amines/*PHYSIOLOGY ; Brain Chemistry/DRUG EFFECTS ; Drug Synergism ; Ejaculation/*DRUG EFFECTS ; Male ; Methoxydimethyltryptamines/PHARMACODYNAMICS ; Rats ; Rats, Inbred Strains ; Reserpine/PHARMACODYNAMICS ; Serotonin/*PHYSIOLOGY SO - Acta Pharmacol Toxicol (Copenh) 1986 Oct;59(4):298-302 7 UI - 87086221 AU - Fuller RW ; Snoddy HD TI - Effect of fluoxetine pretreatment on the neurochemical changes induced by amfonelic acid combined with spiperone in rats. AB - Combined treatment with amfonelic acid plus spiperone caused large increases in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and a decrease in dopamine in rat striatum. 5-Hydroxytryptamine (5-HT) was decreased in striatum (but not in hypothalamus), and 5-hydroxyindoleacetic acid (5-HIAA) was increased in the striatum. Pretreatment with fluoxetine, an inhibitor of uptake into 5-HT neurons, antagonized the decrease in 5-HT and the increase in 5-HIAA and in the ratio 5-HIAA/5-HT but did not antagonize the changes in dopamine or its metabolites. The amfonelic acid-spiperone combination apparently causes increased release of dopamine in striatum, and the released dopamine is accumulated by 5-HT nerve terminals via the membrane uptake carrier. Inhibition of that carrier by fluoxetine prevents the release of 5-HT caused by the dopamine influx. MH - Animal ; Corpus Striatum/*DRUG EFFECTS/METABOLISM ; Dopamine/METABOLISM ; Drug Interactions ; Fluoxetin/*PHARMACODYNAMICS ; Hydroxyindoleacetic Acid/METABOLISM ; Male ; Naphthyridines/*PHARMACODYNAMICS ; Propylamines/ *PHARMACODYNAMICS ; Rats ; Rats, Inbred Strains ; Serotonin/METABOLISM ; Spiperone/*PHARMACODYNAMICS SO - J Pharm Pharmacol 1986 Oct;38(10):776-7 8 UI - 87086210 AU - Moritoki H ; Fukuda H ; Kanaya J ; Ishida Y TI - Ketanserin potentiates the prejunctional inhibitory effect of 5-hydroxytryptamine on rat vas deferens. AB - 5-Hydroxytryptamine (5-HT) slightly inhibited the twitch contractions of rat vas deferens caused by single pulse field stimulation at 0.1 Hz. The inhibitory effect of 5-HT was much less in the epididymal portion than in the prostatic portion of the vas deferens. Ketanserin potentiated the prejunctional inhibitory effect of 5-HT and attenuated its stimulatory effect. This potentiation was observable only in the epididymal portion, of the vas deferens. Cyproheptadine and mianserin, but not methysergide, had essentially similar potentiating effects to those of ketanserin. These results suggest that the 5-HT receptor that mediates prejunctional inhibition is not of the 5-HT2 type, and that ketanserin acts by suppressing the 5-HT-induced stimulatory effect, which is possibly mediated by a postjunctional 5-HT2 receptor, thus unmasking the inhibitory effect of 5-HT. MH - Animal ; Drug Synergism ; In Vitro ; Ketanserin/*PHARMACODYNAMICS ; Male ; Muscle Contraction/DRUG EFFECTS ; Muscle, Smooth/DRUG EFFECTS ; Neuroeffector Junction/*DRUG EFFECTS ; Prazosin/PHARMACODYNAMICS ; Rats ; Rats, Inbred Strains ; Serotonin Antagonists/PHARMACODYNAMICS ; Serotonin/ *PHARMACODYNAMICS ; Vas Deferens/DRUG EFFECTS/INNERVATION SO - J Pharm Pharmacol 1986 Oct;38(10):737-41 9 UI - 87080057 AU - Benfield P ; Heel RC ; Lewis SP TI - Fluoxetine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. AB - Fluoxetine is a new antidepressant which enhances serotoninergic neurotransmission through potent and selective inhibition of neuronal reuptake of serotonin. Metabolism by N-desmethylation occurs in man yielding desmethylfluoxetine, which also inhibits serotonin reuptake. Both the parent compound and metabolite possess elimination half-lives of several days facilitating the maintenance of steady-state plasma concentrations during long term treatment. Fluoxetine has overall therapeutic efficacy comparable with imipramine, amitriptyline and doxepin in patients with unipolar depression treated for 5 to 6 weeks, although it may be less effective than tricyclic antidepressants in relieving sleep disorders in depressed patients. Geriatric patients also responded as well to fluoxetine as to doxepin. The symptomatic improvement in patients with unipolar depression during short term fluoxetine treatment has been satisfactorily maintained when therapy was extended for at least 6 months: the relapse rate was low and similar to that of imipramine. Preliminary data have shown that patients with bipolar depression gained similar therapeutic benefit from fluoxetine or imipramine. Other preliminary trials have indicated that fluoxetine may be useful in obsessive-compulsive disorders. Usual doses of fluoxetine cause significantly fewer anticholinergic-type side effects than tricyclic antidepressants. Nausea, nervousness and insomnia are the most frequently reported fluoxetine-related adverse effects, but these have usually not been severe. Therapeutic doses of fluoxetine do not affect cardiac conduction intervals in patients without pre-existing cardiovascular disease and fluoxetine has been relatively safe in the small number of patients who have taken overdoses. It has not been clearly established whether some types of depression may respond more readily to fluoxetine than other antidepressants, and its overall therapeutic efficacy has not been compared with other second generation antidepressants. Thus, with its different and perhaps improved side effect profile compared with older tricyclic antidepressants, fluoxetine offers properties that could be used to advantage in many patients with depression. MH - Animal ; Cardiovascular System/DRUG EFFECTS ; Central Nervous System/DRUG EFFECTS ; Clinical Trials ; Comparative Study ; Depressive Disorder/*DRUG THERAPY ; Drug Interactions ; Endocrine Glands/DRUG EFFECTS ; *Fluoxetin/ ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/METABOLISM/PHARMACODYNAMICS/ THERAPEUTIC USE ; Human ; Kinetics ; Neuroregulators/METABOLISM ; *Propylamines/ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/METABOLISM/ PHARMACODYNAMICS/THERAPEUTIC USE ; Review ; Serotonin/METABOLISM ; Synaptic Receptors/METABOLISM SO - Drugs 1986 Dec;32(6):481-508 10 UI - 87068134 AU - Cunningham KA ; Callahan PM ; Appel JB TI - Discriminative stimulus properties of the serotonin agonist MK 212. AB - In an attempt to clarify the role of 5-hydroxytryptamine (5-HT) in the discriminative stimulus properties of MK 212 (6-chloro-2[1-piperazinyl]pyrazine), male Sprague-Dawley rats were trained to discriminate 0.5 mg/kg of this compound from saline. While the putative 5-HT agonists fenfluramine and m-chlorophenylpiperazine (MCPP) mimicked MK 212 in a dose-related manner, d-lysergic acid diethylamide (LSD), 8-hydroxy-2(di-n-propylamino)tetralin (8-OHDPAT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), quipazine, Ru 24969, and 1-(m-trifluoromethylphenyl)piperazine (TFMPP) failed to substitute completely. The 5-HT1/5-HT2 antagonists BC 105, metergoline, and methysergide completely blocked the MK 212 cue, while the selective 5-HT2 antagonists ketanserin and pirenperone, the dopamine antagonists haloperidol and spiperone, and the beta-noradrenergic antagonist propranolol were without effect. The substitutions of fenfluramine and MCPP for MK 212 support a role for 5-HT in the MK 212 cue; however, the lack of substitution of many other 5-HT agonists is difficult to explain. The complete antagonism by 5-HT1/5-HT2 but not by selective 5-HT2, antagonists suggests the possibility that 5-HT1 receptors mediate the stimulus properties of MK 212. Further research is needed to support this hypothesis and to investigate the relative role of 5-HT and other neurotransmitters in the stimulus effects of MK 212. MH - Animal ; Discrimination (Psychology)/*DRUG EFFECTS ; Discrimination Learning/DRUG EFFECTS ; Dose-Response Relationship, Drug ; Drug Interactions ; Male ; Mice ; Pyrazines/*PHARMACODYNAMICS ; Rats ; Rats, Inbred Strains ; Serotonin/PHYSIOLOGY ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. SO - Psychopharmacology (Berlin) 1986;90(2):193-7 11 UI - 87053416 AU - Benfield P ; Ward A TI - Fluvoxamine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. AB - Fluvoxamine is a new antidepressant which potently and specifically inhibits neuronal reuptake of serotonin. In the absence of other major pharmacological effects it appears that its antidepressant activity stems from facilitation of serotoninergic neurotransmission as a result of reuptake inhibition. Studies suggest that fluvoxamine has overall therapeutic efficacy comparable with that of imipramine and clomipramine in depressive illness. It causes fewer anticholinergic-type and cardiovascular side effects than the tricyclic antidepressants but it is associated with a higher incidence of nausea and vomiting. Elderly patients also respond well to fluvoxamine. Studies are now required to compare fluvoxamine with other second generation antidepressants and to establish whether some types of depressive illness respond more readily to fluvoxamine than other agents. Thus, in patients with depressive illness, fluvoxamine offers a suitable alternative to tricyclic antidepressants and may be especially valuable in patients with concomitant cardiovascular disease, and those unresponsive to or unable to tolerate tricyclic antidepressants. MH - Animal ; Antidepressive Agents/ADVERSE EFFECTS/METABOLISM/ *PHARMACODYNAMICS/THERAPEUTIC USE ; Depressive Disorder/DRUG THERAPY ; Drug Interactions ; Human ; Kinetics ; Oximes/ADVERSE EFFECTS/METABOLISM/ *PHARMACODYNAMICS/THERAPEUTIC USE ; Review ; Serotonin Antagonists/ ADVERSE EFFECTS/METABOLISM/*PHARMACODYNAMICS SO - Drugs 1986 Oct;32(4):313-34 12 UI - 87050784 AU - Nakagami Y ; Suda T ; Yajima F ; Ushiyama T ; Tomori N ; Sumitomo T ; Demura H ; Shizume K TI - Effects of serotonin, cyproheptadine and reserpine on corticotropin-releasing factor release from the rat hypothalamus in vitro. AB - We investigated the effects of serotonin, cyproheptadine and reserpine on corticotropin-releasing factor (CRF) release from the rat hypothalamus, and the effect of cyproheptadine on CRF-induced adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary (AP) in vitro using a perifusion system for rat hypothalami and AP, and a rat CRF radioimmunoassay. Cyproheptadine, 10(-8) M, had a direct inhibitory effect on both basal and 10(-9) M CRF-induced ACTH secretion from the rat AP in vitro. In addition, 10(-9)-10(-7) M cyproheptadine inhibited basal CRF release in a dose-dependent fashion, and also suppressed serotonin- and KCl-induced CRF release. Conversely, 10(-9)-10(-7) M reserpine failed to influence CRF release from the rat hypothalamus. These results indicate that a serotonergic mechanism may be involved in the CRF-releasing mechanism, and inhibition of depolarization-dependent calcium entry into cells and/or nerve endings. In addition an anti-serotonergic mechanism is involved in the inhibitory action of cyproheptadine. MH - Adrenocorticotropic Hormone/SECRETION ; Animal ; Comparative Study ; Corticotropin Releasing Hormone/*SECRETION ; Cyproheptadine/ *PHARMACODYNAMICS ; Drug Interactions ; Hypothalamus/*SECRETION ; Male ; Pituitary Gland, Anterior/SECRETION ; Potassium/PHARMACODYNAMICS ; Rats ; Rats, Inbred Strains ; Reserpine/*PHARMACODYNAMICS ; Serotonin/ *PHARMACODYNAMICS ; Support, Non-U.S. Gov't SO - Brain Res 1986 Oct 29;386(1-2):232-6 13 UI - 87013275 AU - Furukawa Y ; Saegusa K ; Ogiwara Y ; Chiba S TI - Effects of ketanserin on the pacemaker activity and contractility in the isolated, blood-perfused dog atrium. AB - Effects of ketanserin on the pacemaker activity and atrial contractility and on 5-hydroxytryptamine (5-HT)-induced cardiac responses were investigated in the isolated, blood-perfused dog atrium. Ketanserin (1-300 micrograms) injected into the sinus node artery evoked a transient positive followed by a negative chronotropic effect, and a dose above 30 micrograms of ketanserin produced a dose-dependent negative inotropic effect with a little positive one. Ketanserin-induced negative chronotropic and inotropic effects were not affected by atropine in a dose which blocked ACh-induced responses. Propranolol inhibited positive inotropic responses to ketanserin and norepinephrine and significantly augmented the negative chronotropic and inotropic responses to ketanserin. Imipramine did not affect the transient positive followed by negative chronotropic and the negative inotropic responses to ketanserin but it induced the positive cardiac responses following the negative ones. Tetrodotoxin, phentolamine, and diphenhydramine did not modify the effects of ketanserin. From these results, it is concluded that ketanserin might induce the direct negative chronotropic and inotropic effects and the indirect effects by catecholamine release. Ketanserin-induced catecholamine release might not be due to tyramine-like or nicotine-like action. Ketanserin significantly inhibited a low dose (3 micrograms) of 5-HT-induced negative chronotropic and inotropic effects, suggesting the possibility of 5-HT2 receptors in the isolated dog atrium. MH - Animal ; Depression, Chemical ; Dogs ; Drug Interactions ; Heart Conduction System/*DRUG EFFECTS ; Heart Rate/*DRUG EFFECTS ; Imipramine/ PHARMACODYNAMICS ; Ketanserin/*PHARMACODYNAMICS ; Myocardial Contraction/ *DRUG EFFECTS ; Propranolol/PHARMACODYNAMICS ; Serotonin/PHARMACODYNAMICS ; Stimulation, Chemical SO - J Cardiovasc Pharmacol 1986 Sep-Oct;8(5):967-72 14 UI - 87011220 AU - Yamaguchi K ; Nabeshima T ; Kameyama T TI - Potentiation of phencyclidine-induced dopamine-dependent behaviors in rats after pretreatments with serotonin-depletors. AB - This study was designed to assess whether phencyclidine (PCP) produces dopamine (DA)-dependent behaviors such as licking, gnawing and biting (which are not observed in normal rats) in rats after pretreatments with a tryptophan hydroxylase inhibitor, p-chlorophenylalanine (PCPA) and specific serotonergic neuronal toxin, p-chloroamphetamine (PCA). Apomorphine (APO, 0.5 mg/kg) and methamphetamine (MAP, 2.5 mg/kg) mainly induced DA-dependent behaviors, including rearing and sniffing with occasional licking, in the vehicle-pretreated rats. APO (0.5 mg/kg)-induced DA-dependent behaviors significantly increased in the PCA- and PCPA-pretreated rats, in which serotonergic activity was greatly depressed but dopaminergic activity was normal. MAP (2.5 mg/kg)-induced DA-dependent behaviors were also significantly increased in the PCA-pretreated rats but not PCPA-pretreated rats. On the other hand, at doses of 2.5-7.5 mg/kg, PCP mainly caused stereotyped behaviors such as head-weaving, backpedalling, turning and DA-dependent behavior, such as sniffing, in the vehicle-pretreated rats. The PCP-induced stereotyped behaviors were attenuated by pretreatment with PCA and PCPA. In contrast, PCP-induced DA-dependent behavior, sniffing, was converted into more intense behaviors such as licking, gnawing and biting by pretreatment with PCA. These effects of PCP were also observed in rats pretreated with PCPA, although the degree was less than that by pretreatment with PCA. These results may indicate that serotonergic neuronal systems inhibitory regulate dopaminergic systems in PCP-induced behavioral responses. MH - p-Chloroamphetamine/PHARMACODYNAMICS ; p-Chlorophenylalanine/ PHARMACODYNAMICS ; Animal ; Apomorphine/PHARMACODYNAMICS ; Behavior, Animal/*DRUG EFFECTS ; Comparative Study ; Dopamine/*PHARMACODYNAMICS ; Drug Synergism ; Male ; Methamphetamine/PHARMACODYNAMICS ; Phencyclidine/ *PHARMACODYNAMICS ; Rats ; Rats, Inbred Strains ; Serotonin/PHYSIOLOGY/ *SECRETION ; Stereotyped Behavior/DRUG EFFECTS ; Support, Non-U.S. Gov't SO - J Pharmacobiodyn 1986 May;9(5):479-89 15 UI - 86314096 AU - Montgomery AM ; Fletcher PJ ; Burton MJ TI - Behavioural and pharmacological investigations of 5-HT hypophagia and hyperdipsia. AB - Treatment with 5-hydroxytryptamine (5-HT) reliably induced hypophagia in non-deprived rats and in rats tested following a period of food-deprivation, regardless of the presence or absence of water during testing. The hyperdipsic effect of 5-HT, however, was sensitive to changes in the length of food-deprivation, suggesting a possible interaction between 5-HT hyperdipsia and prandial drinking. Both 5-HT hypophagia and hyperdipsia were attenuated by methysergide pretreatment, thus confirming the involvement of peripheral post-synaptic 5-HT receptors in both effects. Pretreatment with propranolol blocked 5-HT hyperdipsia, but did not alter 5-HT hypophagia, thus suggesting that 5-HT hypophagia and hyperdipsia are mediated by different mechanisms at some point subsequent to the stimulation of peripheral 5-HT receptors. These results are consistent with other evidence that 5-HT hyperdipsia is mediated by stimulation of the renin-angiotensin system. It is tentatively suggested that 5-HT hypophagia could result from 5-HT-induced inhibition of cephalic phase insulin secretion. MH - Animal ; Comparative Study ; Drinking/*DRUG EFFECTS ; Drug Interactions ; Eating/*DRUG EFFECTS ; Food Deprivation ; Male ; Methysergide/ PHARMACODYNAMICS ; Propranolol/PHARMACODYNAMICS ; Rats ; Serotonin/ *PHARMACODYNAMICS ; Support, Non-U.S. Gov't SO - Pharmacol Biochem Behav 1986 Jul;25(1):23-8 16 UI - 86311695 AU - Mogilnicka E ; Wedzony K ; Klimek V ; Czyrak A TI - Desipramine induces yawning behaviour in rats. AB - Yawning behaviour in rats injected subcutaneously with antidepressant drugs was studied by direct observation. Desipramine (0.1-30 mg/kg) elicited yawning that began 15-20 min after injection and lasted for 60 min, and the dose-response curve showed a bell-shaped form. Desipramine (10 mg/kg) elicited the maximal effect (mean number of yawns 13.6). Haloperidol (0.02 mg/kg), spiperone (0.2 mg/kg), pimozide (4 mg/kg), reserpine (7.5 mg/kg), alpha-methyl-p-tyrosine (250 mg/kg) and scopolamine (0.5 mg/kg) markedly reduced yawning induced by desipramine, whereas prazosin (1 mg/kg) and phenoxybenzamine (5 mg/kg) were without effect. These findings indicate that desipramine induces yawning by a dopaminergic mechanism, and that endogenous dopamine (DA) is necessary for its occurrence. Yawning was observed also after administration of imipramine, clomipramine, trazodone, its metabolite m-chlorophenylpiperazine and (+/-)sulpiride. These drugs given in a similar dose-range to desipramine produced a weaker effect than desipramine. Selective and potent inhibitors of the uptake of noradrenaline (NA) or 5-hydroxytryptamine (5-HT), (+)oxaprotiline and citalopram, did not elicit yawning. A possibility is considered that certain antidepressant drugs induced yawning through an influence on dopaminergic system. MH - Animal ; Antidepressive Agents/*PHARMACODYNAMICS ; Desipramine/ *PHARMACODYNAMICS ; Drug Interactions ; Haloperidol/PHARMACODYNAMICS ; Male ; Piperazines/PHARMACODYNAMICS ; Rats ; Rats, Inbred Strains ; Receptors, Dopamine/DRUG EFFECTS ; Reflex/*DRUG EFFECTS ; Scopolamine/ PHARMACODYNAMICS SO - Neuropharmacology 1986 Jul;25(7):783-6 17 UI - 86311690 AU - Mendelson SD ; Gorzalka BB TI - Methysergide inhibits and facilitates lordosis behavior in the female rat in a time-dependent manner. AB - Reports in the literature have indicated a facilitatory effect of the serotonin antagonist methysergide on lordosis behavior, suggesting an inhibitory role for serotonergic activity. In the present series of experiments, methysergide (7 mg/kg) was found to inhibit lordosis behavior 30 min after intraperitoneal administration to females, treated chronically with estradiol benzoate, or acutely with estradiol benzoate and progesterone. However, methysergide was found to facilitate lordosis behavior 200 and 300 min after administration to female rats treated acutely with estradiol benzoate. These data suggest a time-dependent inhibitory effect of methysergide, and are consistent with the hypothesis that the activity of serotonin type 2 receptors facilitates lordosis behavior in the female rat. MH - Animal ; Drug Interactions ; Estradiol/PHARMACODYNAMICS ; Female ; Methysergide/*PHARMACODYNAMICS ; Posture ; Progesterone/PHARMACODYNAMICS ; Rats ; Rats, Inbred Strains ; Receptors, Serotonin/DRUG EFFECTS ; Sex Behavior, Animal/*DRUG EFFECTS ; Support, Non-U.S. Gov't SO - Neuropharmacology 1986 Jul;25(7):749-55 18 UI - 86258108 AU - Kim SS ; Reith ME TI - Effect of serotonin on the dissociation of high-affinity binding of [3H]imipramine in mouse cerebral cortex. AB - A low concentration of norzimelidine can be used to selectively measure the rate of dissociation of [3H]imipramine from high-affinity binding sites in the mouse cerebral cortex. Serotonin attenuates the dissociation initiated by norzimelidine. There is no difference between the half-time of dissociation in the presence of both serotonin and norzimelidine and that in the presence of serotonin alone. These effects are similar to but much less pronounced than those observed in the platelet. MH - Animal ; Blood Platelets/METABOLISM ; Cerebral Cortex/*METABOLISM ; Comparative Study ; Desipramine/PHARMACODYNAMICS ; Drug Interactions ; Imipramine/*METABOLISM ; Male ; Mice ; Mice, Inbred BALB C ; Serotonin/ *PHARMACODYNAMICS ; Support, U.S. Gov't, P.H.S. ; Zimelidine/ANALOGS & DERIVATIVES/PHARMACODYNAMICS SO - Neurosci Lett 1986 Jun 18;67(2):123-8 19 UI - 86248624 AU - Serrano JS ; Mi:nano FJ ; Sancibri:an M TI - GABA-induced hypothermia in rats: involvement of serotonergic and cholinergic mechanisms. AB - The effects of gamma-aminobutyric acid (GABA) on body temperature of restrained rats has been studied. GABA (250-1000 mg/kg i.p.) caused a dose-dependent fall in BT of restrained rats at an ambient temperature of 18-22 degrees C. The GABA-induced hypothermic response was attenuated by pretreatment with hexamethonium, p-chlorophenylalanine, methysergide, neostigmine and atropine (% MPE values: 27, 35, 51, 64 and 72 respectively). Pretreatment with methysergide and atropine was more potent than hexamethonium and methysergide in inhibiting the GABA-induced hypothermia (% MPE = 68 and 47 respectively). The antagonism by neostigmine of GABA-induced hypothermia was attenuated by pretreatment with hexamethonium (7.5 mg/kg). Yohimbine and chlorimipramine potentiated GABA hypothermia (% MPE = -82 and -8 respectively). The data indicate that GABA-induced hypothermia may be mediated by serotonin and acetylcholine release. Muscarinic receptors may play an important role in the effect of GABA. The results support the hypothesis that the hypothermia induced by GABA is modulated by nicotinic receptors. MH - p-Chlorophenylalanine/PHARMACODYNAMICS ; Acetylcholine/*PHYSIOLOGY ; Animal ; Body Temperature/*DRUG EFFECTS ; Clomipramine/PHARMACODYNAMICS ; Drug Interactions ; Female ; GABA/ANTAGONISTS & INHIBITORS/ *PHARMACODYNAMICS ; Parasympatholytics/PHARMACODYNAMICS ; Rats ; Rats, Inbred Strains ; Serotonin/*PHYSIOLOGY ; Serotonin Antagonists/ PHARMACODYNAMICS ; Yohimbine/PHARMACODYNAMICS SO - Gen Pharmacol 1986;17(3):327-32 20 UI - 86240361 AU - Lipham LB ; Booth NH ; Jernigan AD ; Robbins JD ; Hatch RC TI - Effect of clonidine, quipazine, and LY 53857 on the prolactin-suppressant action of bromocriptine in rats. AB - The alpha 2-adrenergic agonist clonidine hydrochloride, the serotonin agonist quipazine maleate, and the serotonin (5-HT2) antagonist LY 53857 were tested alone and in various combinations for their capabilities to increase mean serum prolactin (MSP) concentrations in rats given the synthetic ergot alkaloid CB-154 (2-bromo-alpha-ergocriptine), a known prolactin suppressor. The LY 53857 and the combination of clonidine, quipazine, and LY 53857 significantly decreased MSP concentrations. Quipazine given alone (10 mg/kg of body weight) was best able to increase MSP concentration and has potential to antagonize prolactin-depressant effects of ergot alkaloids. MH - Animal ; Bromocriptine/*PHARMACODYNAMICS ; Clonidine/*PHARMACODYNAMICS ; Comparative Study ; Drug Interactions ; Ergolines/*PHARMACODYNAMICS ; Male ; Pituitary Gland, Anterior/DRUG EFFECTS/SECRETION ; Prolactin/ *BLOOD/SECRETION ; Quinolines/*PHARMACODYNAMICS ; Quipazine/ *PHARMACODYNAMICS ; Rats ; Rats, Inbred Strains ; Serotonin Antagonists/ *PHARMACODYNAMICS SO - Am J Vet Res 1986 May;47(5):1089-91 21 UI - 86233607 AU - Becker HC TI - Comparison of the effects of the benzodiazepine midazolam and three serotonin antagonists on a consummatory conflict paradigm. AB - A consummatory conflict procedure that involves an abrupt reduction in magnitude of an expected reward (negative contrast) has been shown to be particularly sensitive to the effects of anxiolytic agents. As previously reported with chlordiazepoxide, another benzodiazepine (BDZ), midazolam released suppressed consummatory performance in a dose-dependent manner. This effect was not due to a general appetitie stimulatory effect of the drug. The effects of three 5-HT antagonists on negative contrast were examined to evaluate the role serotonin may play in the anxiolytic action of BDZ. Methysergide was found to be ineffective, cinanserin tended to reduce contrast at two intermediate doses, and cyproheptadine eliminated the contrast effect in a similar fashion as midazolam. The effectiveness of cyproheptadine may not be attributed to its anticholinergic or antihistaminergic actions since scopolamine and pyrilamine did not produce similar effects. The results are discussed in terms of the role serotonin may play in the anti-conflict action of BDZ, as well as possible interactional effects of GABA. MH - Animal ; Benzodiazepines/*PHARMACODYNAMICS ; Cinanserin/PHARMACODYNAMICS ; Comparative Study ; *Conflict (Psychology) ; Consummatory Behavior/ *DRUG EFFECTS ; Cyproheptadine/PHARMACODYNAMICS ; Drug Interactions ; Male ; Methysergide/PHARMACODYNAMICS ; Neural Transmission/DRUG EFFECTS ; Pyrilamine/PHARMACODYNAMICS ; Rats ; Rats, Inbred Strains ; Scopolamine/ PHARMACODYNAMICS ; Serotonin/*PHYSIOLOGY ; Serotonin Antagonists/ *PHARMACODYNAMICS ; Support, Non-U.S. Gov't SO - Pharmacol Biochem Behav 1986 Apr;24(4):1057-64 22 UI - 86233605 AU - Erinoff L ; Snodgrass SR TI - Effects of adult or neonatal treatment with 6-hydroxydopamine or 5,7-dihydroxytryptamine on locomotor activity, monoamine levels, and response to caffeine. AB - Rats were treated as neonates or adults with desmethylimipramine (DMI) followed by intraventricular 6-hydroxydopamine (6-HDA) or 5,7 dihydroxytryptamine (5,7-DHT). Locomotor activity of treated rats was measured in photocell cages. Neonatal treatment with 5,7-DHT produced hypoactivity during development while neonatal 6-HDA led to hyperactivity. Treatment of adult rats with 5,7-DHT or 6-HDA, while resulting in equivalent monoamine depletions, was without effect on locomotor activity. The dose response function for caffeine was determined in these rats. Depletion of dopamine by either neonatal or adult treatment with 6-HDA decreased caffeine stimulation of locomotor activity. The adenosine receptor agonist l-phenylisopropyladenosine (L-PIA) decreased locomotor activity in all rats in a dose-dependent fashion. MH - Age Factors ; Animal ; Animals, Newborn ; Biogenic Amines/*ANALYSIS ; Brain Chemistry/*DRUG EFFECTS ; Caffeine/*ADMINISTRATION & DOSAGE ; Comparative Study ; Dihydroxytryptamines/*PHARMACODYNAMICS ; Drug Interactions ; Hydroxydopamines/*PHARMACODYNAMICS ; Motor Activity/*DRUG EFFECTS ; Norepinephrine/ANALYSIS ; Rats ; Serotonin/ANALYSIS ; 5,7-Dihydroxytryptamine/*PHARMACODYNAMICS SO - Pharmacol Biochem Behav 1986 Apr;24(4):1039-45 23 UI - 86199200 AU - Van Nueten JM ; Janssens WJ TI - Augmentation of vasoconstrictor responses to serotonin by acute and chronic factors: inhibition by ketanserin. AB - Serotonin induces constrictor responses on smooth muscle tissues from several vascular regions mainly by its interaction with serotonin-S2 receptor sites. The individual sensitivity of various blood vessels to serotonin may vary considerably. Serotonin (e.g. released from aggregating platelets) also induces vascular contractions by amplifying the response to other vasoactive substances. The vascular reactivity to serotonin can be markedly augmented by acute hypoxia (95% N2, 5% CO2; canine coronary arteries) and by cooling from 37 degrees to 29 degrees C (rabbit tibial and canine saphenous arteries). Blood vessels become hyperreactive to the vasoconstrictor component of serotonin in a number of disease states. Isolated perfused kidneys from spontaneously hypertensive rats (SHR) exhibit direct and indirect (amplifying) vasoconstrictor responses to serotonin. The amplifying effect of serotonin is significantly more pronounced in 6-month-old than in 2-month-old SHRs. Both the direct and indirect vasoconstrictor responses to serotonin, whether or not augmented by acute or chronic conditions, are inhibited by the serotonin-S2 receptor antagonist, ketanserin (4 X 10(-10) to 4 X 10(-7) mol/l). Both the hypersensitivity of vascular tissue to serotonin and the amplifying effect of the amine may greatly contribute to hypertension and other cardiovascular disorders. MH - Animal ; Drug Synergism ; Norepinephrine/METABOLISM ; Piperidines/ *PHARMACODYNAMICS ; Rabbits ; Rats ; Rats, Inbred Strains ; Serotonin/ *PHARMACODYNAMICS ; *Serotonin Antagonists ; Sheep ; Support, Non-U.S. Gov't ; Vasoconstriction/*DRUG EFFECTS ; Vasodilation/DRUG EFFECTS SO - J Hypertens [Suppl] 1986 Apr;4(1):S55-9 24 UI - 86168345 AU - Dalton DW TI - The cardiovascular effects of centrally administered 5-hydroxytryptamine in the conscious normotensive and hypertensive rat. AB - The cardiovascular effects of centrally administered 5-hydroxytryptamine (5-HT) have been analysed in conscious normotensive and hypertensive rats. In conscious normotensive rats, 5-HT, (1-30 micrograms) administered intracerebroventricularly (i.c.v.) produced profound and immediate dose-related decreases in heart rate and small increases in blood pressure. The initial pressor responses were followed by secondary secondary depressor responses at high doses of 5-HT. Similar effects were produced by 5-HT i.c.v. in conscious DOCA-salt and spontaneously hypertensive rats, although the magnitude of the pressor responses was substantially greater in hypertensive than normotensive rats. Pretreatment with either N-methylatropine or atenolol intra-arterially reduced the 5-HT-induced bradycardia in normotensive rats; the reduction was enhanced when both antagonists were given in combination. The 5-HT2 antagonist, cyproheptadine (10 micrograms i.c.v.) increased basal blood pressure and heart rate in normotensive rats. Subsequent administration of 5-HT i.c.v. produced biphasic effects on heart rate consisting of an initial tachycardia followed by a marked bradycardia. Methysergide (10 micrograms i.c.v.) pretreatment did not alter resting heart rate, but attenuated the 5-HT induced bradycardia. A higher dose of methysergide, (30 micrograms i.c.v.), decreased resting blood pressure and heart rate. This study has demonstrated, therefore, that the 5-HT induced bradycardia is produced by not only a centrally mediated decrease in sympathetic tone, but also an increase in vagal drive to the heart. The bradycardia is antagonised by centrally administered methysergide, but not by cyproheptadine, which suggests that it is probably mediated through a '5-HT1-like' receptor mechanism. MH - Animal ; Atenolol/PHARMACODYNAMICS ; Atropine Derivatives/ PHARMACODYNAMICS ; Blood Pressure/DRUG EFFECTS ; Bradycardia/CHEMICALLY INDUCED ; Drug Interactions ; Heart/*DRUG EFFECTS ; Heart Rate/DRUG EFFECTS ; Hypertension/CHEMICALLY INDUCED/DRUG THERAPY ; Injections, Intravenous ; Male ; Methysergide/PHARMACODYNAMICS ; Rats ; Serotonin/ *PHARMACODYNAMICS ; Serotonin Antagonists/*PHARMACODYNAMICS SO - J Auton Pharmacol 1986 Mar;6(1):67-75 25 UI - 86163715 AU - Takeuchi K ; Ohtsuki H ; Okabe S TI - Pathogenesis of compound 48/80-induced gastric lesions in rats. AB - Intraperitoneal administration of 0.75 mg/kg of compound 48/80 (a mast cell degranulator) once daily for four days induced extensive gastric lesions in rats. Oral administration of tripelennamine (histamine H1-receptor antagonist) and cimetidine (histamine H2-receptor antagonist) twice daily for four days had little or no effect on the lesion formation. Oral administration of methysergide and cyproheptadine (serotonin antagonists) and FPL-52694 (a mast cell stabilizer) potently inhibited the compound 48/80-induced lesions. Intraperitoneal administration of histamine plus serotonin, or serotonin alone, induced gastric lesions which resembled those induced by compound 48/80. These lesions were potently inhibited by methysergide and cyproheptadine, but not by tripelennamine, cimetidine, and FPL-52694. Single or repeated administration of compound 48/80 significantly increased serum histamine and serotonin levels. After a single administration of compound 48/80, the increased histamine levels rapidly returned to normal levels, but serotonin levels remained high for 7 hr. Histamine and serotonin levels in the gastric mucosa were transiently increased after a single administration of compound 48/80, but remained normal after repeated administration. Single or repeated administration of compound 48/80 had little effect on arterial blood pressure. The compound 48/80-induced gastric lesions appear to be caused primarily by the release of serotonin, but not histamine, from extragastric sources. MH - Animal ; Blood Pressure/DRUG EFFECTS ; Chromones/PHARMACODYNAMICS ; Cimetidine/PHARMACODYNAMICS ; Compound 48-80/*TOXICITY ; Cyproheptadine/ PHARMACODYNAMICS ; Drug Interactions ; Gastric Mucosa/DRUG EFFECTS/ METABOLISM/PATHOLOGY ; Histamine/BLOOD/METABOLISM/TOXICITY ; Male ; Mast Cells/DRUG EFFECTS ; Methysergide/PHARMACODYNAMICS ; Rats ; Serotonin/ BLOOD/METABOLISM/TOXICITY ; Stomach Diseases/*CHEMICALLY INDUCED/ PATHOLOGY ; Tripelennamine/PHARMACODYNAMICS SO - Dig Dis Sci 1986 Apr;31(4):392-400 26 UI - 86132660 AU - Pranzatelli MR ; Snodgrass SR TI - Serotonin-lesion myoclonic syndromes. II. Analysis of individual syndrome elements, locomotor activity and behavioral correlations. AB - This study evaluated the behavioral elements of three 5-HT-related syndromes (intraperitoneal 5-hydroxytryptophan after intracisternal 5,7-dihydroxytryptamine (DHT), p-chloroamphetamine (PCA), fenfluramine (FF), or combinations of drugs) scored from video-tapes and their relationship to locomotor activity (LMA) photocell recording, regional monoamine concentration and S-1 receptor binding. Rearing was eliminated by drugs which produce the myoclonic syndrome and was the single best indicator of control treatments (saline or 5-HTP in unlesioned rats and saline in DHT-lesioned rats). Global 'abnormality', hunching (rigid arching of back), hindlimb abduction, forepaw myoclonus, stereotyped lateral head movements, backing, and immobility occurred significantly only in drug-treated rats. Multiple forms of myoclonus (appendicular and truncal) and convulsions were dose-dependent drug effects. Both 5-HTP (after DHT) and PCA increased LMA significantly, but hyperactivity induced by PCA could be blocked by giving 5-HTP concomitantly. Substantial 5-HT presynaptic destruction by DHT prevented backing but not other behavioral or locomotor effects of FF and PCA. Drug combinations did not produce additive behavioral effects. Backing, immobility, and locomotor activity best differentiated between drug treatments, and could be used to correctly allocate animals to drug groups. Drug treatments also could be differentiated by reducing the number of behavioral variables into summary variables (principal components) and by discriminant analysis. Only forepaw myoclonus and total behavioral score were correlated with 5-HT concentrations (brainstem), indicating behavioral heterogeneity. Our study suggests that there is a common core 'myoclonic-serotonergic' syndrome (forepaw myoclonus, head weaving, hindlimb abduction, hunching) of stimulation of 5-HT receptors plus additional drug-specific elements (backing, LMA). Although brainstem receptors appear to be an important locus for some of these behaviors, S-1 receptors do not explain the behavioral supersensitivity to 5-HTP in our DHT-lesioned rats. MH - p-Chloroamphetamine/*PHARMACODYNAMICS ; Amphetamines/*PHARMACODYNAMICS ; Animal ; Comparative Study ; Dihydroxytryptamines/*PHARMACODYNAMICS ; Drug Interactions ; Fenfluramine/*PHARMACODYNAMICS ; Hydroxytryptophan/ *PHARMACODYNAMICS ; Male ; Motor Activity/*DRUG EFFECTS ; Myoclonus/ *CHEMICALLY INDUCED ; Rats ; Rats, Inbred Strains ; Receptors, Serotonin/ *DRUG EFFECTS ; Syndrome ; 5,7-Dihydroxytryptamine/*PHARMACODYNAMICS SO - Brain Res 1986 Jan 29;364(1):67-76 27 UI - 86132659 AU - Pranzatelli MR ; Rubin G ; Snodgrass SR TI - Serotonin-lesion myoclonic syndromes. I. Neurochemical profile and S-1 receptor binding. AB - This paper and the following one describe the effects of L-5-hydroxytryptophan (5-HTP) (after 3 intracisternal injections of 5,7-dihydroxytryptamine (DHT], fenfluramine (FF), p-chloroamphetamine (PCA) and drug combinations on (i) brain regional amine concentration (HPLC with LEC) and serotonin S-1 receptor binding; and (ii) 'serotonergic' behaviors in the same adult rats. Serotonin (5-HT) neurotoxins produced significantly different regional profiles of 5-HT depletion. Multiple DHT injections caused a 90-100% depletion of 5-HT concurrently in neocortex, hippocampus, striatum, septum/accumbens, pons, cerebellum, and cervical cord. Only PCA significantly depleted midbrain. Drug combinations with DHT resembled DHT alone rather than additive depletions, except for PCA + DHT, which produced a hybrid pattern of depletion. The S-1 binding assay, using cold 5-HT to displace [3H]5-HT, was performed with and without ascorbate, EDTA, CaCl2, and pargyline. Without ascorbate, binding was specific, saturable, region-dependent, and non-linear with high (Kd 1-3 nM) and low affinity (10-20 nM) components but no cooperativity (0.8 less than nH less than 1.0). Bmax and Kd did not differ significantly between vehicle- and drug-treated animals in neocortex, hippocampus, striatum, thalamus, hypothalamus, midbrain, pons, medulla, cervical cord, cerebellum, or septum/accumbens two weeks after lesioning, while the assay did detect a 60% reduction in Bmax induced by ascorbic acid (1 mM). The effects of assay conditions exceeded the changes sometimes reported in S-1 receptor Bmax after 5-HT lesions. MH - p-Chloroamphetamine/*PHARMACODYNAMICS ; Amphetamines/*PHARMACODYNAMICS ; Animal ; Biogenic Amines/ANALYSIS ; Brain/*METABOLISM ; Brain Chemistry/ DRUG EFFECTS ; Comparative Study ; Dihydroxytryptamines/*PHARMACODYNAMICS ; Drug Interactions ; Fenfluramine/*PHARMACODYNAMICS ; Hydroxytryptophan/ *PHARMACODYNAMICS ; Male ; Myoclonus/*CHEMICALLY INDUCED/METABOLISM ; Rats ; Rats, Inbred Strains ; Receptors, Serotonin/*METABOLISM ; Syndrome ; 5,7-Dihydroxytryptamine/*PHARMACODYNAMICS SO - Brain Res 1986 Jan 29;364(1):57-66 28 UI - 86113019 AU - Sakamoto Y ; Krzanowski JJ ; Lockey RF ; Duncan R ; Polson JB ; Szentivanyi A TI - The mechanism of ergonovine-induced airway smooth muscle contraction. AB - There have been three articles in the clinical literature of ergonovine maleate-induced bronchospasm. The effect of the alkaloid on isolated canine tracheal smooth muscle was analyzed to investigate the mechanism of ergonovine-induced airway smooth muscle contraction. Both ergonovine and 5-hydroxytryptamine (5HT, serotonin) contracted the smooth muscle preparations with EC50s of 1.35 X 10(-8) mol/L and 5.06 X 10(-7) mol/L, respectively. The maximal contractile response observed with ergonovine was approximately 30% less than that observed with 5HT. Methysergide competitively blocked both ergonovine and 5HT responses with similar calculated pKB values (8.33 against ergonovine and 8.46 against 5HT) and also similar pA2 values determined by Schild plots (8.50 and 8.45, respectively). The relative affinity and efficacy of ergonovine versus 5HT were determined by use of a concentration of the irreversible antagonist, phenoxybenzamine, which partially blocked receptor sites. The calculated affinity of ergonovine was about 16 times higher than that of 5HT. The relative efficacy at EC100 for ergonovine was 0.2, but at EC10 it was 41.9 (5HT efficacy = 1). Ergonovine 10(-9) or 10(-8) mol/L shifted the 5HT dose-response curve to the right without reducing the maximal response, but the shift was nonparallel. Blockade of muscarinic (atropine), alpha 1-adrenergic (prazosin), beta-adrenergic (propranolol), H1 (pyrilamine), or H2 (cimetidine) receptors did not alter ergonovine-induced contraction. These data indicate that ergonovine directly contracts canine tracheal smooth muscle as a result of its combination with 5HT receptors. This effect may result in precipitation of an asthmatic attack in susceptible individuals. MH - Animal ; Dogs ; Dose-Response Relationship, Drug ; Drug Antagonism ; Drug Interactions ; Ergonovine/ADMINISTRATION & DOSAGE/*PHARMACODYNAMICS ; Methysergide/PHARMACODYNAMICS ; Muscle Contraction/*DRUG EFFECTS ; Muscle, Smooth/DRUG EFFECTS ; Serotonin/ADMINISTRATION & DOSAGE ; Trachea/ *PHYSIOLOGY SO - J Allergy Clin Immunol 1986 Feb;77(2):354-64