Amperozide – effect on prolactin release in the rat

Amperozide, a new putatively antipsychotic drug was investigated for its effect on prolactin release in the rat. A significant decrease in the plasma concentration of prolactin was found at 30 minutes after treatment with amperozide. However, there was no effect of amperozide on prolactin release from isolated pituitary cells. These results suggest that there is no direct effect of amperozide on the pituitary lactotrophs and that the attenuation of prolactin secretion in vivo is mediated at a higher level.     

Amperozide – a new putatively antipsychotic drug with a limbic mode of action on dopamine mediated behaviour

Amperozide, a new putatively antipsychotic drug, was found to exert a functional selectivity for the limbic system of the brain. Thus, amperozide was as active as both classical and atypical neuroleptics on hypermotility induced by a low dose of amphetamine. On the other hand, amperozide did not produce catalepsy, nor did it reverse amphetamine-induced stereotypies. Moreover, amperozide inhibited exploratory behaviour in mice. The present results indicate an antipsychotic effect of amperozide, with a minimal risk for EPS when used in the clinic.     

Amperozide and emotional behaviour

The new putatively antipsychotic drug amperozide is characterized pharmacologically by a specific limbic mode of action. Thus amperozide is a potent antagonist of muricidal behaviour (ED₅₀=0.16 mg/kg) as well as aggression between isolated male mice. Although amperozide displays anxiolytic properties in Vogel's conflict test as well as an antidepressive effect in the despair test, the drug does not interfere with motor coordination or cause sedation (ED₅₀> 50 mg/kg). These results could make amperozide very interesting as an antipsychotic drug in the clinic, with effect on both postive and negative symptoms.     

Effects of amperozide,a putative antipsychotic drug,on rat midbrain dopamine neurons recorded in vivo

The effect of the putative antipsychotic compound amperozide on the electrical activity of single identified midbrain dopamine (DA) neurons was investigated in the chloral hydrate anesthetized male rat. While the activity of DA cells in the substantia nigra was unaffected, DA neurons of the ventral tegmental area (VTA), the origin of the mesolimbocortical DA system, were affected in either of two ways: 1) increased firing rate and burst firing, i.e. an excitation, or 2) regularization of the firing pattern. Reversible cold inactivation of the medial prefrontal cortex (PFC) induced a pacemaker-like firing of VTA-DA cells, an effect blocked by amperozide in the cells excited by the drug. Cells responding with a regularization were not protected against the effect of PFC inactivation. These different effects of amperozide, which may in part be mediated by 5-HT₂ receptor blockade, suggest an antipsychotic activity of amperozide, particularly in schizophrenia with negative symptoms.     

Effects of amperozide in schizophrenia

Ten male inpatients (aged 29±6 years) with a DSM-III diagnosis of schizophrenia participated in a 4-week open dose escalation study of amperozide, a novel 5-HT₂ receptor antagonist. The maximum daily dose of amperozide was 20 mg. A close dose-plasma concentration relationship showed considerable interindividual variation in the steady-state plasma levels at a given dose. Approximately equal concentrations of amperozide and its metabolite, N-deethylated amperozide, were seen in plasma. The prolactin levels were not increased during amperozide treatment. No changes occurred in hematological or other laboratory parameters. ECG showed changes in T-wave morphology and a prolongation of the QT_c time. One patient was with-drawn from the trial due to aggravation of psychotic symptoms, and two patients had a brief, temporary discontinuation of the drug due to somatic illness. Six patients were improved during amperozide treatment, as assessed by the Clinical Global Improvement Scale. Among the responders the total CPRS was reduced by a mean of 64% and total BPRS score by a mean of 46%. Mild tremor was a frequent side effect, but other extrapyramidal symptoms were rare. Nausea was seen in six patients and of a more pronounced character in one patient. In general, the severity of the side effects increased with increasing doses of amperozide.     

Selective reduction by the 5-HT antagonist amperozide of alcohol preference induced in rats by systemic cyanamide.

This investigation was undertaken to determine the effect of a unique psychotropic agent on the volitional drinking of alcohol induced pharmacologically in the rat by an inhibitor of aldehyde dehydrogenase. Following administration of cyanamide in a dose of 10 mg/kg twice daily for 3 days, the pattern of drinking of ethyl alcohol was determined in each of 12 Sprague-Dawley rats by means of a standard preference test for 3-30% alcohol vs. water. Then, each rat was offered water and its maximally preferred concentration of alcohol, which ranged from 7-15%. After a 4-day predrug test, either the saline control vehicle or the diphenylbutylpiperazinecarboxamide derivative, amperozide, was administered subcutaneously. The injections of amperozide were given b.i.d. at 1600 and 2200 h over 3 days in a dose of 0.5, 1.0, or 2.5 mg/kg. The intake of alcohol during the sequence of amperozide injections was significantly reduced in a dose-dependent manner in terms of both absolute g/kg and proportion of alcohol to water intake, whereas the saline control vehicle was without any effect on alcohol consumption. Although the highest dose of amperozide reduced the total intake of fluid due to the sharp decline in alcohol drinking, neither the consumption of food nor level of body weight was affected by any dose of the drug either during or after its administration. Because amperozide acts centrally on the synaptic activity of dopaminergic and serotonergic neurons in limbic system structures, it is envisaged that the drug ameliorates the aberrant drinking of alcohol by virtue of a direct effect on either one or both of these classes of neurons.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of amperozide on rat cortical 5-HT2 and striatal and limbic dopamine D2 receptor occupancy: implications for antipsychotic action.

Amperozide (FG 5606, N-ethyl-4-[4',4'-bis(p-fluorophenyl)butyl]-1-piperazine-carboxamide) is an atypical antipsychotic drug which has relatively weak in vitro affinity for striatal dopamine2 (D2) receptors and strong affinity for cortical 5-HT2 receptors. The in vivo affinity for 5-HT2 binding sites in rat cortex was 1.1 mg/kg. In striatum or olfactory tubercle, doses of amperozide up to 40 mg/kg did not displace radioligand binding to D2 receptors. Amperozide, haloperidol and ritanserin had similar in vivo potency in blocking the 5-HT2 binding site, but only haloperidol displaced D2 receptor binding. Based on the clinically effective dose of amperozide (0.14-0.28 mg/kg per day), it is suggested that the antipsychotic effect of amperozide is related, in part, to its in vivo interaction with the 5-HT2 receptor and that amperozide cannot be expected to exert its antipsychotic action by blockade of D2 receptors in the striatum or limbic regions.     

The cardiovascular effects of amperozide: interactions with cocaine

Amperozide is a 5-HT2A receptor antagonist that significantly reduces the acquisition and expression, by rats, of a cocaine conditioned place preference. In order to rule out the possibility that amperozide affects a cocaine conditioned place preference due to effects on blood pressure or heart rate, the cardiovascular effects of amperozide were investigated. Alternating cumulative doses of amperozide (0.5, 1.0, 1.5 and 2.5 mg kg(-1)) or saline and phenylephrine (8 microg kg(-1)) were administered through the femoral vein of awake freely-moving Sprague-Dawley rats and blood pressure and heart rate were recorded from the femoral artery. A single dose of cocaine (5.0 mg kg(-1)) was administered after all the amperozide or saline doses were given. Amperozide (0.5, 1.0, 1.5 and 2.5 mg kg(-1)) did not have any significant effect on blood pressure compared to the saline control treatment to the same animals. However, 0.5 mg kg(-1) amperozide significantly decreased heart rate at 5 and 10 min. after administration. but higher doses did not further depress heart rate. Amperozide did not affect the increased blood pressure and decreased heart rate caused by phenylephrine. an alpha1-adrenoceptor agonist. In addition, amperozide did not affect the cardiovascular response to an intravenous dose of 5.0 mg kg(-1) cocaine. These results suggest that amperozide does not cause direct cardiovascular effects. The mechanism by which the lowest dose of amperozide caused a decrease in heart rate is unknown. Amperozide affects neither alpha-adrenoceptor mediated vasoconstriction nor the increased sympathetic activity caused by the peripheral and central effects of cocaine. The significance of these results, in terms of locomotor activity and the cocaine conditioned place preference paradigm, is discussed.     

Effects of amperozide on induced turning behaviour in 6-OHDA lesioned rats

The effect of amperozide on DA synapses was studied in 6-OHDA lesioned rats exhibiting a specific turning behaviour in response to the DA agonists apomorphine and pergolide or indirectly acting stimulating agents like amphetamine. Amperozide, unlike classical neuroleptics, failed to antagonize apomorphine induced turning behaviour in a regular fashion, but showed pergolide antagonism within the D2 receptor selective dose range, suggesting a type of selective interference with dopaminergic nerve transmission which differs from that caused by classical neuroleptics. Furthermore, amperozide antagonized the turning behaviour induced by amphetamine, presumably by interfering with the availability of newly synthesized DA and NA suggesting a similar influence also on other DA releasing agents. Although amperozide potentiated the effects of α-MPT, the drug seemed not to influence the reserpine sensitive pool of DA.     

Effect of amperozide on the synthesis and turnover of monoamines in rat brain

The effects of amperozide on the synthesis and the turnover of monoamines in different brain regions of the rat were determined using both ex vivo and in vivo biochemical techniques (i.e. post-mortem measurements of the tissue levels by HPLC-EC, and direct measurements with the in vivo voltammetry technique). It was found that amperozide slightly increased the DOPA accumulation and the DOPAC content in limbic brain areas but not in the striatum. The DOPA accumulation was also slightly increased in the noradrenaline rich cortical region indicating increased synthesis of noradrenaline. Furthermore, amperozide increased the utilization of noradrenaline after tyrosine hydroxylase inhibition by α-methyl-p-tyrosine. The synthesis of 5-HT was not significantly altered by amperozide. In conclusion, the biochemical data obtained in this study suggest that amperozide produces preferential effects on the mesolimbic dopaminergic system. In addition, amperozide also interacts with the noradrenergic system.     

High frequency oral movements induced by long-term administration of amperozide but not FG5803 in rats

Long-term studies of antipsychotic-induced oral movements may serve as a rat model of acute and tardive movement disorders. Vacuous chewing movements (VCM), tongue protrusions (TP), and jaw tremors (TR) were studied in rats during acute and chronic administration of two potential antipsychotics, amperozide and FG5803. Comparisons were made with haloperidol and vehicle. Single intraperitoneal injections of amperozide (0.2, 1, or 5 mg/kg) or FG5803 (1.2, 6, or 30 mg/kg) were without effect on oral behaviors. During long-term drug administration, withdrawal and readministration, endpoint analysis was focused on changes in supranormal oral movements. The maximal mean control frequencies found at 29 sessions during 14 months experiment +2 standard deviations were used to define the upper limit of the normal range. FG5803 (1.2, 6, or 30 mg/kg per day) administered via the drinking water for 12 months, did not produce significant deviations from this normal range with respect to VCM, TP, or TR, and this drug was not studied further. Rats receiving amperozide (0.2, 1, or 5 mg/kg per day) showed dose-related increases in oral movements over the year. The changes began after 3 months of treatment with amperozide 1 and 5 mg/kg per day, but became statistically significant only during the second half of the treatment year. Amperozide 0.2 mg/kg per day did not produce significant changes in oral movements during administration for a year, but drug withdrawal resulted in a significant rise in TP behavior. Haloperidol (1 mg/kg per day) produced increases in supranormal oral movements which tended to level out after 9 months. In all groups with significant elevations (i.e. haloperidol and amperozide 1 and 5 mg/kg per day), there was a persistence of such movements during a month of drug withdrawal. During treatment with amperozide (1 or 5 mg/kg per day), some rats developed a high frequency chewing behavior up to 175 VCMs/min. It is concluded that long-term treatment with amperozide, but not FG5803, produced a tardive pattern of supranormal oral movements. The importance of these findings for the clinical future of amperozide is difficult to predict, due to the unexpected finding of high-frequency chewing, which has not been noticed before during extensive studies of classical neuroleptics.     

Synthesis of Dopamine and 5-HT in Anatomical Regions of the Rat's Brain is Unaffected by Sustained Infusion of Amperozide

Abstract: The 5-HT_2A antagonist, amperozide, is considered to be a potentially useful drug for the treatment of substance abuse. The effects of this drug on the Sprague-Dawley rat were examined on the synthesis of dopamine and serotonin (5-HT) as well as on the intakes of food and water and the level of body weight. Amperozide was delivered subcutaneously by osmotic minipump in doses of 2.5 mg/kg or 5.0 mg/kg per day for 7 days. After injection of 100 mg/kg NSD-1015, each brain was dissected post mortem into midbrain, pons, hypothalamus, septum, nucleus accumbens, striatum, frontal cortex and the hippocampus. Neither concentration of amperozide altered the synthesis of dopamine or 5-HT, as measured in terms of the formation of 1–3,4-dihydroxyphenylalanine (L-DOPA) and 5-hydroxytryptophan (5-HTP), respectively, in any of the 8 brain regions analyzed. Both doses of amperozide reduced food intake by 20% within 24 hr after implantation of the pumps, but feeding resumed postoperatively at the control level within 48 hr. Amperozide affected neither the intake of water nor the level of body weight. The lack of effect on the synthesis of dopamine and 5-HT and the absence of side effects on the intakes of food and water suggest that amperozide may be a specific agent for suppressing alcohol drinking.     

Antiarrhythmic effect of amperozide, a novel psychotropic compound with class III antiarrhythmic properties, on digoxin-induced arrhythmias in the guinea-pig

Amperozide is a novel psychotropic compound with specific effect in limbic brain areas. Preliminary findings have also indicated an antiarrhythmic effect in-vitro. Injections of saline, amperozide, melperone, thioridazine, bretylium or lignocaine, were given i.p. to anaesthetized guinea-pigs, which 10 min later were given digoxin s.c. to induce arrhythmia. In a series of control experiments none of these compounds caused arrhythmia in combination with the vehicle of digoxin. The time to arrhythmia was significantly prolonged after treatment with amperozide, melperone and bretylium compared with saline, but there were no differences between the treatments. The digoxin concentrations in plasma at death varied considerably within the groups and no statistical significance was found.     

Locomotor effects of amperozide. Antagonism of amphetamine-induced locomotor stimulation

Amperozide given subcutaneously (0.25 mg/kg) depressed amphetamine-induced locomotor activity by 40%. In the absence of amphetamine (1.5 mg/kg), this dose of amperozide had no effect on locomotor activity during the 60 min test period. Amperozide (0.1-1 mg/kg) dose-dependently decreased the locomotor activity of mice as measured in motron boxes. Only doses of amperozide greater than 0.25 mg/kg resulted in statistically significant (p less than 0.05) decreases in motor activity. Pretreatment of mice with flumazenil (10 mg/kg p.o., 30 min) or bicuculline (2 mg/kg i.p., 10 min) had no effect on amperozide (1 mg/kg)-induced hypomotility. These doses of the drugs had no effect per se. These results suggest that dopaminergic mechanisms might be involved in the amperozide-induced hypomotility.     

Determination of the place conditioning and locomotor effects of amperozide in rats: a comparison with cocaine

Amperozide promotes social interactions in rats (Rattus norvegicus) and reduces craving for cocaine and alcohol without producing adverse side effects. Amperozide administration produced a place preference in the dose range from 3.0 to 10.0 mg/kg. Locomotor behavior tended to be suppressed on the days of amperozide pairings, elevated on the days of vehicle pairings, and elevated on test days. Administration of 20.0 mg/kg but neither 2.0 nor 0.2 mg/kg cocaine produced place preference. Rats exhibited a greater place preference for the chamber paired with 2.0 mg/kg and 20.0 mg/kg but not 0.2 mg/kg cocaine compared to the chamber paired with 5.0 mg/kg amperozide. The results indicate that amperozide is appetitive. The most appetitive dose of amperozide (5.0 mg/kg) is less appetitive than the most appetitive dose of cocaine (20.0 mg/kg). More research is needed before conclusions regarding the degree of abuse potential for amperozide can be made.     

Effect of amperozide on the dopamine synthesis activity in the tuberoinfundibular neurons

The ability of amperozide (N-ethyl-4-[4,4-bis(p-fluorophenyl)butyl]-1-piperazinecarboxamide) , a potentially antipsychotic agent, to activate the tuberoinfundibular dopamine (TIDA) neurons was studied by measuring the accumulation of dihydroxyphenylalanine (DOPA) in the median eminence after inhibition of DOPA decarboxylase. The activity of the TIDA neurons was markedly elevated in a dose-related manner after treatment with amperozide (1 and 10 mg/kg). A significant stimulation was also found following treatment with the atypical antipsychotic agent clozapine (20 mg/kg) while the typical antipsychotic drug haloperiodol had no effect on TIDA neuron activity. The stimulatory effect of amperiozide on the TIDA neurons is suggested to be mediated by a non-dopaminergic mechanism.     

The effects of the atypical antipsychotic amperozide on vacuous jaw movements in rats: a novel dose response profile

Classic neuroleptic drugs produce a syndrome of vacuous jaw movements in rats, and this syndrome has been offered as an animal model of early onset extrapyramidal side effects. The atypical antipsychotics do not produce elevations in vacuous jaw movements, or do so only at very high doses. The purpose of the present study was to determine the impact of the putative antipsychotic, amperozide, on vacuous jaw movements in rats. Groups of rats received daily injections of haloperidol (0.2, 0.4, or 0.8 mg/kg), clozapine (2.0, 4.0, 8.0 mg/kg), amperozide (2.0, 4.0, 8.0 mg/kg) or vehicle for 4 weeks. Once per week, rats were observed for the presence of vacuous jaw movements. Haloperidol increased vacuous jaw movements with increasing doses. Clozapine only produced elevations in vacuous jaw movements at the highest dose. In contrast, increasing doses of amperozide resulted in decreasing vacuous jaw movements for this portion of the dose-response curve. This is the first report of the effect of amperozide on vacuous jaw movements and results are discussed in terms of a potentially unique behavioral profile with respect to this behavior. Received: 22 February 1996/Final version: 15 December 1997     

The putatively antipsychotic agent amperozide produces behavioural stimulation in the rat

Summary Amperozide (FG 5606; N-ethyl-4-[4,4-bis(p-fluorophenyl) butyl]-1-piperazinecarboximide) is a new putatively antipsychotic compound with a postulated 5-HT₂ antagonistic profile. Somewhat surprisingly amperozide dose dependently induced a behavioural stimulation in reserpinized and in nonpretreated rats. The behaviour consisted of both forward and backward locomotion as well as forepaw circling and a grooming like behaviour. Since the behavioural pattern clearly differ from that produced by classical dopaminergic or serotonergic agonists (e. g. apomorphine or 8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT), and has not been previously reported, we decided to investigate the origin of this effect.In the behavioural paradigms it was not possible to antagonize the amperozide stimulation in reserpinized rats with the dopamine receptor blockers haloperidol, raclopride or R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine, SCH 23390. Neither the 5-HT₂ receptor blocking agent ritanserin nor the tryptophan and tyrosine hydroxylase inhibitor DL-3,4-dihydroxy-phenyl--propylacetamide, H22/54, could block the motoric stimulation or the forepaw circling behaviour produced by amperozide. However, the noradrenaline synthesis inhibitor bis- (4-methyl-1-homopiperazinylthiocarbonyl)-disulfide, FLA 63, as well as the -adrenoceptor antagonist phenoxy-benzamine, could partly inhibit the locomotor stimulation. Hence, noradrenaline seems to be, at least in part, involved in the behavioural stimulatory effect of amperozide. synthesis rate (DOPA formation) in normal or reserpinized animals in the striatal or the limbic brain regions. In reserpinized animals amperozide also failed to antagonize the decrease in DOPA formation after apomorphine and 3-hydroxy-benzylhydrazine HCl, NSD 1015, in these regions. Thus, amperozide failed to show agonistic or antagonistic action on central dopamine receptors. However, in the noradrenaline rich cortical region amperozide induced an increase in DOPA accumulation. The compound also increased the levels of normetanephrine as well as antagonized the decrease in DOPA accumulation by clonidine in the cortical brain region. Amperozide also increased the disappearence rate of noradrenaline after inhibitor of tyrosine hydroxylase by -methyl-para-tyrosine. These data suggest that, biochemically, amperozide has got ₂ antagonistic properties. However, it is not evident that these biochemical properties are responsible for the behavioural effects of amperozide. Send offprint requests to Nicholas Waters at the above addressParts of this work were presented at the Society for Neuroscience 18th Annual Meeting, Toronto, 13–18 November 1988     

Electrophysiological effects of amperozide in papillary muscles from ferrets, guinea-pigs and rabbits

Amperozide, a novel psychotropic agent, in concentrations lower than 10 microM caused a homogenous prolongation only of the action potential in both guinea-pig and rabbit papillary muscle. In concentrations greater than or equal to 10 microM, amperozide caused a flattening of the action potential plateau and the later part of the repolarization phase became slower (longer), probably reflecting an impaired repolarizing Na-Ca exchange current. The overshoot (OS) and the rate of rise of the action potential (dV/dtmax) were depressed. It is concluded that amperozide has a blocking action on the transmembrane calcium current since Isi (second inward current), DIA (depolarization induced automaticity) and the peak force of contraction were depressed. The blocking of the Isi was use-dependent resembling the actions of calcium-antagonists like verapamil, except that it was less potent at equimolar concentrations. Amperozide in concentrations where it acted as an Isi-blocker (above 10 microM), had depressing effects only on ouabain-induced oscillatory events. No major differences in the effects of amperozide were apparent between guinea-pig, ferret or rabbit papillary muscles.     

Amperozide and clozapine but not haloperidol or raclopride increase the secretion of oxytocin in rats

The aim of the present study was to investigate whether amperozide, an antipsychotic drug which possesses anti-aggressive and anxiolytic-like properties, stimulates the secretion of oxytocin and if so, by which receptor mechanism. For this purpose, female or male Sprague Dawley rats were given amperozide (0.5, 2.5 and 5.0 mg/kg IP), ritanserin (5.0 mg/kg), raclopride (2.0 mg/kg) and prazosin (1.0 mg/kg) and were subsequently decapitated for collection of blood (30 and 120 min) after injection. Oxytocin levels were measured with radioimmunoassay. Amperozide 2.5 and 5 mg/kg increased plasma levels of oxytocin significantly (P<0.05 and <0.001). The effect appeared maximal about 30 min after injection of the drug and oxytocin levels were almost back to basal within 120 min. Similar effects were obtained in female and male rats as well as in animals that were freely fed or food deprived for 24 h. CSF levels of oxytocin were also increased. Ritanserin, a 5-HT₂-receptor antagonist but not the D₂ receptor antagonist raclopride or the ₁-adrenoceptor antagonist prazosin stimulated oxytocin release. In addition, clozapine, a neuroleptic with potent HT₂-antagonistic properties, was a potent releaser of oxytocin, whereas haloperidol was without effect. A possible role for oxytocin in the behavioural effects of amperozide and clozapine remains to be explored.