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Background: Triptans are used as antimigraine agents. Some cases of hepatotoxicity by triptans have been reported. However, the exact mechanism of triptan-induced hepatotoxicity is not clear yet. Methods: In this study, the cytotoxic effects of rizatriptan were investigated in freshly isolated rat hepatocytes using accelerated cytotoxicity mechanism screening. We designed experiments to evaluate toxicity markers, such as cell death, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential, lysosomal membrane integrity and the amount of reduced and oxidized glutathione in the rizatriptan-treated hepatocytes. Results: Cytotoxicity caused by rizatriptan in rat hepatocytes was concentration-dependent. An increase in ROS formation accompanied by a significant rise in lipid peroxidation, mitochondrial depolarization and loss of lysosomal membrane integrity was observed. Cellular glutathione reservoirs were decreased and a significant amount of oxidized glutathione was formed. All the aforementioned rizatriptan-induced cellular events were significantly (p<0.05) prevented by ROS scavengers, antioxidants, endocytosis inhibitors and adenosine triphosphate (ATP) generators. Also, the present results demonstrated that CYP450 is involved in rizatriptan-induced oxidative stress and cytotoxicity mechanism and different CYP450 inducers had different effects on the toxicity. Conclusion: It is suggested that the adverse effect of rizatriptan towards hepatocytes is mediated by oxidative stress and the hepatocytes lysosomes and mitochondria play an important role in rizatriptan-induced cell injury., (© Georg Thieme Verlag KG Stuttgart · New York.)

Reflux esophagitis (RE), a major gastrointestinal disorder results from excess exposure of the esophageal mucosa to acidic gastric juice or bile-containing duodenal contents refluxed via an incompetent lower esophageal sphincter. Recent studies implicated oxygen derived free radicals in RE induced esophageal mucosal damage resulting in mucosal inflammation. Thus, control over free radical generation and modulation of inflammatory responses might offer better therapeutic effects to counteract the severity of RE. In this context we investigated the effect of melatonin against experimental RE in rats. Melatonin pretreatment significantly reduced the haemorrhagic lesions and decreased esophageal lipid peroxidation aggravated by RE. Moreover, the depleted levels of superoxide dismutase and glutathione observed in RE were replenished by melatonin signifying its free radical scavenging properties and antioxidant effects resulting in the improvement of esophageal defense mechanism. Further melatonin repressed the upregulated levels of expression of proinflammatory cytokines like, TNF-alpha, IL-1beta and IL-6 in RE. However, increased levels of the anti-inflammatory cytokine IL-10 remained unaltered after melatonin administration signifying its immunomodulatory effect through suppression of Th1-mediated immune responses. The involvement of receptor dependent actions of melatonin against RE were also investigated with MT2 receptor antagonist, luzindole (LUZ). LUZ failed to antagonize melatonin's protective effects against RE indicating that melatonin mediated these beneficial effects in a receptor-independent fashion. Thus, esophageal mucosal protection elicited by melatonin against experimental RE is not only dependent on its free radical scavenging activity but also mediated in part through its effect on the associated inflammatory events in a receptor-independent manner.

Periventricular leukomalacia is a major cause of cerebral palsy. Perinatal white matter lesions associated with cerebral palsy appears to involve glutamate excitotoxicity. When injected intracerebrally into newborn mice, the glutamatergic analog, ibotenate, induces white matter cysts mimicking human periventricular leukomalacia. Intraperitoneal injection of melatonin was previously shown to be neuroprotective in this mouse model. The goal of the present study was to compare in this model the protective effects of agomelatine (S 20098), a melatonin derivative, with melatonin. Mice that received intraperitoneal S 20098 or melatonin had significant reductions in size of ibotenate-induced white matter cysts when compared with controls. Although agomelatine and melatonin did not prevent the initial appearance of white matter lesions, they did promote secondary lesion repair. Interestingly, while melatonin effects were only observed when given within the first two hours following the excitotoxic insult, agomelatine was still significantly neuroprotective when administered eight hours after the insult. The protective effects of agomelatine and melatonin were counter-acted by co-administration of luzindole or S 20928, two melatonin receptor antagonists. Agomelatine, acting through melatonin receptors, could represent a promising new drug for treating human periventricular leukomalacia and have beneficial effects on neuroplasticity.

Eugenosedin-A is a newly synthesized compound with special serotonergic, alpha- and beta1-adrenergic blocking actions. Intravenous injection of eugenosedin-A significantly caused dose-dependent decreases in the mean arterial blood pressure and heart rate in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). The effects of eugenosedin-A-decreased blood pressure and heart rate in SHR were more potent than in WKY. In in vitro experiments, eugenosedin-A competitively antagonized the serotonin-, norepinephrine- and clonidine-induced vasocontraction in a concentration-dependent manner in isolated thoracic aorta of WKY and SHR. We also observed that eugenosedin-A competitively antagonized the isoproterenol-induced positive inotropic effects in a concentration-dependent manner in the isolated left atrium of WKY and SHR. These findings clearly suggested that eugenosedin-A possesses alpha1/alpha2, beta1 and 5-HT2A receptor-blocking activities. The order of pA2 values in isolated tissues of WKY was 5-HT2A > alpha1/alpha2 > beta1. However, the order of pA2 values in isolated tissues of SHR was alpha1/alpha2 > 5-HT2A > beta1. Similarly, we found that the in vitro functional activity of eugenosedin-A is quite different between WKY and SHR. On the other hand, in the isolated rabbit ear artery sensitized with 16 mmol/l K+, eugenosedin-A antagonized 5-nonyloxytryptamine- and serotonin-induced vasocontractions, indicating that it also blocked 5-HT1B and 5-HT2A receptors. In radioligand binding experiments, eugenosedin-A had significant binding affinities on alpha1/alpha2, beta1, 5-HT1B and 5-HT2A receptors. Finally, we suggest that the hypotensive effects of eugenosedin-A can be attributed to its multiple actions on the blockade of 5-HT1B, 5-HT2A, alpha and beta1 receptors in both WKY and SHR strains., (Copyright 2004 S. Karger AG, Basel)

Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT, EC 2.3.1.87) is the penultimate enzyme in melatonin biosynthesis. This enzyme is of special biological interest because large changes in its activity drive the large night/day rhythm in circulating melatonin in vertebrates. In this study the kinetic mechanism of AANAT action was studied using bacterially expressed glutathione S-transferase (GST)-AANAT fusion protein. The enzymologic behavior of GST-AANAT and cleaved AANAT was essentially identical. Two-substrate kinetic analysis generated an intersecting line pattern characteristic of a ternary complex mechanism. The dead end inhibitor analog desulfo-CoA was competitive versus acetyl-CoA and noncompetitive versus tryptamine. Tryptophol was not an alternative substrate but was a dead end competitive inhibitor versus tryptamine and an uncompetitive inhibitor versus acetyl-CoA, indicative of an ordered binding mechanism requiring binding of acetyl-CoA first. N-Acetyltryptamine, a reaction product, was a noncompetitive inhibitor versus tryptamine and uncompetitive with respect to acetyl-CoA. Taken together these results support an ordered BiBi ternary complex (sequential) kinetic mechanism for AANAT and provide a framework for inhibitor design.

Alpha-ethyltryptamine (AET), a monoamine oxidase inhibitor and potent monoamine releasing agent, has been sold illicitly as a substitute for the entactogen 3,4-methylenedioxy-N-methylamphetamine (MDMA), and is the first example of an indolealkylamine analog demonstrated to substitute in MDMA-trained animals. Previous studies have demonstrated that MDMA and AET have similar effects on unconditioned motor behavior in rats. Furthermore, the locomotor-activating effects of both MDMA and AET are blocked by pretreatment with fluoxetine, a selective serotonin (5-HT) uptake inhibitor, suggesting that the two compounds may share a presynaptic mechanism of action. This study examined the effects of AET using measures of startle plasticity, specifically prepulse inhibition (PPI), and habituation. PPI, a measure of sensorimotor gating, is reduced in rats treated with hallucinogens, 5-HT releasers, and dopamine agonists. In contrast, startle habituation is reduced in rats treated with hallucinogens and 5-HT releasers. AET (1.25, 2.5, 5, and 10 mg/kg) decreased PPI of acoustic startle and reduced the habituation of tactile startle. To determine whether AET produces these effects via pre- or postsynaptic actions, fluoxetine (10 mg/kg) was used as a pretreatment. By itself, fluoxetine did not disrupt PPI, but did reduce startle habituation. Fluoxetine pretreatment prevented the AET-induced disruption of PPI and reduced the AET-induced disruption of startle habituation. Combined with previous findings, these results confirm that AET produces behavioral effects that mimic those of other indirect 5-HT agonists and that the effects of AET on startle plasticity are due to the release of presynaptic 5-HT.

In 1965 the first study of this series reported different effects of neuroleptics in rats, supporting clinical differences. At the one end, haloperidol presented as a potent and specific antagonist of the psychostimulants amphetamine and apomorphine. Haloperidol-like neuroleptics have marked effects on psychomotor agitation, delusions and hallucinations and bind with high affinity to dopamine-D2 receptors. Pipamperone, at the other end, presented with weak "dopamine" antagonism and more striking tryptamine antagonism. Pipamperone is known to improve disturbed sleep, social withdrawal and other symptoms of chronic schizophrenia in the relative absence of extrapyramidal symptoms. These effects have been attributed to central serotonin-S2 antagonism, on the basis of the clinical effects of ritanserin. As shown by the present analysis of relative tryptamine versus apomorphine antagonism of 57 neuroleptics, in comparison to relative S2 vs. D2 binding, there is a continuity in the series. About 30% of the compounds can be considered to act primarily as serotonin antagonists, but few are markedly more potent than pipamperone. In amphetamine-challenged rats pipamperone-like activity is reflected in preferential inhibition of the excessive oxygen consumption rather than of agitation. Risperidone inhibits oxygen consumption (0.016 mg/kg) at the same dose as haloperidol inhibits agitation. Other low-dose effects of risperidone include reversal of amphetamine-induced withdrawal, antagonism of agitation induced by a sequential tryptamine and apomorphine challenge and LSD-antagonism. In dogs, the antiemetic activity of risperidone is characterized by high oral effectiveness which lasts one day and agrees with pharmacokinetic data when allowance is made for the active metabolite 9-hydroxyrisperidone.(ABSTRACT TRUNCATED AT 250 WORDS)

Several reports have speculated that the tryptamine-derived drug alpha-ethyltryptamine (AET) may have effects similar to those of the amphetamine-derived drug 3,4-methylenedioxymethamphetamine (MDMA). Indeed, the US Drug Enforcement Administration has recently placed AET on the Schedule I list because of its putative similarity to MDMA. The Behavioral Pattern Monitor, which quantifies locomotor and investigatory responses of rats, was used to characterize the effects of AET in a paradigm that distinguishes between the effects of traditional hallucinogens, amphetamine-like stimulants, and MDMA-like drugs. First, a dose-response study revealed that all doses of AET tested (5, 10, 20 mg/kg) significantly increased locomotor activity. Locomotor hyperactivity is produced by MDMA or amphetamine-like stimulants, but not by classical hallucinogens, such as LSD or mescaline. Additionally, AET significantly decreased measures of investigatory behavior. Similar decreases occur with MDMA or hallucinogen administration. Second, as with MDMA, the locomotor hyperactivity induced by AET was attenuated by pretreatment (10 mg/kg) with the serotonin reuptake inhibitor fluoxetine. Thus, AET, a tryptamine-derived drug, appears to produce an MDMA-like profile of behavioral changes by virtue of releasing presynaptic serotonin.

The anti-immobility effect of the selective melatonin receptor antagonist, luzindole, was investigated in the behavioral despair test using three different strains (C3H/HeN, C57BL/6J and albino ND/4) of mice. The time of immobility of the C3H/HeN during the 240 s swimming period measured at noon (12:00 to 14:00 h) was 47.8 +/- 3.0 s (n = 63) and at midnight (00:00 to 02:00 h) was 67.7 +/- 2.8 s (n = 68) (P less than 0.001, when compared with the noon value), when the levels of endogenous melatonin are presumably low and high, respectively. Melatonin (30 mg/kg) given i.p. did not modify the time of immobility at either time of measurement. Luzindole (30 mg/kg i.p.) reduced the time of immobility in a dose-dependent manner, the effect being more pronounced at midnight (60% reduction) than at noon (39% reduction). The effect of luzindole was time-dependent, showing a maximal effect at 60 min. The anti-immobility effect of luzindole (10 mg/kg i.p.) was prevented by the administration of melatonin (30 mg/kg i.p.). Luzindole (30 mg/kg i.p.) did not modify the time of immobility either at noon or midnight in the albino ND/4 mouse, or in the C57BL/6J mouse, which does not produce melatonin. Our results suggest that endogenous melatonin plays a role during swimming in the C3H/HeN mouse behavioral despair test. We conclude that luzindole may exert antidepressant-like activity in the C3H/HeN mouse by antagonizing the action of endogenous hormone.

1 Adult fowls (Gallus domesticus) with cannulae chronically implanted in the IIIrd cerebral ventricle and various other sites of the brain, received infusions or injections of tryptamines and catecholamines into the brain; effects of and interactions between these substances on behaviour, electrocortical activity and body temperature were studied. Reserpine-induced arousal, was investigated in young and adult fowls. 2 Tryptamine and alpha-methyltryptamine, given intraventricularly or into the hypothalamus of intact fowls evoked behavioural and bilateral electrocortical arousal, postural changes, elevation of body temperature and tachypnoea; behavioural and bilateral electrocortical arousal were obtained with infusions into the mesencephalon. Ipsilateral electrocortical arousal only, resulted from infusion of alpha-methyltryptamine into the hypothalamus or mesencephalon of fowl encephale isole preparations. The above effects in intact fowls were reduced or replaced by sleep following administration of noradrenaline or alpha-methylnoradrenaline into the IIIrd ventricle or hypothalamus. Pretreatment of intact fowls with an amine oxidase inhibitor surprisingly attenuated or reversed the excitant effects of intraventricular tryptamine. 3 5-Hydroxytryptamine (hydrogen maleinate, creatinine sulphate or oxalate) given intraventricularly or infused into the hypothalamus, elevated body temperature; tachypnoea and postural changes developed at some stage during the elevation of body temperature. Sleep also was induced, although with the oxalate this was succeeded by marked arousal. 4 Behavioural and electrocortical sleep induced by 5-hydroxytryptamine infused into the hypothalamus were replaced by arousal on infusing tryptamine into the hypothalamus, and vice versa. 5 Dexamphetamine infused into the hypothalamus induced drowsiness or sleep which even reversed arousal elicited by systemically administered dexamphetamine. 6 Reserpine-induced arousal was achieved in young and adult fowls pretreated with mebanazine; this arousal was attenuated or replaced by sleep following intraventricular noradrenaline or dopamine but not by 5-hydroxytryptamine nor by noradrenaline or dopamine applied to the hypothalamus. Prenylamine also induced arousal following pretreatment of chicks with mebanazine.

Ten new compounds, N-aryl substituted piperazinealkylindanes, have been synthesized. The most active one 1-(2-[4-(3-chlorophenyl)-1-piperazinyl]-ethyl)-indane (compound 9), displayed evident central serotoninolytic properties in the 5-hydroxytryptamine (5-HTP) head twitch test in mice, as well as in the tryptamine convulsions test and the quipazine-stimulated hind paw flexor reflex test in rats.

EEG tracings from conscious restrained rabbits were analyzed by inspection and amplitude integration (electrogenesis). Intravenously, tryptamine in doses of 0.1 and 0.5 mg/kg increased electrogenesis, whereas 1 mg/kg initially decreased and subsequently increased electrogenesis. Higher doses (3, 6 and 12 mg/kg) always caused an immediate and dose-dependent decrease in electrogenesis. Neither atropine nor reserpine pretreatment prevented this decrease, whereas chlorpromazine and methysergide abolished it. Intravenous infusions of tryptamine at 1 mg/kg/min caused a nonsignificant increase in electrogenesis but 2 and 4 mg/kg/min infusions caused a sustained decrease. These results show that tryptamine has a biphasic effect on the cortical EEG: low doses enhance synchrony while high doses alert the EEG. Moreover, analysis of the behavioral, EEG and peripheral effects of tryptamine indicate that different sites of action account for the multiple responses observed. Chlorpromazine and methysergide selectively inhibit the exictatory responses.

Competitive and noncompetitive antagonists were used to study the receptors which mediate the contraction elicited by 5-hydroxytryptamine (5-HT) and tryptamine (TRP) in the isolated rabbit aorta. The response to 5-HT was more susceptible to inhibition by competitive antagonists selective for 5-HT receptors, such as cyproheptadine, 5-methylgramine, 5-methoxygramine or 2-bromolysergic acid diethylamide, than was the response to TRP; the estimated apparent dissociation constants (KB value) for each antagonist was significantly lower when 5-HT rather than TRP was the agonist. If either of the two agonists and an antagonist were competing for the same single receptor, the KB value should be independent of the agonist. The 5-HT response was also more sensitive to the noncompetitive antagonist, dibenamine. A noncompetitive antagonist of alpha adrenergic receptors, benextramine tetrahydrochloride monohydrate (BHC), depressed the maximal TRP response 25 to 35% without affecting the 5-HT response. After blockade of alpha adrenergic receptors with BHC, KB values determined for each of the competitive antagonists using either 5-HT or TRP were no longer significantly different. Also after blockade by BHC, TRP and 5-HT responses were now equally sensitive to dibenamine. After adrenergic nerve terminals had been removed by stripping off the adventitia of the aorta, the response to TRP was still partially antagonized by BHC. It is concluded that in this preparation TRP directly activates both alpha adrenergic and 5-HT receptors and the 5-HT response is mediated by the 5-HT receptor with no involvement of alpha receptors.

Four indoleamine antagonists were evaluated for relative potencies as inhibitors of tryptamine-induced forepaw clonus and 5-hydroxytryptophan-evoked head twitches. Methergoline was approximately three times more potent against the forepaw clonus than the head twitch response, whereas methysergide exhibited nearly equal activity in both tests. Cyproheptadine and cinanserin showed a profile opposite to methergoline and a greater degree of selectivity, being 25 to 40 times more potent as inhibitors of the 5-hydroxytryptophan- than of the tryptamine-induced response. These findings clearly demonstrate that the rank order of potency of indoleamine antagonists varies greatly depending upon the test procedure employed.

Tryptamine and 5-HT mediate vasoconstriction in the isolated perfused rat tail artery. These agonists were differentiated by the classical serotonin receptor antagonists methysergide and ketanserin which were significantly more potent against 5-HT-induced responses. Neither prazosin nor RX 781094 alone or in combination reduced the vasoconstriction produced by tryptamine. Tetrahydro-beta-carboline (THBC) was devoid of agonist properties and behaved as a competitive antagonist of tryptamine but not of 5-HT. THBC also had alpha-adrenoceptor blocking properties in this preparation.

Earlier observations have shown that septal lesions released operant responding punished by foot-shock, but did not change behavior punished by electrical stimulation of the dorsal periaqueductal gray (DPAG) substance of the rat brain. In contrast, chlordiazepoxide facilitated both kinds of punished responding. In order to further study the mechanism of brain stimulation punishment, dose-response curves of two minor tranquilizers, chlordiazepoxide and pentobarbital, of two tryptamine antagonists, methysergide and cyproheptadine as well as of amphetamine on lever-pressing behavior of rats maintained by water reinforcement and punished by DPAG stimulation were determined. A multiple schedule with a variable-interval 2 min (VI 2) non-punished component and a continuous reinforcement (CRF) component in which every response was both rewarded and punished was used. Chlordiazepoxide and pentobarbital caused dose-dependent increases in punished responding. Unpunished VI response rates were also moderately increased by the minor tranquilizers. In contrast, neither methysergide nor cyproheptadine increased punished or unpunished responding at doses that have been previously shown to markedly release behavior punished by foot-shock, in the rat. Conversely, amphetamine, a drug that usually does not release responding punished by peripheral noxious stimulation, caused dose-dependent increases in responding suppressed by DPAG punishment without affecting VI response rate. These and previous results with septal lesions suggest that neither the septo-hippocampal system nor its serotonergic input from the mesencephalon mediate response suppression by DPAG electrical stimulation, in contrast to their active role in peripheral punishment. This difference may also explain the marked facilitatory effect of amphetamine on responding punished by brain stimulation shown by the present results.

Tryptamine and 5-hydroxytryptamine (5-HT) infused through the pulmonary circulation of rat isolated lungs released a spasmogen resembling slow reacting substance of anaphylaxis which we have denoted SRS-T and a PGE-like activity. SRS-T was not extractable from Krebs solution by several organic solvents at neutral or acid pH. It is therefore unlike other types of SRS activity. The PGE-like release had a threshold at about 2 microgram/ml of tryptamine or 5-HT and did not increase with increasing doses (up to 10 microgram/ml); this release was abolished by methysergide, BC 105 and BW 501c67 but not by morphine. Comparison of agonist potencies of 5-HT and tryptamine on rat stomach strip and rat pulmonary artery and of antagonist potencies of methysergide, BC 105 and morphine on these tryptamine receptors lead to the conclusion that the release receptors are unlike either of the myotropic receptors. In terms of antagonist specificity the release receptors are closest to those in rat stomach strip.

1-Phenyl-3-(2-thiazolyl)-2-thiourea (200 mg/kg, 1 h) protected the adrenergic nerve plexus in the mouse atrium against the destructive action of i.v. 5,7-dihydroxytryptamine. Protection was also observed with ethanol (4 g/kg, 1 h) and with nialamide (50 mg/kg, 2 h).

This article reviews anti-inflammatory and antihypersensitivity drugs under these 4 headings: Functional or physiological antagonists; Selective pharmacological inhibitors; Broad spectrum anti-inflammatory drugs; Miscellaneous inhibitors. The compounds considered include sympathomimetic amines, anticholinergic drugs, antihistamine drugs, tryptamine antagonists and dopamine antagonists, glucocorticosteroids and non-steroidal anti-inflammatory drugs, disodium cromoglycate and diethylcarbamazine citrate. The relationship of the pharmacological actions of these compounds is considered in the context of clinical conditions. The potential for immunomodulatory pharmacology is discussed using levamisole as an example.

Amitriptyline (AMI) was studied in rats snd mice in order to find out whether it had a central antiserotonin activity, previously demonstrated for doxepin - a compound chemically related to AMI. It was observed that AMI at low doses antagonized the head twitch response to L-5-hydroxytryptophan or 5-methoxytryptamine, as well as tryptamine-induced convulsions. In the hind limb flexor reflex preparation of the spinal rat AMI acted as a serotonin antagonist: when administered alone, it did not change the flexor reflex but prevented its stimulation induced by serotoninmimetics (LSD, quipazine, fenfluramine) not affecting that one evoked by noradrenalinemimetics (clinidine). At higher doses, AMI revealed a noradrenolytic activity. The results indicate that AMI, similarly as doxepin, has a central antiserotonin activity.

Tryptamine and serotonin (5-HT) are relatively potent contractile agonists in the rat fundus, a tissue in which contraction to 5-HT is not mediated by interaction with 5-HT1 or 5-HT2 receptors. The identification of [3H]tryptamine binding sites in the brain and fundus that show high affinity for certain beta-carbolines raised the possibility that 5-HT and tryptamine may be interacting with a similar receptor that is best described as a tryptaminergic receptor in the fundus. The affinity of five 5-HT receptor antagonists, ketanserin, metergoline, 1-(1-naphthyl)piperazine, LY154930 and LY175041 was similar when 5-HT or tryptamine was the agonist, indicating that 5-HT and tryptamine are interacting with the same receptor in the fundus. Furthermore, maximum contractile response to both 5-HT and tryptamine was reduced to the same extent by the calcium channel blocker, diltiazem, and by the calmodulin inhibitor, trifluoperazine. Inasmuch as diltiazem and trifluoperazine did not similarly inhibit contraction to agents interacting with other receptors (i.e., carbamylcholine), these data are consistent with the contention that 5-HT and tryptamine are interacting with the same receptor in the fundus. Consistent with this conclusion is the observation that affinity of the beta-carbolines, harmaline and harmine was also similar when tryptamine or 5-HT was used as the agonist. However, affinity of the beta-carbolines for the tryptamine/5-HT receptor in the fundus was dramatically lower than reported for [3H]tryptamine binding sites in brain membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Tryptamine and its benzo[b]thiophene and 1-methylindole analogues had a lower affinity for receptors in rat stomach fundus strips than did serotonin; the interaction between serotonin and methysergide in this system was competitive, while the interactions between tryptamine and its analogues and methysergide were noncompetitive. In contrast, the affinity of tryptamine and 1-methyl-tryptamine for receptors in rat aorta strips was greater than the affinity for serotonin; all three compounds showed noncompetitive interactions with methysergide. The results support the hypothesis of differing serotonin receptors in the two tissues.

Experiments were performed to examine whether non-hydroxylated tryptamines and 4-chloroamphetamine utilize the membrane 5-hydroxytryptamine carrier to pass into serotoninergic neurones. The accumulation and deamination of 14C-tryptamine by mouse brain slices or homogenates of rat hypothalamus were not inhibited by cocaine or norzimelidine, a selective inhibitor of the neuronal 5-HT uptake. The prevention by alpha-methyltryptamine (10 mg/kg, intraperitoneally), alpha-ethyltryptamine (20 mg/kg intraperitoneally) and 4-chloroamphetamine (20 mg/kg intraperitoneally) of the irreversible inhibtion of monoamine oxidase by pheniprazine (2.5 mg/kg intraperitoneally) and clorgyline (5 mg/kg intraperitoneally) in serotoninergic synaptosomes from mouse brain was not antagonized by pretreatment of the animals with norzimelidine (20 mg/kg intraperitoneally). The partial preventing effect of alpha-ethyl-4-methyl-m-tyramine (H 75/12)(2 X 50 mg/kg intraperitoneally) was, on the other hand, antagonized by norzimelidine. These results do not support the hypothesis that non-hydroxylated tryptamines and 4-chloroamphetamine are transported by the 5-HT carrier.

LSD-25 (32 microgram/kg), d-amphetamine (3.2 mg/kg), and tryptamine (320 to 3200 microgram/kg) given intravenously depressed the response recorded in the visual cortex to electrical stimulation of the optic chiasm of the chloralose anesthetized cat. Relatively large doses of 1 mg/kg of the dibenzothiepin derivatives, methiothepin and octoclothepin, antagonized the depressant effects of both LSD-25 and tryptamine to a greater degree than d-amphetamine.

The selected opioid metenkephalin synthetic peptide analogs Lilly (LY) 127623 and FK 33-824 were tested for behavioral dose effects and potential interaction with N,N-dimethyltryptamine (DMT) and lysergic acid diethylamide-25 (LSD) in adult male Holtzman rats trained on a positive reinforcement fixed-ratio 4 (FR-4) behavioral bar pressing schedule, i.e., a reward of 0.01 ml sugar-sweetened evaporated milk was earned on every fourth bar press. DMT (3.2 mg/kg) and LSD (0.1 mg/kg), administered IP following a 0.9% NaCl 15-20-min control pretreatment, disrupted established food-rewarded FR-4 bar pressing in a consistent and reproducible manner. Animals pretreated IP with predetermined behaviorally noneffective doses of LY 127623 (0.01-0.32 mg/kg) and FK 33-824 (0.001-0.01 mg/kg) 15-20 min prior to receiving DMT demonstrated significant antagonism to DMT-induced disruption of FR-4 bar pressing, while doses of 0.10-0.32 mg/kg LY 127623 and 0.00032-0.0032 mg/kg FK 33-824 significantly antagonized LSD-induced behavioral effects.

A variety of substituent groups has been attached to the exocyclic imine function of 2-imino-3-methylthiazolidine (1) in a search for metabolic precursors of this potent inhibitor of the enzyme indoleethylamine N-methyltransferase (INMT) which would exhibit superior pharmacodynamic properties in animals. It has been determined that chemically stable derivatives of 1 based on succinic, nicotinic, and N-acylated amino acids, although they lack in vitro efficacy, are potent inhibitors of INMT when administered orally or intravenously to rabbits. Metabolic studies carried out with 14C-labeled N,N'-bix(3-methyl-2-thiazolidinylidene)succinamide (3) have established that conversion of this compound to 1 occurs both in the whole rabbit and in the isolated rabbit liver. 1 itself has been shown to be metabolically inert in rabbits, being excreted primarily in the urine.

Experiments have been performed on pentobarbitone anesthetized or decerebrated rats. The nature of the synchronous rhythmical activity which occurs in the inferior olive following the electrophoretic or systemic administration of harmaline, harmine, dihydro-beta-erythroidine and various other compounds, is described. Harmine was shown to reduce the late phase of biphasic unitary action potentials and to evoke massed synchronous rhythmical activity on which the units were superimposed. The beta-carboline was more effective than ACh or DL-homocysteate (DLH) in increasing cell discharge rates. Synchronized rhythmical activity was recorded more than 500 mum from the site of ejection of the rhythm-inducing drugs. Developed rhythmical activity reduced the size of antidromic field potentials, but antidromic invasion could reset the rhythm of submaximal rhythmical activity. The effects of ACh and DLH, glycine, GABA, NA, DA and 5-HT were tested on established rhythmical activity. Of these, 5-HT was the only compound which almost invariably antagonized the rhythm. A number of tryptamine derivatives and reported 5-HT antagonists, as well as parachlorophenylalanine, have been tested, but the results were largely inconclusive. The hypothesis is advanced that the drug-induced rhythm results from the inhibition of a tonic inhibitory serotonergic input. This antagonism releases an innate tendency of olivary cells to discharge both rhythmically and synchronously.

Calves were sensitized with horse plasma (H.P.), 0.2 ml/kg, i.v., and H.P. (0.2 ml/kg) in Freund's complete adjuvant, s.c. The latter injection was repeated 1 week later and the animals were killed 10 days after the second injection. Spirally cut strips of pulmonary artery and vein and the trachealis muscle from the sensitized calves contracted to 5-hydroxytryptamine (5-HT) and specific antigen (horse plasma). Antigen-induced contractions of the pulmonary smooth muscles were significantly blocked (P less than 0.05) by the 5-HT antagonists, methysergide and ketanserin. The trachea, however, appeared less sensitive to the antagonists than the pulmonary vessels. The results suggest that 5-HT participates in the pulmonary anaphylactic reactions of cattle and that ketanserin may be useful in suppressing bovine pulmonary hypersensitivities.

D-Amphetamine (Amph) and p-chloroamphetamine (PCA) induced dose-dependent increases in oropharyngeal myocloniform twitch activity (MTA) in rats anesthetized with urethane. In doses of 80-120 mg/kg, gamma-hydroxybutyric acid (GHB) blocked Amph-induced MTA. The blockade was readily surmountable. Pretreatment with reserpine markedly enhanced the myoclonigenic effect of Amph and rendered it insensitive blockade by GHB, 160 mg/kg. PCA and tryptamine also effectively stimulated MTA, but unlike Amph were antagonized by low doses of the serotonin (5-HT) antagonist methysergide. In doses which blocked Amph, GHB failed to antagonize the myoclonigenic effect of PCA. It is concluded that: (a) the actions of Amph and PCA on MTA is less sensitive to GHB blockade than DA-mediated MTA; and (c) the GHB-Amph antagonism may be of a functional nature, i.e. result from a depression of the firing activity of DA neurons produced by GHB. Since reserpinization abolished the GHB effect on Amph-induced MTA, the functional integrity of granular DA binding and releasing mechanisms appears to be a pre-requisite for the antagonism between GHB and Amph.

The effects of tryptamine on blood glucose levels were studied. Tryptamine induced significant hypoglycemia in mice. The hypoglycemia elicited by tryptamine was strongly antagonized by methysergide, an antagonist of both 5-HT1 and 5-HT2 receptors. A 5-HT2 receptor antagonist, ketanserin, partially inhibited the tryptamine-induced hypoglycemia. These results suggest that tryptamine-induced hypoglycemia is mediated by 5-HT1 and 5-HT2 receptors.

1-Pyridyl-3,4-dihydro-beta-carbolines (2a-2f) were synthesized by two methods. The central action of these compounds was investigated in mice and rats using behavioral tests. The most active 6-methoxy-1-(3-pyridyl)-3,4-dihydro-beta-carboline (2e) possesses potential antidepressant properties, as it reversed the effects of reserpine (sedation, hypothermia and ptosis), potentiated the stimulation induced by levodopa given jointly with pargyline, and reduced the immobility time in the despair test. Moreover, compound 2e inhibited the spontaneous locomotor activity, evoked tremor and produced an analgesic effect.

In helically-cut strips of cerebral arteries isolated from dogs, serotonin, tryptamine, 5-hydroxytryptophan and tryptophan caused a dose-related contraction. The potency was in the order of serotonin greater than tryptamine much greater than 5-hydroxytryptophan = tryptophan. In femoral arterial strips, only serotonin and tryptamine produced contractions. In cerebral arteries, the dose-response curve for serotonin was shifted to the right and downward by treatment with cinanserin, whereas in femoral and mesenteric arteries, the curves were shifted to the right. The contractile response of cerebral arteries to tryptamine was attenuated by cinanserin in concentrations above 10(-7) M; however, 10(-5) M was required to significantly reduce the response of femoral arteries. Phentolamine reduced the contractile response of femoral arteries to tryptamine, but not the response of cerebral arteries. It may be concluded that the different antagonism of cinanserin against the serotonin action on cerebral and femoral arteries is due to the ability of high concentrations of serotonin to induce relaxations of cerebral but not femoral arteries or to the different nature of receptors. Tryptamine appears to elicit contractions of cerebral arteries via a stimulation of tryptamine receptors, but elicit those of femoral arteries via stimulation of both alpha-adrenergic and tryptamine receptors. Whether or not receptors for serotonin and tryptamine are the same was not determined.

The effects of various neuroleptics were studied on N, N-dimethyltryptamine (DMT, 3.2 mg/kg) and d-amphetamine (3.2 mg/kg) induced hyperthermia in the rabbit. Complete dose-effect curves were obtained. The order of potency for antagonism of DMT-induced hyperthermia was: methiothepin greater than octoclothepin greater than or equal to oxyprothepin greater than perathiepin greater than dokloxythepin greater than mianserine greater than loxapine greater than oxypertine greater than chlorpromazine greater than pipamperone greater than fluphenazine greater than thiothixene greater than haloperidol greater than molindone. The order of potency for antagonism of d-amphetamine hyperthermia was: haloperidol greater than chlorpromazine greater than oxypertine greater than octoclothepin and methiothepin. For these five drugs, the order of potency for antagonism of amphetamine hyperthermia was the reverse of the order for antagonism of DMT hyperthermia. Methiothepin reduced d-amphetamine-induced hyperthermia effectively at a very high dose (0.32 mg/kg) and variably at lower doses. The results indicate that neuroleptics differ markedly in their specificity of antagonism of DMT and d-amphetamine which may act through different neurotransmitter mechanisms (tryptaminergic vs. adrenergic).

1. Methylation of tryptamine in the 1-position had little effect on the potency of the drug as a pressor agent in the intact anaesthetized rat. 2. In contrast, substitution of a benzo[b]thiophene ring system for the indole ring decreased the pressor activity. 3. Pretreatment of the animals with reserpine reduced the pressor effect of tryptamine and its benzo[b]thiophene analogue while increasing the effect of the 1-methylindole analogue. 4. Pretreatment with phenoxybenzamine reduced the pressor effect of all three compounds.

In order to investigate the role played by serotonergic mechanisms in self-stimulation (SS) behavior, the effects of two tryptamine antagonists, cyproheptadine and methysergide on SS were measured. Also the influence of antitryptaminic drug pre-treatment on the facilitatory effect of amphetamine, a pro-adrenergic drug, on SS was studied. Rats with brain electrodes permanently implanted at the lateral hypothalamus and trained to lever-press for response-contingent brain electric stimulus presentation were used. Stimulus current was maintained at threshold level. Both tryptamine antagonists used potentiated the enhancing effect of amphetamine on low SS rates, displacing to the left its dose-effect curve; cyproheptadine was at least three times more potent than methysergide. In addition, cyproheptadine, but not methysergide, caused dose-related increases in SS rate, when given alone. These results suggest that brain serotonergic systems play an inhibitory role in SS, opposing the facilitatory influence of adrenergic mechanisms.