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At least 19 recordsLinked to original sources
PubMed2005

Pizotyline effectively attenuates the stimulus effects of N-methyl-3,4-methylenedioxyamphetamine (MDMA).

MDMA (N-methyl-3,4-methylenedioxyamphetamine) produces a discriminative stimulus (DS) effect in animals, but attempts to completely block this action with selective neurotransmitter antagonists have not been very successful. Biochemically, MDMA can increase synaptic levels of serotonin, dopamine, and norepinephrine that, conceivably, might interact with multiple populations or subpopulations of neurotransmitter receptors. The present study attempted to antagonize the DS effects of MDMA using the nonselective agents clozapine, cyproheptadine, and pizotyline. An extensive and comparative radioligand binding profile was also obtained for the latter two agents. The purported antagonists were administered in combination with the training dose of MDMA to groups of Sprague-Dawley rats trained to discriminate 1.5 mg/kg of MDMA from saline vehicle in a standard two-lever operant paradigm using a VI-15s schedule of reinforcement. Clozapine was without effect at the doses evaluated, and cyproheptadine only partially attenuated MDMA-appropriate responding. In contrast, pizotyline (AD50=2.5 mg/kg), in combination with the MDMA training dose, resulted in a dose related decrease in percent drug-appropriate responding to saline levels. In a separate group of animals trained to discriminate the structurally-related agent N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA) from vehicle, pretreatment with pizotyline also resulted in a substantial decrease in drug-appropriate responding. The results with cyproheptadine and pizotyline in the binding assays confirmed that these agents display high affinity for multiple subpopulations of serotonergic, dopaminergic, adrenergic, histaminergic, and cholinergic receptors. The overall results of the present investigation indicate that pizotyline, which is clinically available in some countries, might be of clinical utility in the treatment of MDMA overdose.

Animals↗
PubMed1990

A comparative study of naproxen sodium, pizotyline and placebo in migraine prophylaxis.

318 patients satisfying the Ad Hoc Committee's criteria for common or classical migraine were entered into an 8 week single-blind placebo recording phase to establish, by diary cards, the frequency and severity of their attacks. 176 patients completed this and had records indicating 4-8 episodes in the 8 week period, with sufficient severity to reduce activity and/or work; these patients were randomized by a predetermined code, into three double-blinded groups: naproxen sodium 550 mg bid (60 patients), pizotyline 0.5 mg tid (59 patients), or placebo (57 patients). The patients were followed at monthly intervals for 12 weeks, with 25 dropping out (3 on naproxen sodium, and 2 each on pizotyline and placebo because of "side effects;" the remaining 18 because of noncompliance or reasons unrelated to therapy). Approximately 25% of patients in each of the 3 groups complained of side effects. Statistical analysis showed that both naproxen sodium and pizotyline were better than placebo, and of overall equivalent (i.e. equal) efficacy in the prophylaxis of migraine. In some respects, naproxen sodium was slightly more effective than pizotyline in the first month of treatment.

Adolescent↗
PubMed1984

Pizotyline-induced cholestatic jaundice.

We treated a case of drug-induced cholestatic jaundice in which the causative agent was pizotyline (Pizotifen), a phenothiazine-related drug. The patient's symptoms were compatible with either hepatitis or biliary obstruction. Diagnostic laboratory studies were performed to exclude both of these entities. The history of drug ingestion plus the clinical and histologic features established pizotyline as the causative agent.

Aged↗
PubMed1986

Verapamil does not antagonize LSD-induced stimulus control.

Discriminative stimulus control was established in rats (N = 6) with LSD (100 microg/kg) and saline using a 2-lever response choice task and an FR10 schedule of food reinforcement. Subjects were then tested once per week with either pizotyline (BC-105) or verapamil alone or in combinations with LSD. In In agreement with previous reports, pizotyline antagonized LSD and, when tested alone, exhibited modest agonistic effects (18% LSD-appropriate). In contrast, verapamil failed to block LSD at any dose tested. Verapamil alone appeared to have somewhat greater agonistic activity (35% LSD-appropriate) than did pizotyline but neither drug substituted completely for LSD. These data suggest that calcium channel antagonism by pizotyline is not essential to its anti-LSD effects.

Animals↗
PubMed1988

Interactions between serotonergic agonists and antagonists in rats trained with LSD as a discriminative stimulus.

Drugs purported to have selective affinities for 5-HT1A, 5-HT1B, and 5-HT2 receptors were tested in rats trained with 0.1 mg LSD versus saline. Included were 5-methoxy-dimethyltryptamine (MDMT), 2,5-dimethoxy-4-methyl-amphetamine (DOM), 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), m-trifluoromethylphenyl-piperazine (TFMPP), and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU-24969). Tests were then repeated in the presence of either pizotyline or pirenperone. DOM substituted for LSD and both were blocked by pizotyline and pirenperone. MDMT, 8-OH-DPAT, TFMPP, and RU-24969 substituted less completely and were variably affected by the antagonists. An unexpected result was potentiation of the stimulus or disruptive effects of certain doses of 8-OH-DPAT and TFMPP by pizotyline and pirenperone. The present findings suggest more complex interactions between these drugs than has previously been assumed.

Animals↗
PubMed1991

Agonist and antagonist properties of serotonergic compounds in pigeons trained to discriminate either quipazine or L-5-hydroxytryptophan.

The serotonin (5-HT) receptor-related compounds metergoline, pirenperone, ketanserin, cyproheptadine, pizotyline, methysergide, lysergic acid diethylamide, mianserin and cinanserin were studied in pigeons trained to discriminate l-5-hydroxytryptophan (l-5-HTP) (18.0 mg/kg) from saline and in pigeons trained to discriminate quipazine (1.0 mg/kg) from saline. Metergoline did not generalize to either quipazine or l-5-HTP but did antagonize drug-appropriate responding in both groups. Ketanserin potently blocked the quipazine discriminative stimulus and neither generalized to nor attenuated the l-5-HTP discriminative stimulus. Pirenperone, cinanserin, cyproheptadine, methylsergide, pizotyline and mianserin attenuated the quipazine discriminative stimulus at low doses and, at higher doses, generalized to the l-5-HTP discriminative stimulus. No antagonism of the l-5-HTP-discriminative stimulus or generalization to the quipazine-discriminative stimulus were observed with these compounds. A correlation coefficient of 0.93 was calculated between the potencies of 5-HT compounds to generalize to the l-5-HTP stimulus and the binding affinities of these compounds for a 5-HT1 receptor in rat brain. In addition, a correlation coefficient of 0.78 was calculated between the potencies of 5-HT compounds to attenuate the quipazine stimulus and the binding affinities of these compounds for the 5-HT2 receptor in rat brain. These observations suggest cyproheptadine, pizotyline, methysergide, lysergic acid diethylamide, mianserin and cinanserin are agonists at the 5-HT1 receptor in the l-5-HTP discrimination and antagonists at a 5-HT2 receptor in the quipazine discrimination in pigeons.

5-Hydroxytryptophan↗
PubMed1992

Stimulus effects of ibogaine in rats trained with yohimbine, DOM, or LSD.

The stimulus effects of ibogaine were compared with those of yohimbine, an alpha 2-adrenoceptor antagonist, 2,5-dimethoxy-4-methylamphetamine (DOM), a 5-hydroxytryptamine2 (5-HT2) agonist, and lysergic acid diethylamide (LSD), a nonspecific 5-HT agonist. Rats were trained with either yohimbine (6 mg/kg), DOM (0.6 mg/kg), or LSD (0.1 mg/kg) vs. no treatment in a two-lever discrimination task. Tests of generalization were then conducted with ibogaine. In yohimbine-trained animals, 39.7% of responses following ibogaine (15 mg/kg) were on the drug-appropriate lever, but this response level was not significantly different from no treatment-appropriate responding. A response distribution that was significantly different from responding under both drug and no treatment training conditions was observed in DOM-trained rats after administration of 15 mg/kg ibogaine. Pizotyline (BC-105) blocked all DOM-appropriate responding produced by ibogaine. In LSD-trained animals, 20 mg/kg ibogaine mimicked LSD. Pizotyline blocked LSD-appropriate responding produced by ibogaine in five of six animals. The present data suggest the involvement of 5-HT2 receptor activity, and the possibility of a 5-HT1A contribution, in the stimulus properties of ibogaine.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1983

Additional evidence that L-5-hydroxytryptophan discrimination models a unique serotonin receptor.

The purpose of the present studies was to investigate further the role of central serotonin (5-HT) in mediating the L-5-hydroxytryptophan (L-5-HTP) discriminative cue. Rats were trained to discriminate the stimulus properties of 35 mg/kg L-5-HTP combined with RO 4-4602, a peripheral decarboxylase inhibitor. Considering that several 5-HT antagonists were unable to block the L-5-HTP discriminative cue in our earlier studies, we extended these studies to include the two other presumed 5-HT antagonists mianserin and BC-105 (pizotyline). Only BC-105 completely blocked the training dose of L-5-HTP. Furthermore, the blockade of the L-5-HTP cue was both graded and surmountable by increasing the dose of L-5-HTP, suggesting a competitive antagonism. In neurochemical studies, the regional brain levels of 5-HT, norepinephrine and dopamine were determined after the injection of the training dose of L-5-HTP. Marked changes in the levels of 5-HT were found, while the levels of the catecholamines were changed only slightly or not at all. Furthermore, dose-response studies of L-5-HTP demonstrated an orderly dose-related increase in the levels of 5-HT in brain and in the percent responding on the L-5-HTP lever, while no such relationship was found for brain catecholamines. These results agree with previous pharmacological studies and suggest that the L-5-HTP discrimination is mediated by a central 5-HT receptor that has pharmacological properties distinct from those receptors identified in previous behavioral models of 5-HT receptor stimulation.

5-Hydroxytryptophan↗
PubMed1984

The stimulus properties of para-methoxyamphetamine: a nonessential serotonergic component.

A group of six rats was trained to discriminate the effects of para-methoxyamphetamine (PMA; 3 mg/kg, 15 min pretreatment time) and saline in a two-lever choice task using a fixed ratio 10 schedule of water reinforcement. Stimulus control was assumed to be present when 80% or more of the first ten responses were appropriate for the treatment condition on each of five consecutive days. PMA established stimulus control in each of the subjects. The mean number of sessions prior to the onset of criterion performance was 19 (SE = 2, range = 14-24). A second group of ten rats was similarly trained with lysergic acid diethylamide (LSD; 0.1 mg/kg, 15 min pretreatment time) and saline. In rats trained with PMA, LSD yielded intermediate results, i.e., significantly different from both training conditions. Likewise, the response distribution was intermediate in nature when LSD-trained subjects were tested with PMA. Pizotyline did not antagonize PMA-induced stimulus control in rats trained with PMA and saline but did antagonize the intermediate responding produced by PMA in LSD-trained subjects. It is concluded that PMA-induced stimulus control does not depend upon activation of serotonergic receptors but that PMA does possess some LSD-like effects which are mediated serotonergically.

Amphetamines↗
PubMed1990

The chemotherapy of rodent malaria. XLV. Reversal of chloroquine resistance in rodent and human Plasmodium by antihistaminic agents.

The inherent blood schizontocidal activities of five antihistaminic compounds, cyproheptadine hydrochloride (CYP), ketotifen hydrogen fumarate (KET), pizotyline hydrogen maleate (PIZ), azatadine maleate (AZAT) and loratadine (LOR) were examined against the following organisms: chloroquine-sensitive (CS) Plasmodium berghei and chloroquine-resistant (CR) P. yoelii ssp. NS in mice; and CS Tak 9 clone 96 and CR K1 strain of P. falciparum in vitro. Chloroquine, verapamil and desipramine were used as comparison standards. CYP, KET, PIZ were active against the CS strain in vivo with ED90 levels between 20 and 30 mg kg-1 (given sc daily for four days). They were slightly more active against the CR strain. AZA was active, but much less so than the other compounds. LOR, verapamil and desipramine were inactive in vivo at the doses tested. Against CS P. falciparum in vitro, all five antihistaminics and desipramine were active at EC50 concentrations ranging from about 50-80 mumol l-1, while verapamil was only active at 175 mumol l-1. Against the CR strain of this parasite, CYP, PIZ and LOR were slightly more active than against the CS strain, but KET, AZAT, desipramine and verapamil were significantly less active. The action of all these compounds in combination with chloroquine was then examined both in vivo and in vitro. The ability of verapamil and desipramine to reverse chloroquine resistance in vitro was confirmed, but only a low level of reversal was seen with these compounds in vivo. However, CYP, KET, PIZ and AZAT produced a marked reversal of chloroquine resistance both in vivo and in vitro. The implications of these observations in relation to further laboratory and clinical research are discussed.

Animals↗
PubMed1980

An autosomal dominant syndrome of hemiplegic migraine, nystagmus, and tremor.

A mother and son suffer from hemiplegic migraine with onset in childhood. Both have nystagmus which has not changed for many years, but the date of onset is uncertain. They have an asymmetrical tremor, clinically indistinguishable from essential tremor. Neuroophthalmological examination revealed inability to produce smooth pursuit, gaze-paretic nystagmus, rebound nystagmus, failure of fixation suppression of the vestibuloocular reflex both horizontally and vertically, and low gain of the optokinetic system. These abnormalities, confirmed by electrooculography, are commonly seen in disease of the cerebellum and brainstem. Treatment with propranolol and pizotyline lessened the number of episodes of hemiplegia and improved the tremor. Hemiplegic migraine has been reported in association with nystagmus, retinal degeneration, deafness, and ataxia in varying combinations in three other families with autosomal dominant inheritance. These associated neurological manifestations likely represent system degenerations rather than the effect of repeated ischemia imputable to the migraine itself. The syndrome of hemiplegic migraine, tremor, and ocular smooth pursuit system disorder seen in this family appears to be inherited as a single autosomal dominant trait, although more than one autosomal dominant gene may be involved.

Adolescent↗
PubMed1981

The stimulus properties of gamma-hydroxybutyrate.

Fourteen rats were trained to discriminate the effects of gamma-hydroxybutyrate (GHB) (sodium salt, 200 mg/kg) and saline in a two-lever choice task using a fixed ratio 10 schedule of water reinforcement. Intermediate responding, i.e., responding not fully appropriate for either training condition was observed in tests following morphine, lysergic acid diethylamide, chlordiazepoxide, and the presumed GABA-mimetics muscimol, gamma-butyrolactone, baclofen, and 3-aminopropane sulfonic acid. Naloxone blocked the intermediate results following morphine, but had no effect on GBH-induced stimulus control. The GABA antagonist bicuculline partially blocked GHB, but pizotyline, phentolamine, and butaclamol were without effect. It is concluded that the compound stimulus produced by GHB is most closely associated with GABAergic systems, but that minor opiate and serotonergic components are present as well.

Animals↗
PubMed1995

The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. I: Antagonist correlation analysis.

Investigations conducted over the past 3 decades have demonstrated that serotonergic receptors, specifically the 5-HT2A and 5-HT2C subtypes, play an important role in the behavioral effects of hallucinogenic compounds. The present study was designed to determine the respective significance of these two receptors in the stimulus effects of LSD and (-)DOM in the rat. Specifically, the interactions of a series of serotonergic antagonists (risperidone, pirenpirone, metergoline, ketanserin, loxapine, LY53857, pizotyline, spiperone, cyprohepatadine, mesulergine, promethazine, and thioridazine) with the LSD stimulus and the (-)DOM stimulus in LSD-trained subjects was defined. From these data, IC50 values were determined for the inhibition of the LSD-appropriate responding elicited by either 0.1 mg/kg LSD (15-min pretreatment time) or 0.4 mg/kg (-)DOM (75-min pretreatment). In addition, the affinities of these antagonists for 5-HT2A and 5-HT2C receptors were determined in radioligand competition studies, 5-HT2A affinity correlated significantly with IC50 values for the blockade of the LSD (r = +0.75, P < 0.05) and (-)DOM (r = +0.95, P < 0.001) stimuli in the LSD trained subjects. 5-HT2C affinity did not correlate significantly with either series of IC50 values. These data indicate that (1) the stimulus effects of LSD, and (2) the substitution of (-)DOM for the LSD stimulus are mediated by agonist activity at 5-HT2A receptors.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1995

The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of m-chlorophenylpiperazine.

m-Chlorophenylpiperazine (mCPP), a major metabolite of the atypical antidepressant trazadone, has been observed to produce marked physiological and behavioral effects in both humans and animals. These effects have been attributed to the interaction of mCPP with serotonergic receptors. The present study was designed to characterize those interactions of mCPP with central serotonergic receptors which mediate mCPP-induced stimulus control. A series of serotonergic antagonists (mesulergine, pizotyline, ketanserin, spiperone, risperidone, ritanserin, metergoline, pirenpirone, and LY53857) was tested for the ability to block the mCPP stimulus. The affinity of these antagonists for 5-HT2A and 5-HT2C receptors was then correlated with maximal percent inhibition of the mCPP stimulus. Kd at the 5-HT2C receptor was inversely proportional (r = -0.75, P < 0.05), and Kd at the 5-HT2A receptor directly proportional (r = +0.67, P < 0.05) to the maximal percent inhibition of the mCPP stimulus. The 5-HT2C selectivity ratio [Kd(5-HT2A)/Kd(5-HT2C)] of the antagonists was directly proportional (r = +0.86, P < 0.01) to maximal percent inhibition of the mCPP stimulus. A multiple regressions analysis indicated that 81% of the variance in the ability of a given antagonist to block the mCPP stimulus could be predicted on the basis of its affinity for 5-HT2A and 5-HT2C receptors. It is concluded that the stimulus effects of mCPP are mediated predominantly by a combination of agonist activity at 5-HT2C receptors and antagonist activity at 5-HT2A receptors.

Animals↗
PubMed1981

Caffeine-induced stimulus control.

Six rats were trained to discriminate the effects of caffeine (60 mg/kg, pretreatment time: 1 hour) and saline in a two-lever choice task using a fixed ratio 10 schedule of water reinforcement. Stimulus control was assumed to be present when 80% or more of the first ten responses were appropriate for the treatment condition on each of five consecutive days. The mean number of sessions prior to the onset of criterion performance was 22 (SE = 3; range = 11--32). In trained subjects, doses of caffeine of 30, 10, and 3 mg/kg were followed by a progressively smaller proportion of responses on the caffeine-appropriate lever. Stimulus control by caffeine began to diminish about four hours after administration and was completely absent after 24 hours. The caffeine cue generalized partially to d-amphetamine and completely to aminophylline. Neither pizotyline nor spiperone antagonized stimulus control induced by caffeine.

Aminophylline↗
PubMed1988

A comparison of the discriminative stimulus properties of l-5-hydroxytryptophan in the presence of either citalopram or Ro 4-4602.

The establishment of stimulus control by 5-HTP, the amino acid precursor for serotonin (5-HT), has been reported previously [1-3]. In the present investigation, two groups of rats were trained with 5-HTP versus saline in a 2-lever discrimination procedure. Prior to the administration of 5-HTP, subjects were pretreated with either Ro 4-4602, an inhibitor of peripheral decarboxylase (R-HTP), or citalopram, a specific 5-HT reuptake inhibitor (C-HTP). Neither C-HTP nor R-HTP was antagonized completely by either pirenperone or pizotyline. When C-HTP and R-HTP were tested in a third group of rats trained with LSD, complete generalization was not observed. The results of cross tests in the R-HTP and C-HTP groups with LSD, TFMPP, 8-OH-DPAT, C-HTP, and R-HTP indicate that the stimuli induced by R-HTP and C-HTP are similar but not identical. Taken together, these data suggest that 5-HTP produces a compound stimulus that is not readily explained in terms of either 5-HT1 or 5-HT2 receptors alone.

5-Hydroxytryptophan↗
PubMed1992

Reversal of testosterone-induced dominance by the serotonergic agonist quipazine.

Anabolic steroids and other androgens, such as testosterone propionate (TP), have a facilitatory role in the expression of aggressive behavior. Based upon literature indicating an inverse relationship between aggression and the central neurotransmitter serotonin (5-HT), the present study was undertaken to investigate the role of 5-HT in androgen-induced aggression. In this study, an animal model of aggression involving competition between male rat pairs for sugar pellets was used to investigate the effects of TP. When TP was administered daily (30 mg/kg) to nondominant rats, these animals became dominant. Dominant behavior was found to be stable throughout the study with continued daily administration of TP. To test the serotonergic component of TP-induced aggression, the serotonergic agonist 2-(1-piperazinyl) quinolone dimaleate (quipazine) was administered acutely to TP-dominant rats. Quipazine dose dependently reduced aggressive dominance in TP-dominant rats, as well as in naturally dominant rats. When the serotonergic antagonists pirenpirone or pizotyline were coadministered with quipazine to either group of dominant rats, they blocked the effect of quipazine in reducing dominance. However, when 1-[1H-Indol-4-yloxy]-3-[isopropylamino]-2-propanol (pindolol), a drug that acts at both beta-adrenergic receptors and at 5-HT1A and 5-HT1B receptors, was coadministered with quipazine there was a reversal of the quipazine effect on aggression only in TP-dominant rats. These results indicate that androgen-induced aggression may involve a complex alteration in serotonergic neurotransmission.

Anabolic Agents↗
PubMed1994

Serotonergic control of androgen-induced dominance.

The present study investigates the role of serotonergic systems in anabolic steroid-induced aggression. An animal model of aggressive dominance was used to assess the chronic effects of testosterone propionate. When rats that had become dominant following administration of testosterone propionate received serotonergic agonists with selectivity for the 5-HT1A receptor (8-OH-DPAT, buspirone, gepirone), the 5-H1B receptor (eltoprazine, TFMPP), or the 5-HT2A/2C receptor (DOM), a dose-dependent decrease in dominance was demonstrated. Pretreatment with three serotonergic antagonists (pizotyline, pirenpirone, and pindolol) blocked agonist-induced reductions in dominance in varying degrees. Nonserotonergic agonists with CNS depressant effects were also tested in dominant animals. The benzodiazepine, chlordiazepoxide, did not reduce dominance except at doses that interfered with motor behavior. The opioid agonist, morphine, dose dependently decreased dominance, but this effect was reversible with administration of the serotonergic antagonist, pirenpirone, suggesting the antidominant effect of morphine had a serotonergic component. Biochemical experiments demonstrated that following chronic testosterone propionate, there was a decrease in levels of 5-HT and 5-HIAA in the hippocampus but not in the striatum or the frontal cortex. Chronic testosterone propionate also caused an increase in the affinity of [3H]8-OH-DPAT for the 5-HT1A receptor but no corresponding change in the density of 5-HT1A binding sites in the hippocampus. There was also no change in the properties of the 5-HT2 receptor in the frontal cortex following chronic testosterone propionate. These data suggest that serotonergic systems may play an important role in the control of anabolic steroid-induced aggressive dominance.

Aggression↗