piperidines and pirenperone

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is caused by the loss of Fragile X-linked mental retardation protein (FMRP), an RNA binding protein that can bind and recognize different RNA structures and regulate the target mRNAs' translation involved in neuronal synaptic plasticity. Perturbations of this gene expression network have been related to abnormal behavioral symptoms such as hyperactivity, and impulsivity. Considering the roles of FMRP in the modulation of mRNA translation, we investigated the differentially expressed genes which might be targeted to revert to normal and ameliorate behavioral symptoms. Gene expression data was analyzed and used the connectivity map (CMap) to understand the changes in gene expression in FXS and predict the effective drug candidates. We analyzed the GSE7329 dataset that had 15 control and 8 FXS patients' lymphoblastoid samples. Among 924 genes, 42 genes were selected as signatures for CMap analysis, and 24 associated drugs were found. Pirenperone was selected as a potential drug candidate for FXS for its possible antipsychotic effect. Treatment of pirenperone increased the expression level of Fmr1 gene. Moreover, pirenperone rescued the behavioral deficits in Fmr1 KO mice including hyperactivity, spatial memory, and impulsivity. These results suggest that pirenperone is a new drug candidate for FXS, which should be verified in future studies.

Topics: Animals; Disease Models, Animal; Fragile X Mental Retardation Protein; Fragile X Syndrome; Mice; Mice, Knockout; Neuronal Plasticity; Piperidines

Spontaneous isometric contractions were measured in rings of sheep mesenteric lymphatic vessels in vitro. 5-Hydroxytryptamine (5-HT) produced a concentration-dependent decrease in spontaneous contraction frequency and force which was not antagonised by either the nonspecific 5-HT(1)/5-HT(2) receptor antagonist methysergide (1 microM) or the 5-HT(3) receptor antagonist ondansetron (1 microM). The 5-HT(4) receptor agonist BIMU-8 mimicked the inhibitory effect of 5-HT and its effects were abolished by the 5-HT(4) receptor antagonist DAU 6285 (1 microM). DAU-6285 also abolished the inhibitory effect of 5-HT and unmasked a weak excitatory response, which was mimicked by the 5-HT(2) receptor agonist alpha-methyl-5-hydroxytryptamine maleate. This excitatory response was, in turn, blocked by the 5-HT(2) receptor antagonist pirenperone (1 microM). The results of this study suggest that sheep mesenteric lymphatics possess both 5-HT(4) receptors and 5-HT(2) receptors. The inhibitory 5-HT(4) receptor appeared to be the predominant subtype since the excitatory response to 5-HT could only be observed in the presence of the 5-HT(4) receptor antagonist DAU 6285.

Topics: Animals; Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; In Vitro Techniques; Isometric Contraction; Lymphatic System; Methysergide; Muscle, Smooth; Ondansetron; Piperidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sheep

Stimulus control was established in a group of nine rats using a dose of EGb 761 of 10 mg/kg, administered i.p., 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 24 sessions was required to reach criterion performance. Subsequently, it was observed that EGb 761-induced stimulus control is significantly antagonized by the selective 5-HT1A antagonist WAY-100635, but is unaffected by the 5-HT2 antagonist pirenperone. Furthermore, EGb 761 generalized to the selective 5-HT1A agonist, 8-hydroxy-dipropylaminotetralin [8-OH-DPAT], and this generalization was blocked by WAY-100635. The present results indicate that EGb 761 is able to induce stimulus control when administered via the intraperitoneal route, and that its stimulus effects are mediated in part by activity at the 5-HT1A receptor.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Discrimination, Psychological; Dose-Response Relationship, Drug; Flavonoids; Ginkgo biloba; Injections, Intraperitoneal; Male; Piperazines; Piperidines; Plant Extracts; Plants, Medicinal; Pyridines; Rats; Rats, Inbred F344; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Reinforcement Schedule; Serotonin Antagonists; Serotonin Receptor Agonists

Action potential duration (APD) lengthening is believed to underlie the cardiac arrhythmogenicity of ketanserin, a serotonin (5-HT)2A/2C receptor antagonist. We wished to determine (a) whether this activity involves blockade of 5-HT2A/2C receptors and (b) the precise mechanism of ketanserin-induced APD prolongation. APs were recorded in guinea pig isolated papillary muscles by conventional "floating" microelectrodes, and potassium currents in guinea pig isolated myocytes were recorded in the whole-cell configuration. Ketanserin (1-10 microM) increased APD (EC50 value for enhancing APD at 90% repolarization (APD90) 3.1 +/- 2.7 microM, n = 24), without affecting resting potential, maximum upstroke velocity (Vmax) or AP amplitude (APA). Pirenperone (10 microM), a ketanserin congener, similarly increased APD90 from 204 +/- 3 to 241 +/- 7 ms (p < 0.001, n = 6). No increase in APD was observed, however, with ritanserin or ICI 170809, even at high concentrations (10 microM, n = 6, respectively), two 5-HT2A/2C receptor antagonists chemically distinct from ketanserin, thereby excluding the involvement of 5-HT2A/2C receptors in mediating APD lengthening. That APD prolongation was mediated specifically by the benzolyl-piperidine moiety of ketanserin and pirenperone was confirmed by 1-propyl-4(4-fluorobenzoyl)piperidine (PFBP), which evoked APD lengthening effects remarkably similar to those produced by ketanserin and pirenperone (EC50 3.73 +/- 2.6 microM, n = 12). In isolated cardiomyocytes, ketanserin (1-32 microM) selectively and concentration-dependently reduced the IKr component of the delayed outward current (IK) without affecting the inward rectifier current, IK1. Thus, ketanserin (32 microM) significantly reduced IK at a potential value of -20 mV from 813 +/- 65 to 569 +/- 55 pA (p < 0.001, n = 6), whereas at a potential value of -110 mV, IK1 was not significantly affected (730 +/- 103 vs. 603 +/- 143 pA, respectively; n=6). The results demonstrate that APD is prolonged by ketanserin and congeners but not be chemically different 5-HT2A/2C receptor antagonists. The benzoyl-piperidine moiety appears to mediate the APD-prolonging effects of ketanserin and pirenperone specifically. Furthermore, ketanserin-induced APD lengthening does not appear to involve 5-HT2A/2C receptors but is consecutive to direct blockade of myocardial potassium channels.

Topics: Action Potentials; Amphetamines; Animals; Guinea Pigs; Heart; Ketanserin; Male; Piperidines; Potassium Channels; Serotonin Antagonists

The results of studies on mice indicate that the antinociceptive effects of kappa-opioid agonists are due, in part, to activation of the 5-HT2 type of serotonin receptor. One objective of this study was to determine if the discriminative effects of spiradoline, a kappa-opioid agonist, are mediated by 5-HT2 receptors in rats also. A second objective was to confirm findings that dopamine receptor antagonists produce spiradoline-like discriminative effects (Ohno et al., 1992). Rats were trained to discriminate between spiradoline (3.0 mg/kg) and saline in a discrete-trial avoidance/escape procedure. In subsequent tests of stimulus generalization, the discriminative effects of spiradoline were not mimicked by fenfluramine (0.3-10 mg/kg) or fluoxetine (1.0-10 mg/kg), drugs that enhance serotonergically mediated neurotransmission, nor were they blocked by the 5-HT2 antagonists pirenperone (0.01-1.0 mg/kg) and ketanserin (0.1-10 mg/kg), or potentiated by fluoxetine pretreatment. Neither the dopamine receptor antagonists haloperidol (0.01-0.3 mg/kg) and sulpiride (3.0-100 mg/kg) nor the agonists apomorphine (0.03-0.3 mg/kg) and d-amphetamine (0.1-3.0 mg/kg) engendered spiradoline-like discriminative effects. These results demonstrate further the pharmacological specificity of the discriminative effects of spiradoline, but provide no evidence for mediation by serotonergic or dopaminergic systems.

Topics: Analgesics; Animals; Avoidance Learning; Biogenic Monoamines; Discrimination, Psychological; Dopamine Antagonists; Fenfluramine; Fluoxetine; Generalization, Stimulus; Ketanserin; Male; Piperidines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Selective Serotonin Reuptake Inhibitors; Serotonin; Synaptic Transmission

The kappa opioid, U50,488, was examined alone and in combination with the 5HT2 antagonists, ketanserin, pirenperone and LY 53857. Squirrel monkeys responded under a shock titration procedure in which shock intensity increased every 15 s from 0.01 to 2.0 mA in 30 steps. Five responses terminated the shock for 15 s, after which the shock resumed at the next lower intensity. The level at which the monkeys kept the shock 50% of the time (median shock level/MSL) was determined. U50,488 alone produced dose-dependent increases in median shock level whereas none of the 5-HT2 antagonists altered responding under this procedure. When ketanserin (0.032-5.6 mg/kg) was administered in combination with U50,488, very high doses of ketanserin (3.2-5.6 mg/kg) shifted the U50,488 dose-effect curve to the left. Neither pirenperone (0.032-10.0 micrograms/kg) nor LY53857 (0.01-0.32 mg/kg) altered the U50,488 dose-effect curve in any monkey. Taken together, these data do not support a role for the 5-HT2 system in kappa-induced antinociception in the primate.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Ergolines; Ketanserin; Male; Piperidines; Pyrrolidines; Receptors, Opioid, kappa; Saimiri; Serotonin Antagonists

The administration of 5-methoxy-N,N-di-methyl-tryptamine (5-MeODMT), O-2.0 mg.kg-1 SC -15 min, produced a dose-dependent facilitation of the male rat sexual behavior, as evidenced by a decrease in the number of intromissions to ejaculation and in the ejaculation latency. The effects produced by 5-MeODMT (1 mg.kg-1) were antagonized by pindolol (4 mg.kg-1 SC -30 min), but not pirenperone (0.25 mg.kg-1 SC -30 min) or metergoline (1 mg.kg-1 SC -30 min), administration. As expected, 5-HTP (25 mg.kg-1 SC -60 min) produced an increased number of mounts and intromissions to ejaculation and an increase in the ejaculation latency in benserazide (25 mg.kg-1 SC -90 min) pretreated animals. Pindolol (4 mg.kg-1) by itself produced the same effects as seen after 5-HTP administration, and the combination of these compounds produced additive effects. Betaxolol (8 mg.kg-1 SC -30 min) had no effects of its own and did not interact with 5-HTP. The results suggest that stimulation of brain 5-HT1 or 5-HT2 receptors produces facilitation and inhibition, respectively, of the male rat sexual behavior.

Topics: 5-Hydroxytryptophan; Adrenergic beta-Antagonists; Animals; Benserazide; Betaxolol; Dose-Response Relationship, Drug; Female; Male; Metergoline; Methoxydimethyltryptamines; Pindolol; Piperidines; Rats; Rats, Inbred Strains; Sexual Behavior, Animal; Stimulation, Chemical

The effects of the 5-HT2 receptor antagonists pirenperone, cinanserin and ritanserin on impairment of working memory in an animal model of cerebral ischemia were investigated, using a three-panel runway task. A 5-min period of ischemia caused a significant increase in the number of errors (attempts to pass through two incorrect panels of the 3 panel gates at 4 choice points). Pirenperone at 0.32 and 1.0 mg/kg, cinanserin 10 mg/kg and ritanserin 3.2 mg/kg administered i.p. immediately after blood flow reperfusion significantly reduced the increase in errors expected to occur 24 h after the 5 min of ischemia. These results suggest that the blockade of 5-HT2 receptors prevents the impairment of working memory following transient forebrain ischemia.

Topics: Animals; Cinanserin; Ischemic Attack, Transient; Male; Memory; Piperidines; Rats; Rats, Inbred Strains; Ritanserin; Serotonin Antagonists

Cognitive deficits resulting from neuropathological brain changes such as Alzheimer's Disease or normal aging are most likely due to alterations in multiple neurotransmitter systems. While the majority of preclinical studies have focused on the effects of acetylcholine (ACh), it has been shown that activation of the serotonergic (5-HT) pathways in the central nervous system interferes with passive avoidance retention in rats. In contrast, decreased 5-HT activity has been shown to improve learning and memory in rats using similar procedures. In the present experiment, 5-HT antagonists were evaluated for their effects on performance in a delayed match to sample task (DMTS) in two groups of squirrel monkeys: one in which the baseline level of performance was low (less than 65% correct, N = 5; group 1) and another in which DMTS performance was high (greater than 80% correct, N = 3; group 2) but impaired by exposure to hypoxia. Initial parametric tests exposing group 2 to various levels of oxygen deprivation were conducted to determine optimal conditions for performance deficits. Each monkey in both normoxia (group 1) and hypoxia (group 2) served as his own control and received an individualized range of doses for each test compound. For both groups, ketanserin and mianserin, the 5-HT2-selective antagonists, produced dose-dependent increases in DMTS performance at 0.3-1.5 mg/kg PO and 0.05-1.5 mg/kg PO, respectively. Pirenperone, another 5-HT2-selective antagonist, was active in improving performance in group 1 at 0.001 to 0.2 mg/kg PO but was not effective against hypoxia-induced performance deficits.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Avoidance Learning; Cognition; Dose-Response Relationship, Drug; Hypoxia; Ketanserin; Male; Memory; Mianserin; Piperidines; Psychomotor Performance; Reinforcement Schedule; Saimiri; Serotonin Antagonists

Relatively little is known regarding the role of 5-HT2 receptor activity in male rat sexual behavior. Previous work has yielded equivocal results, and both facilitation and inhibition of copulation have been reported to follow administration of selective 5-HT2 antagonists. In the present series of experiments, the ability of a variety of 5-HT2 antagonists to block inhibition induced by the 5-HT2/5-HT1C agonist DOI was examined. Systemic ritanserin, pirenperone and ketanserin all potently blocked DOI-induced (1.0 mg/kg SC) inhibition of mounts, intromissions and ejaculations. None of these drugs influenced the sexual behavior of the male rats when given alone in doses that effectively blocked DOI-induced inhibition. In addition, unlike ritanserin and ketanserin, pirenperone produced a biphasic effect on DOI-induced inhibition, exhibiting a diminished blockade at higher doses. This may be due to activity at receptors other than 5-HT2. Overall, the present data suggest that activity at 5-HT2 receptors mediates an inhibition of male rat sexual behavior.

Topics: Amphetamines; Animals; Copulation; Ejaculation; Female; Ketanserin; Male; Piperidines; Rats; Rats, Inbred Strains; Ritanserin; Serotonin Antagonists; Tranquilizing Agents

The selective serotonin type-2 (S2) receptor blocker pirenperone (0.24 mg/kg, SC) attenuates morphine-produced tail-flick antinociception in intact rats, but not in rats with transected spinal cords. These results suggest that S2 receptor blockade does not affect intraspinal opioid antinociception. Together with evidence that there are virtually no S2 receptors in the dorsal spinal cord, supraspinal S2 receptors are implicated in the mediation of morphine-produced antinociception.

Topics: Analgesics; Animals; Male; Morphine; Nociceptors; Piperidines; Rats; Reaction Time; Spinal Cord

Methylxanthines produce a quasi-morphine withdrawal syndrome (QMWS) in opiate naive rats. Additionally, methylxanthine-induced suppression of conditioned behavior in rats is reversed by the alpha 2 adrenergic agonist clonidine which also attenuates true opiate withdrawal and the QMWS. Therefore, the operant behavioral effects of 3-isobutyl-1-methylxanthine (IBMX) provide a model with which to study mechanisms involved in the expression of opiate withdrawal. In order to examine the role of serotonin (5-HT) in the rate-decreasing effects of IBMX on operant behavior, the 5-HT precursor 5-hydroxytryptophan, and 5-HT reuptake blocker fluoxetine were administered in combination with IBMX to rats performing a fixed-ratio 30 operant for food reinforcement. Both drugs failed to reverse the behavioral suppression caused by relatively low doses of IBMX, suggesting that elevated 5-HT neurotransmission contributes to, rather than attenuates, the QMWS. The relatively selective 5-HT2 antagonists mianserin and pirenperone blocked the IBMX-induced suppression, whereas the classic 5-HT antagonist methysergide had no effect. The results indicate that the operant behavioral effects of IBMX and possibly the QMWS may be mediated by serotonergic mechanisms.

Topics: 1-Methyl-3-isobutylxanthine; 5-Hydroxytryptophan; Animals; Fluoxetine; Male; Methysergide; Mianserin; Morphine; Piperidines; Rats; Serotonin; Serotonin Antagonists; Substance Withdrawal Syndrome

5-Hydroxy-L-tryptophan (5-HTP), 25 mg kg-1 IP, in combination with the peripheral 5-HTP decarboxylase inhibitor benserazide, 25 mg kg-1 IP, and the selective inhibitor of neuronal 5-hydroxytryptamine (5-HT) re-uptake, zimeldine, 10 mg kg-1 IP, suppressed lordosis in ovariectomized female rats, treated with estradiol benzoate (EB) or with EB plus progesterone (P). The suppression of lordosis produced by 5-HTP was antagonized by the beta-receptor blocker (-)pindolol, which also is a selective 5-HT1 receptor antagonist, but not by the 5-HT2 receptor antagonists metitepine or pirenperone, nor by the beta-receptor blocker betaxolol. The EB- or EB plus P-activated lordosis was also suppressed by administration of the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Together, these observations indicate an important role of central 5-HT1A receptors in the mediation of lordosis behavior in the female rat.

Topics: 5-Hydroxytryptophan; 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Betaxolol; Estradiol; Female; Male; Methiothepin; Pindolol; Piperidines; Posture; Propanolamines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Sexual Behavior, Animal; Tetrahydronaphthalenes

Experiments were designed to distinguish between central and peripheral effects on temperature preference and body temperature of drugs injected intraperitoneally (IP) in infant mice ranging in age from 3 to 10 days postpartum. These compared a drug restricted to the periphery ("peripheral" drug) with a drug of similar action that reaches the central nervous system (CNS) as well as the periphery. Two different classes of drugs were utilized to test central versus peripheral actions independently with drugs that have different modes of action: 1-aromatic amino acid inhibitors and serotonin receptor antagonists. Although the decarboxylase inhibitor NSD 1015, which reaches the central nervous system from IP injection, can significantly decrease temperature preference (Tpref), the peripheral inhibitor carbidopa had no significant effects on Tpref or on body temperature (Tb). Furthermore, pretreatment with NSD 1015 prevented the elevation of Tpref produced by the serotonin precursor 5-hydroxytryptophan (5-HTP); however carbidopa pretreatment had no effect on the increased Tpref produced by 5-HTP. In other experiments, the peripheral serotonin antagonist BW 501C was not able to prevent elevated Tpref produced by 5-HTP, although the specific 5-HT2 antagonist pirenperone, which reaches the CNS as well as the periphery, blocks the 5-HTP elevation of Tpref. Taking all of these results together, we conclude that the changes in Tb and Tpref following these treatments require a decarboxylase inhibitor or 5-HT antagonist that reaches the CNS. However, the well known and potent peripheral vasoconstrictor action of serotonin requires that peripheral effects of drugs be considered when manipulations are not restricted to the CNS.

Topics: 5-Hydroxytryptophan; Aging; Amidines; Animals; Behavior, Animal; Body Temperature; Body Temperature Regulation; Carbidopa; Carboxy-Lyases; Central Nervous System; Double-Blind Method; Drug Interactions; Hydrazines; Injections, Intraperitoneal; Mice; Peripheral Nerves; Piperidines; Serotonin Antagonists

Acute exposure to continuous (CCWS) or intermittent (ICWS) cold-water swims elicits non-opioid and opioid forms of analgesia respectively. Intrathecal administration of methysergide blocks ICWS, but not CCWS analgesia. The present study evaluated the role of serotonin (5-HT) receptor subtypes in the mediation of CCWS and ICWS analgesia on the tail-flick and jump tests following administration of methysergide, a non-specific 5-HT antagonist and pirenpirone and ketanserin, two 5-HT2 receptor subtype antagonists. Systemic methysergide was more effective in reducing CCWS analgesia (50-58%, 0.1-1.0 mg/kg) than ICWS analgesia (21%, 5 mg/kg) on both pain tests. Systemic pirenpirone (0.04-0.2 mg/kg) and ketanserin (1-5 mg/kg) were also more effective in reducing CCWS analgesia (43-57%) on both tests than ICWS analgesia (pirenpirone: 0.4 mg/kg, 34%; ketanserin: 5 mg/kg, 21%) on the tail-flick test. Indeed, both 5-HT2 receptor antagonists potentiated ICWS analgesia on the jump test. While serotonin antagonist effects upon hypothermia could not account for CCWS analgesia effects, similar potentiations in ICWS analgesia and hypothermia were observed following pirenpirone and ketanserin. Finally, both 5-HT2 receptor antagonists differentially reduced CCWS hypothermia and potentiated ICWS hypothermia. These data suggest differential serotonergic modulation of the two forms of swim analgesia with opioid-mediated ICWS analgesia acting through spinal 5-HT1 receptors and non-opioid-mediated CCWS analgesia acting through supraspinal 5-HT2 receptors.

Topics: Analgesia; Endorphins; Ketanserin; Methysergide; Physical Exertion; Piperidines; Receptors, Serotonin; Serotonin Antagonists

The present studies have attempted to evaluate the role of 5-HT2 receptors in the regulation of sexual behavior of male rats by determining the effects of 5-HT2 receptor antagonists, pirenperone, LY53857 and LY281067, and a 5-HT2 receptor agonist, DOI. The administration of 1 mg/kg s.c. pirenperone produced a total suppression of ejaculatory response and lower doses had no effect. However, the administration 0.1 mg/kg s.c. of either LY53857 or LY281067 restored ejaculatory capacity to rats that were unable to ejaculate and produced significant decreases in ejaculatory latency in rats with full sexual capacity. Although all of these agents are 5-HT2 antagonists, LY53857 and LY281067 lack the additional monoaminergic activity of pirenperone. Since the effects of pirenperone were opposite from the effects of the selective 5-HT2 antagonists, the suppressive effects of this agent were probably related to its other monoaminergic activity e.g. alpha 1 antagonist activity. This proposal was supported by the observation that the administration of prazosin, an alpha 1 antagonist, significantly increased ejaculatory latency and suppressed the stimulatory effects of LY53857. In contrast to the stimulatory effects of the selective 5-HT2 antagonists, the administration of DOI, resulted in a suppression of sexual performance, which was blocked by pretreatment with LY53857.

Topics: Amphetamines; Animals; Copulation; Ejaculation; Ergolines; Female; Lysergic Acid; Male; Piperidines; Prazosin; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin Antagonists; Sexual Behavior, Animal

Alpha-melanocyte stimulating hormone (MSH) has been found to exert a short- and a long-term inhibitory action on lordosis. The present series of experiments examined the possibility that these effects are mediated by MSH-induced alterations in activity at serotonin type II receptors. In Experiment 1, quipazine (serotonin type II agonist) was found to significantly attenuate the short-term effect of MSH while only partially attenuating the long-term action of MSH. In the second experiment, doses of MSH and of pirenperone (serotonin type II antagonist) that did not inhibit lordotic responding when administered alone were found to inhibit responding when administered together. It was also found that 20 ng MSH produced a long-term, but not a short-term inhibition of receptivity. The results of Experiment 3 indicated that the inhibition observed in Experiment 2 could be reversed by quipazine. These results suggest that alterations in serotonin activity are one mechanism by which the effects of MSH are produced. The relevance of this to the regulation of reproductive states is discussed.

Topics: alpha-MSH; Animals; Female; Piperidines; Quipazine; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Sexual Behavior, Animal

The involvement of serotonin type-2 (S2) receptors in morphine-induced analgesia was assessed by challenging the effect of 10 mg/kg of morphine sulphate (IP) with the S2 receptor blockers, pirenperone and ketanserin. Tail-flick latencies were assessed at 0, 30, 60, 90 and 120 min after injections by measuring the time that it took each rat to remove its tail from a 52 degrees C water bath. Pirenperone, at 0.08, 0.16, and 0.24 mg/kg (SC) attenuated morphine-induced antinociception. In contrast, only the high 10 mg/kg (SC) dose of ketanserin attenuated the effect of morphine. Because pirenperone easily enters the central nervous system whereas ketanserin does not, these results indicate the involvement of central S2 receptors in morphine-induced antinociception. The 10 mg/kg dose of ketanserin, however, did not attenuate the antinociception produced by 100 mg/kg of ketamine. Thus, the antianalgesic effect of S2 receptor blockers may be specific to opioid-mediated analgesia.

Topics: Analgesia; Animals; Dose-Response Relationship, Drug; Ketamine; Ketanserin; Male; Morphine; Piperidines; Rats; Reaction Time; Receptors, Serotonin; Serotonin Antagonists

The present study was designed to examine the possible involvement of both an anti-serotonin action and a catecholamine-stimulating action in the mechanism of the inhibition of the muricide in rats with lesions of the midbrain raphe. Serotonin antagonists, such as cyproheptadine (10 mg/kg), cinanserin (10 mg/kg) and pirenperone (1 mg/kg), given alone showed little suppression of muricide in rats with raphe lesions, although the first two drugs were inhibitory at very large doses. Methamphetamine showed no inhibition of muricide at 0.32 mg/kg (i.p.), but exerted a marked inhibition of muricide when combined with the above serotonin antagonists. In addition, the dose-response curve for cyproheptadine and cinanserin was shifted markedly to the left when combined with L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) (100 mg/kg i.p.), but not with lisuride (0.32 mg/kg i.p.). Similarly, pirenperone produced a marked inhibition of muricide at doses of 0.32-1.8 mg/kg (i.p.) when combined with L-threo-DOPS, but not when combined with lisuride. These results suggest that the combination of an anti-serotonin action with noradrenergic activation is important for inhibiting muricide, at least in rats with raphe lesions. A similar mechanism also seems to be valid for the anti-muricidal effect of antidepressant drugs.

Topics: Aggression; Animals; Catecholamines; Cinanserin; Dose-Response Relationship, Drug; Drug Interactions; Male; Methamphetamine; Norepinephrine; Piperidines; Raphe Nuclei; Rats; Rats, Inbred Strains; Serotonin Antagonists

The present series of experiments examined the effects of pretreating pirenperone-injected mice with a variety of non-serotonergic receptor antagonists on retrieval of a one-trial inhibitory (passive) avoidance task. Water-deprived mice were trained to avoid drinking from a water spout located in the avoidance chamber by pairing foot-shock with licks from the water spout. Retention was measured as the suppression of drinking (latency to drink) 48 h later. Pre-test administration of pirenperone (1.0 mg/kg) significantly enhanced retrieval (increased latencies). The suppression of drinking could not be attributed to the non-specific effects of pirenperone on behavior in general, as the performance of non-contigently shocked mice injected with the same dose of pirenperone did not exhibit a similar elevation in latencies. Of the seven pretreatment drugs examined, only phenoxybenzamine (1.0 mg/kg) completely blocked the pirenperone-induced response. Bicuculline (1.0 mg/kg) partially attenuated the enhanced performance resulting from pre-test pirenperone administration. The results suggest that the pirenperone-induced response may be partly due to activation of noradrenergic (alpha) neurotransmission.

Topics: Animals; Avoidance Learning; Bicuculline; Brain; Haloperidol; Male; Memory; Mental Recall; Mice; Mice, Inbred Strains; Phenoxybenzamine; Piperidines; Propranolol; Receptors, Adrenergic; Receptors, Serotonin; Retention, Psychology; Scopolamine; Synaptic Transmission; Tranquilizing Agents

The behaviorally disruptive effects of the optical isomers of 1-(3,4-methylenedioxyphenyl-2-aminopropane) (MDA) and its N-methyl derivative (MDMA) were evaluated in 27 mice trained to bar-press for a liquid food reinforcement. In addition, a second study was conducted in which mice were pretreated with either saline or the 5-HT-2 antagonist, pirenpirone, prior to the administration of either MDMA or MDA using the same behavioral procedure. The results indicated that the behaviorally disruptive effects produced only by R(-)-MDA, but not those of S(+)-MDA, R(-)-MDA, nor of S(+)-MDMA, were significantly attenuated by pirenpirone. These findings support previous research findings which indicate that this isomer may be producing its behaviorally disruptive effects via an action on 5-HT-2 receptors.

Topics: 3,4-Methylenedioxyamphetamine; Amphetamines; Animals; Conditioning, Operant; Drug Combinations; Isomerism; Mice; N-Methyl-3,4-methylenedioxyamphetamine; Piperidines; Serotonin Antagonists

The effect of the selective 5-HT3 receptor antagonists ICS 205-930 and MDL 72222 on head shaking behavior induced by L-5-HTP and behavioral symptoms induced with 5-methoxy-N,N,-dimethyltryptamine (5-MeODMT) in rats was evaluated. Both drugs dose-dependently reduced L-5-HTP-induced head shaking but were at least 600 times less potent than pirenperone and ketanserin and at least 50 times less potent than methysergide. ICS 205-930 and MDL 72222 were more than 1000 times less potent than pirenperone or methysergide and 100 times less potent than ketanserin in blocking 5-MeODMT-induced forepaw treading and tremor. Since it appears that head shakes induced by L-5-HTP are mediated by 5-HT2 receptors, these data suggest that ICS 205-930 and MDL 72222 do not significantly interact with 5-HT2 receptors in the brain. Furthermore, the data suggest that ICS 205-930 and MDL 72222 lack appreciable antagonistic activity at the 5-HT receptor(s) mediating those behavioral effects induced by 5-MeODMT.

Topics: 5-Hydroxytryptophan; Animals; Behavior, Animal; Indoles; Male; Methoxydimethyltryptamines; Methysergide; Piperidines; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists; Tranquilizing Agents; Tropanes; Tropisetron

The induction of penile erections by a variety of compounds with a direct or indirect effect on serotonin (5HT) receptors was investigated in rats. L-5-Hydroxy-tryptophan (L-5HTP) induced penile erections when co-administered with nialamide and the peripheral decarboxylase inhibitor benserazide, indicating that the site of action for inducing penile erections is within the central nervous system. Penile erections were also induced by the 5HT uptake inhibitors zimelidine, fluoxetine, citalopram, Org 6997, by the 5HT-releasing agent fenfluramine and by the putative 5-HT1B receptor agonist 1-(3'-chlorophenyl)-piperazine (mCPP). The 5HT1A-agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) did not induce penile erections. The less selective 5HT receptor agonists 5-methoxy-N,N-dimethyl-tryptamine (5MeODMT), 5-methoxytryptamine (5MeOT), dl-lysergic acid diethylamide (LSD) and Ru 24969 were also ineffective. Induction of penile erections by quipazine appeared only when this compound was co-administered with the 5HT2 receptor antagonist pirenperone. Receptor antagonists were tested against penile erections induced by Org 6997. The beta-adrenoceptor antagonists that also have 5HT1 antagonistic properties, (S)-pindolol and dl-propranolol, antagonized Org 6997-induced penile erections but butoxamine and metoprolol did not. Spiperone and pirenperone in doses selective for 5HT1A and 5HT2 receptors respectively were also inactive. Haloperidol, 0.46 mg/kg, partially attenuated penile erections induction. The data are discussed in the light of the hypothesis that penile erections induction by serotonin-mimetic compounds is mediated by 5HT1B receptors in the striatum.

Topics: 5-Hydroxytryptophan; Animals; Apomorphine; Benserazide; Haloperidol; Male; Nialamide; Penile Erection; Piperidines; Propranolol; Quipazine; Rats; Rats, Inbred Strains; Receptors, Serotonin; Tranquilizing Agents

Although the discriminative stimulus effects of the clinically useful ergot derivative lisuride have previously been related to dopamine (DA) neuronal systems, the involvement of DA D1 and D2 receptor subtypes in the lisuride cue has been characterized for the first time in the present experiment. In rats trained to discriminate lisuride (0.04 mg/kg) from saline, appropriate doses of the putative D2 agonist LY 171555 (0.008-0.063 mg/kg) substituted completely whereas the D1 agonist SKF 38393 (2.0-16.0 mg/kg) evoked primarily saline-lever responding. When given in combination with lisuride (0.04 mg/kg), the D2 antagonist (-)-sulpiride (5-30 mg/kg), but not the D1 antagonist SCH 23390 (0.125-0.5 mg/kg), blocked the lisuride cue. Combination tests also suggested that bromuride and pirenperone have DA antagonist properties. Although the specificity of these agents is not fully known, these results support the conclusion that D2 but not D1 receptors play an important role in the stimulus effects of lisuride. Although a role for serotonin in the similar stimulus properties of lisuride and SCH 23390 cannot be ruled out, partial substitution of SCH 23390 (0.0625-0.35 mg/kg; administered alone) for lisuride complements previous observations which suggest that the two DA subtypes may be functionally linked in vivo.

Topics: Animals; Benzazepines; Discrimination Learning; Ergolines; Lisuride; Male; Neurons; Piperidines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Sulpiride

The behavioural effects of intravenously administered tryptamine were examined in mice. Tryptamine in a dose greater than 15 mg/kg induced distinct head-weaving and hindlimb abduction. These behavioural syndromes appeared immediately after the injection and disappeared within 3 min. The changes in time course of the behaviour induced by tryptamine were consistent with those of the levels of tryptamine in the brain. Pretreatment with p-chlorophenylalanine, a depleter of 5-hydroxytryptamine (5-HT), failed to alter the effects of tryptamine on head-weaving or hindlimb abduction but did result in head-twitches which were never seen after tryptamine alone. Metergoline strongly antagonized the behavior induced by tryptamine. Pirenperone and haloperidol inhibited the behavioural syndrome, antagonizing the head-weaving in particular. alpha-Methyl-p-tyrosine, a depleter of dopamine, reduced the head-weaving without affecting the hindlimb abduction. These results indicate that the 5-HT syndrome induced by intravenous administration of tryptamine is due to the direct effect of tryptamine on the 5-HT receptor. Tryptamine-induced behaviour, especially head-weaving, seems to be linked with dopaminergic neurones.

Topics: Animals; Behavior, Animal; Brain; Dopamine; Haloperidol; Indoleacetic Acids; Metergoline; Mice; Piperidines; Receptors, Serotonin; Serotonin; Tryptamines

The effects of the 5-HT2 antagonist pirenperone on temperature preference were observed 1 hr after injection in mice aged 3, 5 and 7 days and at doses of 0.16, 0.48 and 1.6 mg/kg body weight. Although all 3 doses produced significant decreases in preferred temperature at 3 days, only the highest dose had significant effects at ages 5 and 7 days. Analysis of the data suggests that the dose-response relationship depends on age in a way that would be consistent with a shift in the dose-response curve with increasing age.

Topics: Aging; Animals; Behavior, Animal; Choice Behavior; Dose-Response Relationship, Drug; Mice; Piperidines

Thermoregulatory effects of the selective 5-HT2 antagonist pirenperone were studied 1 hr after IP injection in mice aged 1, 3, 5, 7 and 10 days postpartum. Compared with vehicle injected littermates, a dose of 0.16 mg/kg decreased temperature preference (T pref) on a thermal gradient at all ages. No significant effects were observed on body temperature (Tb) at any of the ages. An increased dose (0.48 mg/kg) caused no greater effect on T pref and no significant effect on Tb. These results indicate that Tb and T pref are separable on the basis of receptor pharmacology, and are discussed in relation to drug effects on 5-HT2 receptors.

Topics: Animals; Animals, Newborn; Body Temperature; Mice; Mice, Inbred Strains; Piperidines; Thermosensing

The experiments examined the effects of acute administration of three different serotonergic receptor antagonists (ketanserin, pirenperone and mianserin) on one-trial passive avoidance retention in mice. Administration of each antagonist 30 min before training produced a dose-dependent impairment in retention. In contrast, administration of each of the antagonists immediately after training produced a dose-dependent improvement in retention. The time-dependent effects of pre- and post-train antagonist administration were assessed using pirenperone. In both cases, the effects on test performance were determined to be time-dependent. The results provide additional evidence suggestive of a differential role of the serotonergic nervous system in the processes underlying learning and memory.

Topics: Animals; Avoidance Learning; Ketanserin; Male; Memory; Mianserin; Mice; Piperidines; Receptors, Serotonin; Retention, Psychology; Serotonin Antagonists; Time Factors

The capacity of the putative S2 serotonin receptor antagonists, pirenperone, pipamperone, ketanserin and cinanserin, to block the myoclonic syndrome produced by 30 mg/kg of L-5-hydroxytryptophan (5-HTP) [after lesioning 5-hydroxytryptamine (serotonin, 5-HT)-containing neurons with 5,7-dihydroxytryptamine (DHT)] or 15 mg/kg of fenfluramine (FF) or p-chloroamphetamine (PCA) was tested in adult male Sprague-Dawley rats. S2 antagonists inhibited limb (arrhythmic and asynchronous) and axial (truncal) myoclonus in a dose-dependent manner in the rank order of potency: pirenperone greater than pipamperone greater than ketanserin = cinanserin. Abnormal movements (myoclonus, lateral head weaving) of the myoclonic syndromes were better antagonized than postural abnormalities (hindlimb abduction, hunching of back). Centrally acting drugs, selective for S2 receptors (pirenperone, pipamperone), exhibited greater antimyoclonic properties than the non-selective 5-HT antagonist methysergide, which was as effective as ketanserin and cinanserin. Significant non-specific reduction in myoclonus without the improvement of other behavioral responses followed treatment with sedative/neuroleptic drugs, such as haloperidol (but not the non-neuroleptic dopamine antagonist sulpiride), clonazepam and diazepam. The anticonvulsants valproic acid (100 and 300 mg/kg), adrenocorticotrophic hormone (ACTH; 100 and 300 U/kg), diphenylhydantoin (15 mg/kg), and phenobarbital (20 mg/kg) and drugs which do not act principally at S2 receptors were ineffective in these models. These data support the hypothesis that myoclonus in behavioral models induced by 5-HT is S2 receptor mediated. S2 antagonists could have a role in the treatment of human myoclonus.

Topics: 5-Hydroxytryptophan; Animals; Brain Chemistry; Butyrophenones; Cinanserin; Ketanserin; Male; Myoclonus; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin Antagonists

A series of 11 agents was analyzed at both 5-hydroxytryptamine1A (5-HT1A) sites labeled by [3H]-8-hydroxy-2-(N,N-dipropylamino)tetralin and total 5-HT1 binding sites labeled by [3H]-5-HT in rat brain membranes. Three distinct patterns of relative inhibition were noted. First, drugs such as 8-hydroxy-2-(N,N-dipropylamino)tetralin n-(3-acetylaminophenyl)piperazine hydrochloride, 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]-1,2-benziso-thiazol-3 -(2H)one-1,1-dioxidehydrochloride] and buspirone display 1.0 to 15 nM potency for the 5-HT1A subpopulation of 5-HT1 binding sites but are more than two orders of magnitude less potent at total 5-HT1 sites. Secondly, 5-methoxy-N,N-dimethyltryptamine and methysergide are approximately one order of magnitude more potent at 5-HT1A than total 5-HT1 sites. In the third group, 5-HT, d-lysergic acid diethylamide, 1-(m-trifluoromethylphenyl)piperazine, 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyrimidinyl) 1H indole, quipazine and pirenperone are essentially equipotent at both 5-HT1A and 5-HT1 sites. Thus, the 5-HT1A binding site has a pharmacological profile which, depending on the agents studied, could be significantly different from the pharmacological profile derived from total 5-HT1 binding. Drug interactions were also analyzed with canine basilar artery segments using 5-HT, 10 putative serotonergic agonists and a selective 5-HT2 antagonist, pirenperone. The maximal contraction was obtained using 5-HT (Cmax = 6.6 +/- 0.6 g). However, each of the 10 other putative 5-HT agonists elicited a less forceful contraction of the canine basilar artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Basilar Artery; Dogs; Dose-Response Relationship, Drug; In Vitro Techniques; Kinetics; Lysergic Acid Diethylamide; Piperidines; Rats; Receptors, Serotonin; Serotonin; Spiperone; Tetrahydronaphthalenes; Tritium; Vasoconstriction

Serotonin (5-HT) induces inositol phosphate production and the efflux of 45Ca2+ in a smooth muscle cell line (A7r5) derived from rat aorta. These effects were pharmacologically characterised and compared to data obtained in radioligand binding studies performed with the 5-HT2 ligand [3H]ketanserin in rat brain cortex membranes. 5-HT causes in increase in the levels of inositol trisphosphate (InsP3), inositol bisphosphate (InsP2) and inositol phosphate (InsP1). InsP3 production was rapid and transient whereas InsP1 accumulated in a time and concentration dependent manner. The 5-HT stimulated InsP1 accumulation (pEC50 = 6.48) was potently and competitively inhibited by the 5-HT2 specific antagonists, pirenperone and ketanserin, whereas antagonists of other 5-HT receptors were active only at high concentrations. There was a significant correlation between inhibition of 5-HT stimulated InsP1 accumulation and 5-HT2 binding (r = 0.98, P = 0.0035). 5-HT stimulated the efflux of 45Ca2+ from preloaded cells with a pEC50 of 7.59. The rank order of potency for agonist induced Ca2+ efflux, 5-HT greater than alpha-methyl-5-HT greater than 1-methyl-5-HT greater than RU 24969 (5-methoxy-3[1,2,3,6,-tetrahydropyridin-4-yl]-1-H indole) greater than 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)-tetralin) greater than 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)-tetralin) greater than 5-CT (5-carboxamidotryptamine) is typical for a 5-HT2 receptor mediated event. The effect of 5-HT was competitively blocked by ketanserin (pA2 = 8.22).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aorta; Calcium; Cell Line; Cerebral Cortex; Inositol Phosphates; Ketanserin; Kinetics; Muscle, Smooth, Vascular; Piperidines; Rats; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Sugar Phosphates; Time Factors

The beta-carboline harmine was found to facilitate lordosis behavior in ovariectomized rats primed with estradiol benzoate. Moreover, harmine reversed the inhibition of lordosis by the serotonin type 2 (5-HT2) antagonists pirenperone and ketanserin in rats primed with estradiol benzoate and progesterone. These results suggest that harmine facilitates lordosis by enhancing activity at 5-HT2 receptors.

Topics: Alkaloids; Animals; Estradiol; Female; Harmine; Ketanserin; Ovariectomy; Piperidines; Posture; Progesterone; Rats; Rats, Inbred Strains; Receptors, Serotonin; Sexual Behavior, Animal

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)

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Body Temperature Regulation; Ketanserin; Male; Methoxydimethyltryptamines; Pindolol; Piperidines; Pyrazines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Spiperone; Tetrahydronaphthalenes

Pirenperone, a new serotonin antagonist with a selective affinity for the 5-HT2 receptor, was administered in conjunction with tests for the antinociceptive effects of morphine sulphate and electrical brain-stimulation at sites in the periaqueductal gray (PAG) and nucleus raphe magnus (NRM). Nociception was assessed by tail-flick latencies in a warm water bath and pirenperone (0.04-0.16 mg/kg) had no effect on baseline scores. When administered prior to morphine, pirenperone (0.16 mg/kg) caused significant attenuation of analgesia induced by morphine. Comparable effects of pirenperone were observed when analgesia was produced by electrical stimulation of the NRM. In contrast, pirenperone had no effect on the analgesic effects of PAG stimulation. This pattern of results suggests that a system involving supraspinal 5-HT2 receptors may modulate some of the antinociceptive effects of morphine and stimulation of the NRM. The differential effects of pirenperone on stimulation-produced analgesia at sites in the NRM and PAG is consistent with separate neural substrates for the analgesia observed from stimulation of these two brain regions.

Topics: Animals; Central Nervous System; Electric Stimulation Therapy; Male; Morphine; Neural Pathways; Pain; Pain Management; Periaqueductal Gray; Piperidines; Raphe Nuclei; Rats; Reaction Time; Receptors, Serotonin

Rats were trained to discriminate between the stimulus properties of 0.6 mg/kg l-cathinone and its vehicle in a two-lever, food-motivated operant task. Once trained, rats showed a dose-dependent decrease in discrimination performance with lower l-cathinone doses and analysis of the dose-response relationship indicated an ED50 of 0.19 mg/kg. Administration of either dl-or d-cathinone produced a pattern of discriminative responding similar to l-cathinone with ED50s of 0.29 and 0.63 mg/kg, respectively. Thus, the potency of the racemeric cathinone lies approximately midway between that of the two isomers. Time-course data indicate that l-cathinone has a peak effect at 15-30 min post-administration with a duration of 180 min. Pretreatment with the serotonic receptor blocker pirenperone did not affect l-cathinone discrimination, whereas pretreatment with 0.2 mg/kg haloperidol, a dopamine receptor blocking agent, attenuated the l-cathinone discrimination. These data suggest that the stimulus properties of l-cathinone are possibly mediated by brain dopaminergic systems.

Topics: Alkaloids; Animals; Discrimination, Psychological; Dose-Response Relationship, Drug; Generalization, Psychological; Haloperidol; Male; Piperidines; Rats; Rats, Inbred Strains; Stereoisomerism; Time Factors

Genetically obese Zucker rats and their lean littermates were trained to discriminate between the stimulus properties of 2.0 mg/kg fenfluramine and its vehicle in a two-lever, food-motivated operant task. Both groups learned the discrimination at the same rate and all rats showed a dose-related decrease in discriminative performance with lower fenfluramine doses. Analysis of the dose-response curves indicated an ED50 for the obese rats of 0.56 mg/kg and for the lean group of 0.42 mg/kg. Time-course experiments indicted that the obese rats maintain errorless discrimination through 90 min post-injection but discriminate significantly less than the lean rats at 960 min post-administration. These results suggest a similar sensitivity to fenfluramine in obese and lean rats with a difference in the time-course of drug action. Pre-treatment with the specific serotonin receptor antagonist pirenperone significantly attenuated fenfluramine discrimination in lean rats without a similar effect in the obese rats. Possible reasons for this observation are offered.

Topics: Animals; Discrimination Learning; Dose-Response Relationship, Drug; Female; Fenfluramine; Obesity; Piperidines; Rats; Rats, Zucker; Serotonin; Serotonin Antagonists; Time Factors

The involvement of serotonin2 (5-HT2) receptors in the expression of opiate withdrawal was examined using a behavioral test for acute morphine dependence. The 5-HT2 antagonists, ketanserin and pirenperone, injected shortly before naloxone, attenuated the naloxone-induced suppression of an autoshaped lever-touch response in rats treated 4 h earlier with a moderate dose of morphine. A low dose of pirenperone was also effective in blocking withdrawal-induced hypothermia. These data support the hypothesis that 5-HT is involved in the expression of opiate withdrawal.

Topics: Animals; Body Temperature; Conditioning, Operant; Ketanserin; Male; Morphine Dependence; Piperidines; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

The newly synthesized compound and putative 5-HT2 antagonist ritanserin, but not the structurally related compound R 56413, resembles pirenperone in that it acts as a pure antagonist in an LSD-saline drug discrimination assay in the rat. Ritanserin exceeded pirenperone in terms of behavioral specificity; the lowest effective dose of ritanserin in antagonizing LSD was one order of magnitude higher than that of pirenperone, but the compound depressed rate of operant responding only at doses that were about 1000-fold higher than those at which pirenperone was effective. Ritanserin exerted effects in an open field test which were reminiscent of anxiolytic drug activity in the rat; its effects were greater than those of pirenperone, R 56413 and the benzodiazepines chlordiazepoxide and diazepam. The results of experiments on antagonism of 5-HT-induced hypothermia and of the 5-HTP-induced head-twitch response fail to support the possibility that the putative anxiolytic effects of ritanserin in the rat can be ascribed simply to a pharmacologically defined action at 5-HT receptors.

Topics: 5-Hydroxytryptophan; Animals; Anti-Anxiety Agents; Anxiety; Chlordiazepoxide; Diazepam; Disease Models, Animal; Histamine H2 Antagonists; Humans; Lysergic Acid Diethylamide; Male; Motor Activity; Piperidines; Pyrimidines; Rats; Rats, Inbred Strains; Ritanserin; Serotonin Antagonists

In two groups of rats trained to discriminate 0.08 or 0.16 mg/kg of lysergic acid diethylamide (LSD) from saline, pirenperone and ketanserin completely blocked the stimulus effect of LSD. Pizotifen (BC-105) blocked the LSD cue when the training dose was 0.08 mg/kg, but had variable effects in the 0.16 mg/kg of LSD-trained group. The antagonism of the 0.08 mg/kg cue occurred at doses of the antagonists which blocked [3H]spiroperidol labeled 5-HT2 receptors in the frontal cortex in vivo; binding in the striatum was unaffected by the LSD antagonists. However, in doses which produce the LSD cue, neither LSD nor the 5-HT agonist, 5-methoxy-N,N-dimethyltryptamine, which substitutes for LSD, inhibited the binding in either the cortex or the striatum. The results are discussed in relation to the possible neuropharmacological basis for the LSD cue.

Topics: Animals; Cerebellum; Corpus Striatum; Frontal Lobe; Ketanserin; Lysergic Acid Diethylamide; Male; Piperidines; Pizotyline; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Serotonin

Topics: Alanine; Animals; Avoidance Learning; Memory; Mental Recall; Piperidines; Rats; Retention, Psychology; Serotonin; Synaptic Transmission

Peripheral administration of the serotonin (5-HT) antagonist pirenperone produced a dose dependent inhibition of sexual behavior in sexually naive and experienced male rats. In Experiment 1, both 75 micrograms/kg and 150 micrograms/kg pirenperone significantly reduced the proportion of naive males mounting, while 150 micrograms/kg also reduced the proportion of naive males intromitting and ejaculating. In Experiment 2, both 75 micrograms/kg and 150 micrograms/kg pirenperone significantly increased mount and intromission latencies in sexually experienced males, as well as decreased intromission frequency, with 150 micrograms/kg more potent in each regard. The 150 micrograms/kg dose also increased the post-ejaculatory interval, and decreased both mount frequency and copulatory efficiency. In Experiment 3, both 150 micrograms/kg pirenperone and 3 mg/kg of the 5-HT agonist quipazine produced significant inhibition of male sexual behavior; however, when co-administered, inhibitory effects of each drug were significantly attenuated. The mutual attenuation of effects by a 5-HT agonist and a 5-HT antagonist suggests that the observed effects of both of these drugs were serotonergically mediated. In the final experiment, the 5-HT antagonist ketanserin was shown to inhibit sexual behavior in a manner similar to that of pirenperone. Results suggest a facilitatory, as well as an inhibitory role for 5-HT in male sexual behavior.

Topics: Animals; Dose-Response Relationship, Drug; Fenclonine; Ketanserin; Male; Piperidines; Quinolines; Quipazine; Rats; Serotonin Antagonists; Sexual Behavior, Animal; Tranquilizing Agents

The peripheral administration of the serotonin type 2 receptor (5-HT2) antagonist pirenperone inhibited sexual receptivity in ovariectomized female rats primed either chronically with estradiol benzoate (EB), or acutely with EB plus varying doses of progesterone. An inhibition occurred at 50, 100 and 150 but not 25 micrograms/kg pirenperone. Increasing the dose of progesterone did not attenuate the inhibitory effect of pirenperone. Two other 5-HT2 antagonists, ketanserin (2.5 mg/kg) and spiperone (250 micrograms/kg), also inhibited receptivity in females primed with EB and progesterone. The inhibitory effect of pirenperone on receptivity was attenuated by the 5-HT agonist quipazine (3 mg/kg), though quipazine alone had no effect on receptivity. Whereas the 5-HT antagonist methysergide (3 mg/kg) failed to have an effect on receptivity in EB-primed females, methysergide co-administered with quipazine facilitated receptivity. Pirenperone also inhibited proceptivity in females primed with EB and progesterone. Although quipazine did not attenuate the pirenperone-induced inhibition of proceptivity, quipazine alone increased proceptivity. Moreover, quipazine facilitated proceptivity in EB-primed rats whether progesterone was present or absent. The results suggest that 5-HT may serve both a facilitatory and inhibitory role in female sexual behavior, perhaps reflecting 5-HT2 and 5-HT1 receptor activity, respectively.

Topics: Animals; Castration; Estradiol; Female; Ketanserin; Methysergide; Piperidines; Progesterone; Quipazine; Rats; Rats, Inbred Strains; Receptors, Dopamine; Serotonin; Sexual Behavior, Animal; Spiperone

Indolealkylamine and phenethylamine hallucinogens disrupted responding maintained under a fixed-ratio 40 (FR-40) schedule of reinforcement. LSD, DMT, mescaline and DOM produced dose-dependent decreases in number of reinforcers and increases in 10-sec periods of non-responding (pause-intervals). The 5HT agonist quipazine, as well as the LSD congener lisuride, altered response patterns in a similar manner. The effects of these drugs were examined after pretreatment with pirenperone, an antagonist with specificity toward the 5HT2 receptor with reference to the 5HT1 receptor. The dose-response curves for the phenethylamine hallucinogens were shifted significantly to the right and to a greater degree than were those for the indolealkylamine hallucinogens. Pirenperone also antagonized the effects of quipazine to a degree similar to that observed with the phenethylamine-type hallucinogens. Pirenperone did not significantly shift the dose-response pattern to lisuride. These data suggest that the behavioral disruption induced by these hallucinogens and quipazine relates at least in part to an effect on 5HT2 receptors, while the effects of lisuride do not involve a significant interaction at the 5HT2 receptor.

Topics: Animals; Conditioning, Operant; Hallucinogens; Lisuride; Lysergic Acid Diethylamide; Male; Mescaline; N,N-Dimethyltryptamine; Piperidines; Quipazine; Rats; Rats, Inbred Strains

Four monkeys (Cercopithecus aethiops) were trained to discriminate 0.06 mg/kg of lysergic acid diethylamide (LSD) from saline in a two-key task in which correct responding was reinforced with food under a fixed ratio 32 schedule. The ED50 of LSD was 0.011 mg/kg. The nonhallucinogenic ergot, lisuride, and the hallucinogen, 5-methoxy-N,N-dimethyltryptamine, substituted completely for LSD (ED50 values were 0.0098 and 0.45 mg/kg, respectively). Mescaline (1-40 mg/kg), d-amphetamine (0.1-0.625 mg/kg) and apomorphine (0.1-0.5 mg/kg) did not substitute for LSD. In antagonism testing with ketanserin (1-10 mg/kg) or pirenperone (0.025 and 0.05 mg/kg), only the highest dose of pirenperone attenuated the LSD stimulus effect (to 55%). A 0.1-mg/kg dose of pirenperone produced nonresponding in three of four animals. The LSD cue was unaffected by clozapine (1 and 2 mg/kg), haloperidol (0.1 mg/kg) and pizotifen (0.6-1.8 mg/kg). The fact that lisuride does not readily cause hallucinations in humans, but yet substituted for LSD in primates, indicates that the LSD cue may not reflect the hallucinogenic properties of LSD. It is suggested that the LSD stimulus effect may depend on receptors (e.g., serotonergic) that, at the moment, are only poorly characterized.

Topics: Animals; Chlorocebus aethiops; Cues; Discrimination Learning; Dose-Response Relationship, Drug; Lysergic Acid Diethylamide; Male; Piperidines; Receptors, Serotonin

The study used the loss of the righting reflex in response to the alpha 2-agonist xylazine in an in vivo rat assay to determine possible effects of the LSD antagonist pirenperone at alpha 2-adrenoceptors. Pirenperone antagonized the response and was more potent (ED50: 0.32 mg/kg) than yohimbine (1.25 mg/kg) and piperoxan (3.30 mg/kg). The data suggest that pirenperone may act at alpha 2-adrenoceptors in vivo.

Topics: Animals; Dioxanes; Female; Idazoxan; Piperidines; Piperoxan; Postural Balance; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Reflex; Serotonin Antagonists; Tranquilizing Agents; Xylazine; Yohimbine

5-HT uptake inhibitors and pirenperone (a 5-HT2 receptor antagonist), which in previous experiments antagonized fenfluramine (5-HT releaser)-induced hyperthermia in heat adapted rats, were tested against hyperthermia induced by the directly acting 5-HT agonist--m-CPP and quipazine. Pirenperone and --to a lesser degree--amitriptyline and femoxetine antagonized the hyperthermia. Citalopram and clomipramine were inactive. It is concluded that hyperthermia induced by 5-HT-like drugs in rats is due to the stimulation of the 5-HT2 receptor and that the antagonistic effect of citalopram and clomipramine against fenfluramine-induced hyperthermia might be connected with their effect on the uptake of 5-HT.

Topics: Adaptation, Physiological; Amitriptyline; Animals; Body Temperature; Citalopram; Clomipramine; Dose-Response Relationship, Drug; Hot Temperature; Male; Piperazines; Piperidines; Propylamines; Quipazine; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists

Although withdrawn from clinical trials because of liver toxicity, the ergot derivative lergotrile has been useful in the treatment of disorders involving dopaminergic systems (e.g., parkinsonism). In various biochemical and behavioral assays, this compound acts most potently as a dopamine (DA) agonist but also has DA antagonist as well as serotonin (5-HT) agonist properties. To elucidate further its effects in vivo, rats were trained to discriminate 0.5 mg/kg of lergotrile from saline in a two-lever water-reinforced task. In tests for similarities to other ergolines, dose-related substitutions were observed with lisuride (0.003-0.04 mg/kg) and d-lysergic acid diethylamide (0.01-0.08 mg/kg); partial substitution occurred with ergonovine (0.063-0.5 mg/kg). The DA agonist apomorphine (0.016-0.5 mg/kg) also substituted for lergotrile whereas the 5-HT agonist quipazine (0.25-2.0 mg/kg) elicited primarily saline-appropriate responding. Tests involving drug combinations indicated that the DA antagonist haloperidol (0.016-0.5 mg/kg) attenuated responding on the drug-appropriate lever; however, neither the DA (D2) antagonist sulpiride (2.0-16.0 mg/kg) nor the 5-HT antagonist BC-105 (1.0-4.0 mg/kg) had an effect upon the lergotrile cue. These results indicate that DA neuronal systems are probably more important than 5-HT neuronal systems in mediating the discriminative stimulus properties of lergotrile; however, the contribution of other neurotransmitter systems (e.g., norepinephrine) to these effects still must be evaluated.

Topics: Animals; Apomorphine; Discrimination Learning; Dose-Response Relationship, Drug; Ergolines; Ergonovine; Haloperidol; Lisuride; Lysergic Acid Diethylamide; Male; Piperidines; Pizotyline; Quipazine; Rats; Rats, Inbred Strains; Sulpiride

Imidazobenzodiazepine (Ro 15-1788, 5 mg/kg) similarly to a lose dose of apomorphine (0.1 mg/kg) decreased the intensity of footshock aggression in male rats. Ro 15-1788 significantly potentiated the antiaggressive action of apomorphine. Pirenperone (0.01 mg/kg) potentiated the effect of both drugs, whereas haloperidol (0.01 mg/kg) had an opposite action. After long-term treatment with apomorphine and Ro 15-1788 the tolerance to their antiaggressive action developed. This change was in agreement with increased serotonin metabolism in the forebrain. Unlike the action on aggressive behavior, Ro 15-1788 similarly to haloperidol (0.05 mg/kg) decreased the motor depressant effect of apomorphine (0.01 mg/kg) in mice. This effect correlated with the lowered serotonin metabolism after Ro 15-1788 administration. Unlike apomorphine, Ro 15-1788 reversed catalepsy induced by haloperidol (0.25 mg/kg). Administration of pirenperone (0.03 mg/kg) and destruction of serotoninergic terminals by p-chloroamphetamine (2 X 15 mg/kg) significantly potentiated the sedative action of apomorphine. It appears that different action of Ro 15-1788 on behavioral effects of apomorphine is related to different influence of Ro-1788 on serotoninergic processes in the striatum and limbic structures.

Topics: Aggression; Animals; Apomorphine; Benzodiazepinones; Brain; Catalepsy; Dose-Response Relationship, Drug; Flumazenil; Haloperidol; Humans; Hydroxyindoleacetic Acid; Male; Mice; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Serotonin; Serotonin

The mechanism of action of 5-hydroxytryptophan (5-HT, 10 mg/kg), quipazin (7 mg/kg), zimelidin (15 mg/kg) and m-chlorophenylpiperazine (5 mg/kg) was examined with the aid of some analyzer substances. The avoidance behavior under stress was used as criterion of estimation. The optimizing effect of 5-HT on the avoidance behavior was demonstrated to be a consequence of serotonin synthesis activation and its release with activation of postsynaptic 5-HT-1-receptors. An adverse effect of quipazin on the avoidance behavior was, to a greater degree, due to the activation of 5-HT-2-autoreceptors rather than of dopamine receptors. The inhibitory effect of m- chlorphenylpiperazine was reversed by administration of pyrenepyrone , a blocker of 5-HT-2-receptors. The inhibitory effect of zimelidine on the avoidance behavior was not removed by clonidin . The positive effect on the avoidance behavior under stress occurs as a result of exposures that activate the synthesis and release of 5-HT as well as of activation of postsynaptic 5-HT-1 receptors.

Topics: 5-Hydroxytryptophan; Acute Disease; Animals; Avoidance Learning; Cyproheptadine; Humans; Hydrazines; Male; Piperazines; Piperidines; Quinolines; Quipazine; Rats; Rats, Inbred Strains; Stress, Psychological; Tranquilizing Agents; Zimeldine

The administration of the putative 5-hydroxytryptamine (5-HT) agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-hydroxytryptophan (5-HTP) produced a facilitation and an inhibition of male rat sexual behavior, respectively. The 5-HTP-induced inhibitory effects were at least partially antagonized by the administration of metergoline, methiothepine or pirenperone. However, none of these agents were able to counteract any facilitatory effects produced by 8-OH-DPAT. It is concluded that 8-OH-DPAT does not facilitate the expression of masculine sexual behavior in the rat by stimulation of 5-HT1 or 5-HT2 receptors.

Topics: 5-Hydroxytryptophan; 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Female; Male; Metergoline; Methiothepin; Naphthalenes; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin Antagonists; Sexual Behavior, Animal; Tetrahydronaphthalenes

The effects of pirenperone and cyproheptadine on the pressor and tachycardic responses to 5-hydroxytryptamine (5-HT) and to dimethylphenylpiperazinium (DMPP) were compared. Both 5-HT antagonists suppressed in a dose-dependent manner the pressor effect of 5-HT, whilst did not noticeably affect the tachycardic effect of 5-HT and the cardiovascular effects of DMPP. On the molecular base, pirenperone was 15 times more potent antagonist of the pressor response to 5-HT than cyproheptadine. It is concluded that not only the 5-HT receptors in arterial smooth muscle but also the 5-HT receptors in sympathetic ganglia and the adrenal medulla responsible for the pressor response to 5-HT are sensitive to the 5-HT antagonists and probably analogous to the central 5-HT2 receptors. The 5-HT receptors in cardiac tissue mediating tachycardia differ in their pharmacological properties from those in arterial smooth muscle responsible for contraction. It is suggested that the ganglionic components of the pressor and tachycardic responses to 5-HT are mediated via different populations of 5-HT receptors in sympathetic ganglia.

Topics: Animals; Blood Pressure; Cyproheptadine; Dose-Response Relationship, Drug; Female; Guinea Pigs; Heart Rate; Male; Piperidines; Receptors, Serotonin; Serotonin; Serotonin Antagonists

The data are provided on the effect of some serotoninergic substances on the avoidance behavior under acute stress. 5-Hydroxytryptophan, zimelidine (low doses), pyrenepyron, ciproheptadine, trazodon (high doses), produced a noticeable positive action on the behavior pattern under study. Quipazin and zimelidine (high doses) provoked an increase in the number of affective manifestations and a rise of the latent avoidance time. Regardless of an appreciable fall in the number of affective manifestations, the powerful sedative effect of m-chlorphenylpiperazine led to an increase in the latent response periods. It was shown that substances that produced a direct or mediated activation effect on the serotoninergic system had an appreciable favourable influence on the avoidance behavior, which was a consequence of a decrease in the animals' emotional excitement. Combination of serotonin-blocking properties (action on S2-autoreceptors) and dopaminergic properties brought about optimal results, provided that pyrenepyron was applied.

Topics: 5-Hydroxytryptophan; Animals; Antidepressive Agents; Brompheniramine; Cyproheptadine; Escape Reaction; Humans; Male; Piperazines; Piperidines; Quipazine; Rats; Rats, Inbred Strains; Serotonin; Stress, Psychological; Tranquilizing Agents; Trazodone; Zimeldine

The effect of pirenperone, a putative 5-HT2 receptor antagonist, on various 5-HT-mediated behavioural responses has been examined. The head twitch response in mice, induced by administration of carbidopa (25 mg/kg) followed by 5-hydroxytryptophan (5-HTP) (200 mg/kg), was inhibited in a dose-dependent manner by pirenperone, with an ED50 of 76 micrograms/kg. The appearance of head weaving, forepaw treading and hind-limb abduction, which followed the administration of tranylcypromine (5 mg/kg) plus L-tryptophan (100 mg/kg) or quipazine (50 mg/kg) to rats, was also inhibited by pretreatment with pirenperone (100 micrograms/kg). Pirenperone did not alter the rate of 5-HT synthesis in the rat brain. Whilst pirenperone (100 micrograms/kg) did decrease methamphetamine-induced locomotor activity in rats, a dose of haloperidol producing a similar inhibition of this response did not alter the 5-HT-mediated behaviour. It is suggested, therefore, that the currently used 5-HT-induced behavioural models are 5-HT2 receptor-mediated.

Topics: 5-Hydroxytryptophan; Animals; Carbidopa; Haloperidol; Male; Methamphetamine; Motor Activity; Piperidines; Quipazine; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists; Tranylcypromine; Tryptophan

The wet-dog shake behaviour induced by 5-hydroxytryptophan (5-HTP) was used as a model of central 5-hydroxytryptamine (5-HT) receptor activity in the rat. The wet-dog shake behaviour induced by 5-HTP was dose-dependent. Selective 5-HT2 receptor antagonists ketanserin, pirenperone and methysergide (with little selectivity) were administered to rats displaying the wet-dog shake behaviour. The three antagonists produced a rapid and dose-dependent inhibition of wet-dog shakes. Pirenperone was more potent than ketanserin, which was more potent than methysergide at inhibiting wet-dog shake behaviour. Since 5-HT2 receptor antagonists inhibit the 5-HTP-induced wet-dog shakes it is proposed that the wet-dog shakes induced by 5-HTP are mediated by activation of 5-HT2 receptors.

Topics: 5-Hydroxytryptophan; Animals; Behavior, Animal; Female; Ketanserin; Methysergide; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin Antagonists

The putative 5-hydroxytryptamine (5-HT) antagonists 2-bromo-LSD, cinanserin, cyproheptadine, pizotifen, methysergide, metitepine, mianserin and metergoline were found to reduce the frequency of the head-twitch response induced by intraperitoneal injections of 320 mg/kg of 5-hydroxytryptophan (5-HTP) in the rat. The antagonist dose-effect curve of these agents was biphasic. It consisted of an initial, steep, phase and a subsequent, shallower, phase. Analysis of the data by means of quantitative and quantal methods yielded different rank orders of potency of antagonist drugs. Only pirenperone, a drug identified earlier as a pure antagonist, produced a simple, monophasic dose-effect curve in antagonizing the effects of 5-HTP. The antagonist effects of pirenperone, and the first phase of the curve of the putative 5-HT antagonists, may reflect antagonist activity at 5-HT2 receptors. The data are consistent with earlier behavioural evidence that the putative 5-HT antagonists act complexly as mixed agonist-antagonists; only pirenperone exerted behavioural effects that suggest it to be a pure antagonist.

Topics: 5-Hydroxytryptophan; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Male; Muscle Contraction; Piperidines; Rats; Rats, Inbred Strains; Serotonin Antagonists

Rats trained to discriminate 1.0 mg/kg of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from saline in a two-lever operant choice task were administered doses of mescaline, LSD, 5-methoxy-N,N-dimethyltryptamine (5-OMe DMT), quipazine, TFMPP and RU-24969. The DOM-stimulus generalized to the three hallucinogenic agents and to quipazine, but not to the purported serotonin agonists TFMPP or RU-24969. Pretreatment of the animals with the 5-HT2 antagonists ketanserin and pirenperone antagonized the effect produced by DOM. Pirenperone also blocked DOM-stimulus generalization to mescaline, LSD, 5-OMe DMT and quipazine. The results of this study suggest that the discriminative stimulus effects of DOM, the three hallucinogenic agents to which DOM-stimulus generalization occurred, and quipazine, may involve those sub-populations of serotonin receptors that are labeled by tritiated ketanserin (i.e. 5-HT2 sites).

Topics: Amphetamines; Animals; DOM 2,5-Dimethoxy-4-Methylamphetamine; Ketanserin; Male; Piperidines; Quinolines; Quipazine; Rats; Rats, Inbred Strains; Serotonin Antagonists

Rats were trained to discriminate between intraperitoneal injections of 0.16 mg/kg of d-lysergic acid diethylamide (d-LSD) and injections of saline in the two-bar (FR 10) food-reinforced drug discrimination procedure. The gradient for responses to LSD was established following pretreatment with saline or one of five doses of pirenperone. It was found that pretreatment with pirenperone caused a parallel shift to the right of the dose-effect curve of LSD. The magnitude of this shift was related to the dose of pirenperone, 0.006 mg/kg of the drug causing a 2-fold shift. A direct linear plot revealed that the curve fitting the data points passed through the origin, but that it was curvilinear rather than linear. The data did not, therefore, accommodate the requirements for reversible, competitive interaction. This finding is discussed in terms of the mixed agonist/antagonist activity of LSD that may occur at binding sites for 5-HT1 and 5-HT2 in the rat brain.

Topics: Animals; Conditioning, Operant; Discrimination Learning; Dose-Response Relationship, Drug; Lysergic Acid Diethylamide; Male; Piperidines; Rats; Rats, Inbred Strains

Pirenperone, which is chemically related to ketanserin, has been reported to be a selective serotonin2 (5-HT2) antagonist and a specific d-LSD antagonist. We now report that pirenperone markedly stimulates prolactin (PRL) secretion in vivo at low doses and blocks the dopamine (DA)-induced inhibition of PRL release from rat pituitary glands in vitro, suggesting it acts as an antagonist at DA2 receptors in the anterior pituitary gland. Ketanserin, also a purported selective 5-HT2 receptor blocker, has no effect on rat PRL secretion in vivo or in vitro, but at high doses, it inhibits the increase in serum PRL levels produced by the two 5-HT agonists, quipazine and 5-methoxy-N,N-dimethyl-tryptamine (5-MeODMT). It had a weak ability to antagonize the PRL-releasing effect of the 5-HT precursor, 5-hydroxytryptophan. These results suggest that serotonergic stimulation of rat PRL secretion by quipazine and 5-MeODMT may be partially mediated by 5-HT2 receptors. The inability of ketanserin to effectively block the effect of 5-HTP suggests its mechanism of stimulating PRL secretion is more complicated than that of the direct acting agonists.

Topics: Animals; Apomorphine; Dose-Response Relationship, Drug; In Vitro Techniques; Ketanserin; Lysergic Acid Diethylamide; Male; Piperidines; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine; Serotonin Antagonists; Tranquilizing Agents

Cyproheptadine and R 50 656, a novel 5-HT2 antagonist, produced a dose-dependent suppression of the pressor response to 5-hydroxytryptamine (5-HT), but did not affect the depressor response. The pressor effect of 5-HT was significantly more sensitive to R 50 656 than to cyproheptadine. On the contrary, the tachycardic response to 5-HT was antagonized only with cyproheptadine. Accordingly, in rats the 5-HT receptors of cardiac tissue differ in their pharmacological properties from both the excitatory and inhibitory 5-HT receptors of vascular smooth muscle.

Topics: Animals; Blood Pressure; Cyproheptadine; Female; Heart Rate; Histamine H2 Antagonists; Male; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin

Topics: Animals; Discrimination, Psychological; Dose-Response Relationship, Drug; Generalization, Stimulus; Lysergic Acid Diethylamide; Male; Mescaline; Piperidines; Quipazine; Rats; Rats, Inbred Strains; Serotonin Antagonists