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At least 685 records · Page 38Linked to original sources

PubMed1988

Stimulation of serum cortisol and prolactin secretion in humans by MK-212, a centrally active serotonin agonist.

The effects of MK-212 [6-chloro-2-(1-piperazinyl)-pyrazine] (10, 20, and 40 mg, orally), a centrally acting serotonin (5-HT) receptor agonist and placebo, on serum cortisol, prolactin, and growth hormone levels were studied in eight healthy men over 3-hr. MK-212 produced a dose-related increase in serum cortisol levels, with the 20- and 40-mg doses producing significant elevations. Serum prolactin levels were significantly elevated only by the 40-mg dose. Serum GH levels were not significantly modified by any dose of MK-212. The cortisol and prolactin responses to the 40-mg dose of MK-212 were positively correlated (rho = + 0.85, p less than 0.02). MK-212 was generally well tolerated by the subjects. Headache and nausea were observed at the higher doses, but did not appear to be related to the increase in serum cortisol and prolactin levels. MK-212 may stimulate the secretion of cortisol and prolactin in humans via a serotonin (5-HT2) receptor mechanism and may be a valuable tool with which to study 5-HT receptor sensitivity in humans.

Adult↗

PubMed1991

Neuroendocrine responses to serotonergic agents in alcoholics.

Previous studies have suggested a possible deficit in serotonergic function in alcoholism. In order to further assess the serotonergic system in alcoholism, the plasma cortisol and prolactin (PRL) responses following 6-chloro-2-[1-piperazinyl]pyrazine (MK-212), a direct-acting serotonin2 (5-HT2)/5-HT1c receptor agonist, L-5-hydroxytryptophan (L-5-HTP), a precursor of 5-HT, and placebo were compared in male alcoholics and normal controls. The increase in plasma cortisol following L-5-HTP was significantly lower in the alcoholic subjects compared with the normal controls. The plasma PRL, but not the plasma cortisol response, following MK-212 was also significantly lower in the alcoholics. L-5-HTP had no significant effect on plasma PRL levels in either group. The basal plasma cortisol and PRL concentrations of the alcoholics and normal controls were not significantly different. These data are consistent with previous reports of a serotonergic abnormality in alcoholism.

5-Hydroxytryptophan↗

PubMed1992

Effect of cocaine injections on the neuroendocrine response to the serotonin agonist MK-212.

This study was undertaken to examine whether several of the hormones that can be released by activation of serotonin receptors will be affected by long-term cocaine administration. Male rats received cocaine injections (15 mg/kg, IP) twice daily for 7 days. Forty-two hr after the last cocaine injection, the rats were challenged with increasing doses (0, 1, 5, 10 mg/kg, IP) of the 5-HT1/5-HT2 agonist MK-212 (6-chloro-2-[1-piper-azinyl]-pyrazine). The following observations were made: (1) cocaine reduced the rate of body weight gain; (2) cocaine inhibited the stimulatory effect of MK-212 on plasma vasopressin, oxytocin, and prolactin concentrations and on plasma renin activity and concentration; (3) cocaine did not inhibit the stimulatory effect of MK-212 on plasma ACTH or corticosterone concentrations. The data indicate that a wide-spectrum 5-HT (serotonin) agonist such as MK-212 can reveal differential neuroendocrine responses. This effect could be related to cocaine-induced changes in the different 5-HT receptor subtypes that regulate the secretion of these hormones.

Adrenocorticotropic Hormone↗

PubMed1992

Effect of the serotonin agonist, MK-212, on body temperature in schizophrenia.

The effects of 6-chloro-2-(1-piperaziny)pyrazine (MK-212), a centrally acting 5-HT1C/5-HT2 agonist, on body temperature and behavior were assessed using a single-blind cross-over design in 23 schizophrenic patients and 22 normal controls. Body temperature was assessed before drug administration and at 30-min intervals for 3 hr. Each subject was administered placebo or MK-212. MK-212 significantly elevated temperature in normal controls. There was no overall MK-212-induced increase in temperature compared to placebo in the schizophrenic patients; however, 13 of 23 (56.5%) patients had a larger increase in temperature after MK-212 than placebo, 3 of 23 (13.1%) had no change, whereas the temperature change after placebo was greater than after MK-212 in 7 of 23 (30.4%) patients. MK-212 produced significant increases in nausea, feeling strange, and arousal but these effects did not differ between groups. These results are consistent with decreased 5-HT2 receptor responsivity in some patients with schizophrenia.

Adult↗

PubMed1982

Serotonin-like actions of quipazine and CPP on spinal motoneurones.

The actions of iontophoretically applied quipazine (QPZ) and 6-chloro-2-[1-piperazinyl]-pyrazine (CPP) were compared with those of serotonin (5-HT) on rat spinal motoneurones. QPZ and CPP qualitatively resembled 5-HT in that both facilitated single unit activity evoked by glutamate. Like 5-HT, the facilitation they produced could be antagonized by metergoline or methysergide. These observations are compatible with the suggestion that the actions of QPZ and CPP are mediated by 5-HT receptors. In rats pretreated with the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), QPZ and CPP remained effective in facilitating the glutamate evoked activity, whereas p-chloroamphetamine (PCA), a known releaser of 5-HT, was without effect. In contrast, PCA produced a long lasting facilitation in untreated rats. These data, taken together, suggest that QPZ and CPP are direct agonists at 5-HT receptors, but do not preclude the possibility that they might also act indirectly.

5,7-Dihydroxytryptamine↗

PubMed1987

Stimulation of corticosterone and beta-endorphin secretion in the rat by selective 5-HT receptor subtype activation.

Changes in plasma concentrations of corticosterone and beta-endorphin (beta-END) were determined in male rats after treatment with the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) or the non-selective 5-HT agonist 6-chloro-2-(1-piperazinyl)pyrazine (MK-212). The administration of either 8-OH-DPAT or MK-212 increased plasma concentrations of both corticosterone and beta-END in a dose-related manner. The corticosterone and beta-END responses to 8-OH-DPAT were antagonized by spiperone and (-)-pindolol, both of which have been shown to have high affinity for the 5-HT1A binding site. In contrast, antagonist which are selective for the 5-HT2 receptor or non-selective 5-HT antagonists were without effect on the hormone responses to 8-OH-DPAT. The MK-212-induced increase in plasma concentrations of corticosterone and beta-END were not affected by treatment with the 5-HT1A antagonists spiperone and (-)-pindolol. However, the corticosterone and beta-END responses to MK-212 were attenuated by the selective 5-HT2 antagonists ketanserin, ritanserin and altanserin, as well as by the non-selective 5-HT antagonist metergoline. It is concluded that stimulation of either 5-HT1A or 5-HT2 receptors results in an activation of the hypothalamic-pituitary-adrenal axis in the rat.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1994

Involvement of the 5-HT2 receptor in the 5-HT receptor-mediated stimulation of prolactin release.

The present study examined the involvement of 5-HT1C and 5-HT2 receptors in the regulation of prolactin release in the rat. Both the mixed 5-HT2/5-HT1C receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), and the preferential 5-HT1C agonist, 2-chloro-6-(1-piperazinyl)pyrazine monohydrochloride (MK-212), elicited a significant increase in plasma prolactin concentration with DOI about 20 times more potent than MK-212. Treatment with DOI, but not with MK-212, induced head twitching in the rat, and this behavior was inhibited by both the mixed 5-HT2/5-HT1C receptor antagonist, ritanserin, and the selective 5-HT2 receptor antagonist, amperozide. DOI-induced prolactin release was also antagonized by ritanserin and amperozide, whereas only ritanserin affected MK-212-induced prolactin release. Furthermore, amperozide did not attenuate d-fenfluramine-elicited prolactin release, which is known to be antagonized by ritanserin. These data suggest that the pharmacological stimulation of prolactin release by DOI is mediated via the 5-HT2 receptor and that the 5-HT1C receptor may be of importance for the physiological regulation of prolactin release.

Amphetamines↗

PubMed1996

Effect of cystathionine as a scavenger of superoxide generated from human leukocytes or derived from xanthine oxidase in vitro.

We studied the direct effects of cystathionine on human leukocyte-generated or xanthine-xanthine oxidase-derived superoxide radicals in vitro. Washed leukocyte suspensions (10(6) cells/ml) prepared from healthy male volunteers were stimulated with phorbol myristate acetate (1 mu M) or opsonized zymosan (1 mg/ml) to generate superoxide radicals, which were measured with a 2-methyl-6-[p-methoxyphenyl]-3,7-dihydroimidazo[1,2-alpha] pyrazin-3-one hydrochloride (MCLA)-chemiluminescence method. Cystathionine (30 mu M to 10 mM) significantly reduced superoxide radical-dependent chemiluminescence in the leukocyte system in a concentration-dependent manner. In addition, in the two different methods of determination of superoxide radicals (MCLA chemiluminescence and nitroblue tetrazolium reduction), cystathionine significantly scavenged the superoxide radicals derived from the xanthine-xanthine oxidase system. However, cystathionine did not inhibit the activity of xanthine oxidase during superoxide generation. On the other hand, cystathionine did not show a scavenging effect against hydroxyl radicals derived from Fe2+ -H2O2 on the erythrocyte membrane. These results indicate that cystathionine itself may possess a scavenging function against superoxide radicals rather than against hydroxyl radicals in vitro.

Cystathionine↗

PubMed1996

Modulation of 5-HT receptor subtype-mediated behaviours by corticosterone.

Malfunction of the serotonergic system and dysregulation of the hypothalamo-pituitary-adrenocortical axis have been implicated in the pathophysiology of depression. Several studies provide evidence for reciprocal influences between glucocorticoids and 5-HT receptors. The effect of repeated treatment with a high dose of corticosterone (50 mg/kg s.c. twice daily for 4 days) on 5-HT receptor subtype-mediated behaviours was studied. It was found that in rats that were repeatedly treated with corticosterone the number of 2-chloro-6-(1-piperazinyl)pyrazine HCl (MK 212)-induced, 5-HT2C receptor-mediated penile erections were reduced, whereas both MK 212 and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced 5-HT2A receptor-mediated head shakes were increased. The (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)-induced lower lip retraction mediated by presynaptic 5-HT1A receptors was unchanged, whereas the open field activity induced by 8-OH-DPAT was enhanced in corticosterone pretreated rats. These changes in 5-HT receptor subtype-mediated behaviours were not seen after a single injection with corticosterone given 24 h or 5 days before. The results suggest that 5-HT2A, 5-HT2C and postsynaptic 5-HT1A receptor-mediated behaviour can be modulated by repeated treatment with a high dose of corticosterone.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1996

Involvement of 5-HT2A receptors in the elevation of rat serum corticosterone concentrations by quipazine and MK-212.

The possible involvement of 5-HT2A or 5-HT2C receptors in the elevation of serum corticosterone in rats by quipazine (2-(1-piperazinyl)quinoline maleate) and MK-212 (6-chloro-(1-piperazinyl)pyrazine), direct-acting 5-HT receptor agonists, was investigated by the use of two newly available receptor antagonists, SB 200646A (N-(1-methyl-5-indolyl)-N'-(3-pyridyl)urea) and MDL 100,907 (R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]- 4-piperidinemethanol). MDL 100,907 blocked the increase in serum corticosterone elicited by quipazine and MK-212 with ED50 values of 0.0028 and 0.0027 mg/kg, s.c., respectively. In contrast, SB 200646A only partially antagonized the serum corticosterone concentration increases by quipazine and MK-212 even at the highest dose tested, 40 mg/kg, i.p. Because published data show the affinities of MDL 100,907 and SB 200646A for 5-HT2C receptors to be nearly identical, whereas the affinity of MDL 100,907 for 5-HT2A receptors is 17500-fold higher than that of SB 200646A, our findings suggest that 5-HT2A receptors rather than 5-HT2C receptors mediate the serum corticosterone increases by both quipazine and MK-212.

Animals↗

PubMed1994

Antiplatelet structure-activity relationship of tetramethylpyrazine.

Tetramethylpyrazine (TMPZ) is an active component of certain plants previously found to have inhibitory effects on platelet function using both in vivo and in vitro assays(1). In this study, we examined the antiplatelet activity of structural analogues of TMPZ in order to assess structural requirements for activity. Functional requirements included nitrogen substitutions on the aromatic ring; substitutions could be either heterocyclic or ring substituted in the meta position. Enhanced antiplatelet activity was associated with increasing the number of alkyl groups on the pyrazine ring as well as increasing the length of unbranched alkyl side chains. Increased inhibition of platelet aggregation correlated with increased lipophilicity of the compounds tested. In addition, several compounds were identified which deserve further pharmacological investigation.

Aminopyridines↗

PubMed1990

Effects of an alpha 2-adrenoceptor antagonist on glucose tolerance in the genetically obese mouse (C57BL/6J ob/ob).

This study examines the effects of a relatively selective alpha 2-adrenoceptor antagonist, 8-(L-piperazinyl)imado-[1,2-alpha] pyrazine (compound A), and the preferential alpha 2-agonist clonidine on blood glucose, glucose tolerance, and plasma insulin levels in the C57BL/6J ob/ob mouse and its lean littermate. While clonidine raised blood glucose levels and impaired glucose tolerance, oral administration of compound A resulted in decreased blood glucose levels, as well as improved glucose tolerance in ob/ob mice. Insulin levels in ob/ob mice treated with clonidine were significantly reduced, while compound A raised insulin levels threefold and blocked the effects of clonidine when co-administered to the same animals. Clonidine-induced hyperglycemia in lean littermates was not accompanied by a decrease in insulin levels, while a small but significant increase in insulin levels was observed by compound A administration. Glycogen synthesis in diaphragm of ob/ob mice was enhanced after oral administration of compound A and was accompanied by an increase in plasma insulin levels. Concomitant treatment with a potent somatostatin analog to inhibit insulin release blocked the effects of the alpha 2-adrenoceptor antagonist, compound A. These observations suggest that the alpha 2-antagonist studied, increased plasma insulin levels with an accompanying reduction in blood glucose and an improvement in glucose tolerance in a genetic model of insulin resistance. Differential sensitivity to alpha 2-agonist in these genetically obese mice, ob/ob, was demonstrated by decreased insulin levels due to clonidine administration.

Administration, Oral↗

PubMed1984

A comparative electrophysiological and biochemical assessment of serotonin (5-HT) and a novel 5-HT agonist (MK-212) on central serotonergic receptors.

The inhibitory effects of microiontophoretically-applied serotonin (5-HT) and 6-chloro-2[1-piperazinyl]pyrazine (MK-212) were examined on spontaneously firing somatosensory cerebral cortical neurons and dorsal raphe neurons in rats anesthetized with chloral hydrate. On cortical neurons, MK-212 caused only weak and variable inhibition of extracellularly recorded neuronal activity, compared to the effects of 5-HT. However, on raphe cells, MK-212 exerted potent inhibitory effects, equivalent to those observed with 5-HT. In contrast to the inhibitory actions of D-lysergic acid diethylamide (LSD) and 5-HT at presumed 5-HT autoreceptors, MK-212 did not affect the in vitro release of [3H]5-HT from slices of rat hypothalamus stimulated by methiothepin. These findings, coupled with previously reported behavioral, biochemical and electrophysiological effects of MK-212 may indicate that this novel serotonergic agonist uniquely discriminates between subsets of serotonergic receptors in the CNS.

Action Potentials↗

PubMed1986

Thermoregulatory responses to serotonin (5-HT) receptor stimulation in the rat. Evidence for opposing roles of 5-HT2 and 5-HT1A receptors.

The effects of serotonergic agonists and antagonists on the body temperatures of rats were investigated. The administration of the serotonin (5-HT) agonist 6-chloro-2(1-piperazinyl)-pyrazine (MK-212) produced a dose-related increase in body temperature. A maximal increase in body temperature of approx. 1.1 degrees C was observed 30 min after the administration of 3 mg/kg of MK-212. In contrast, administration of the putative 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) resulted in marked, dose-related hypothermic responses. Body temperatures were decreased approx. 3 degrees C 30 min after an injection of 0.3 mg/kg of 8-OH-DPAT. Body temperatures were affected differentially by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). Large doses (3-10 mg/kg) of 5-MeODMT elicited hyperthermic responses, whereas small doses (0.5-1.0 mg/kg) produced hypothermic responses. Treatment of rats with ketanserin (3 mg/kg) completely prevented the hyperthermic effects of 5-MeODMT, and, in fact, converted a hyperthermic response to 5-MeODMT into a marked hypothermic response. Ketanserin (0.1-1.0 mg/kg) selectively antagonized the hyperthermic response to MK-212 but did not alter the hypothermic effect of 8-OH-DPAT. Mianserin (10 mg/kg) and pirenperone (0.03 mg/kg) also selectively antagonized hyperthermia induced by MK-212. In contrast, pindolol (0.03-0.1 mg/kg) and methiothepin (10 mg/kg) selectively antagonized hypothermia induced by 8-OH-DPAT but did not alter hyperthermia induced by MK-212. Spiperone (0.1-3 mg/kg) and pizotifen (10 mg/kg) attenuated the effects of both 8-OH-DPAT and MK-212. Xylamidine, a peripheral 5-HT antagonist, had no significant effect on hyperthermia induced by MK-212 or hypothermia induced by 8-OH-DPAT.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1987

Selective desensitization of serotonin (5-HT) receptor-mediated hyperthermia by mianserin and other 5-HT antagonists.

Hyperthermic responses to 6-chloro-2-(1-piperazinyl)-pyrazine (MK-212) and hypothermic responses to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were assessed in rats as an in vivo index of the responsiveness of 5-HT2 and 5-HT1A receptors, respectively. Forty-eight hours after a single injection of mianserin, there was a shift to the right in the dose-response relationship for MK-212-induced hyperthermia. The hyperthermic response to MK-212 was attenuated 1 hr and 48 hr (but not 8, 24 or 96 hr) after the administration of mianserin. The hyperthermic effect of 5-methoxy-N,N-dimethyltryptamine (5MeODMT) also was diminished 48 hr after administration of mianserin. However, mianserin did not alter the hypothermic response to 8-OH-DPAT. A diminished hyperthermic effect of MK-212 also was observed 48 hr after a single injection of loxapine, methysergide, pizotifen and ketanserin. It is concluded that there is a selective decrease in the responsiveness of the 5-HT2 receptors mediating MK-212-induced hyperthermia, 48 hr after a single injection of mianserin or other selected 5-HT antagonists. Moreover, MK-212-induced hyperthermia appears to be a functional measure of the reported decrease in the number of 5-HT2 receptors, 48 hr after a single injection of mianserin.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1989

Apparent antinociceptive properties of piperazine-type serotonin agonists: trifluoromethylphenylpiperazine, chlorophenylpiperazine, and MK-212.

Squirrel monkeys were studied under a titration procedure in which responding adjusted the intensity of an electrical stimulus delivered to the tail (0.1-3.3 mA range in 15 steps). The 5-HT agonists trifluoromethylphenylpiperazine (TFMPP), chlorophenylpiperazine (mCPP), and 6-chloro-2(1-piperazinyl)pyrazine (MK-212) increased the intensity at which shock was maintained. The order of potency was: MK-212 greater than mCPP greater than TFMPP. Reductions in absolute rates of responding were small, and not related systematically to increases in shock intensity. Pretreatment with the nonselective 5-HT antagonist methysergide (0.1-1.0 mg/kg) resulted in a 3- to 10-fold shift to the right of the dose-effect curves for the 5-HT agonists. In contrast, the selective 5-HT2 antagonists ketanserin (0.3-1.7 mg/kg) and pirenperone (0.001-0.1 mg/kg) did not alter the effects of these agonists. This suggests that the apparent antinociceptive actions of these 5-HT agonists are probably mediated by effects at the 5-HT1 receptor subtype.

Animals↗

PubMed1990

Effects of serotonin agonists on operant behavior in the squirrel monkey: quipazine, MK-212, trifluoromethylphenylpiperazine, and chlorophenylpiperazine.

The behavior of squirrel monkeys was studied under fixed-interval (FI) schedules with responding maintained either by food presentation or by termination of stimuli correlated with impending electric shock delivery (stimulus-shock termination). The 5-HT agonists m-trifluoromethylphenylpiperazine (TFMPP), m-chlorophenylpiperazine (mCPP), and 6-chloro-2(l-piperazinyl)pyrazine (MK-212) decreased responding under both the food and shock schedules (0.3-5.6 mg/kg). These decreases in responding were blocked by the nonselective 5-HT antagonists methysergide and mianserin (0.3, 1.0 mg/kg), but not by the selective 5-HT2 antagonists ketanserin (0.3-1.7 mg/kg) or pirenperone (0.001-0.1 mg/kg). Quipazine (0.3-5.6 mg/kg) decreased responding under the food schedule, and this effect was blocked by both the nonselective and selective 5-HT2 antagonists. This pattern of antagonism suggests that the decreases in responding produced by quipazine involve significant actions at 5-HT2 sites, whereas those produced by TFMPP, mCPP, and MK-212 do not. In contrast to the decreases in responding seen with the food schedules, quipazine produced moderate increases in responding under the shock schedules. Moreover, these increases in responding were not blocked by methysergide or mianserin, but instead were enhanced. The results with antagonists suggest that certain behavioral effects of quipazine are probably due to actions at 5-HT2 sites, whereas similar effects of TFMPP, mCPP, and MK-212 are more related to actions at other 5-HT receptor subtypes.

Animals↗

PubMed1993

Discriminative stimulus properties of m-chlorophenylpiperazine.

Stimulus control was established in a group of 10 rats using a dose of m-chlorophenylpiperazine (MCPP) of 0.8 mg/kg, administered IP, 15 min before training. A two-lever operant task using a fixed-ratio 10 schedule of sweetened milk reinforcement was used. Based upon a criterion for the presence of stimulus control of five consecutive sessions during which 83% or more of all responses were on the appropriate lever, a mean of 27 sessions was required to reach criterion performance. Response rates were significantly suppressed by the training dose of MCPP (14 responses/min) as compared with saline sessions (38 responses/min). Subsequent to the establishment of stimulus control, tests of generalization were conducted with m-trifluoromethylphenylpiperazine (TFMPP), 6-chloro-2-(1-piperazinyl)-pyrazine (MK-212), and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU-24969). MCPP generalized completely to MK-212 and TFMPP at doses of the latter drugs of 0.7 and 1.0 mg/kg, respectively. Maximum generalization to RU-24969 was 67% at a dose of 1.0 mg/kg but only 4 of 10 subjects completed the test session. The present results indicate that MCPP is efficacious as a discriminative stimulus. In addition, because of MCPP's relative selectivity for the 5-hydroxytryptamine c(5-HT1C) receptor subjects trained with MCPP may prove valuable in assessing the respective functional contributions of 5-HT1C sites to the actions of a variety of serotonergic agents.

Animals↗