Biomedical subjects

J Arnt

Publications and source records attributed to J Arnt.

At least 19 recordsLinked to original sources

PubMed2002

Effects of the 5-HT(6) receptor antagonist, SB-271046, in animal models for schizophrenia.

The 5-HT(6) receptor is targeted by several new antipsychotics such as clozapine, olanzapine, and sertindole. We studied the effect of SB-271046 [5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide], a specific 5-HT(6) receptor antagonist, in three models for the positive symptoms of schizophrenia---D-amphetamine-induced hyperactivity, and D-amphetamine- or phencyclidine (PCP)-disrupted prepulse inhibition (PPI). We also tested this compound in a model for the negative symptoms of schizophrenia, PCP-disrupted social interaction (SIT) in rats. Induction of side effects by this compound was evaluated by testing its potency to reduce spontaneous motility, and to induce catalepsy in rats. The effect of SB-271046 was compared to clozapine in all models tested. This study showed that SB-271046 had no beneficial effect in PCP-disrupted SIT. However, SB-271046 dose-dependently normalised D-amphetamine-disrupted PPI, but did not reverse PCP-disrupted PPI. In addition, SB-271046 did not antagonise D-amphetamine-induced hyperactivity. Thus, this specific 5-HT(6) receptor antagonist was associated with a clear positive outcome in only one model for the positive symptoms of schizophrenia, and had no beneficial effect in the model for negative symptoms. Consequently, it is clear that SB-271046 is not expected to have an antipsychotic efficacy, at least when given as monotherapy.

Animals↗

PubMed2002

Effects of the 5-HT(7) receptor antagonist SB-258741 in animal models for schizophrenia.

The 5-HT(7) receptor is targeted by several new antipsychotics such as clozapine and risperidone. We studied the effect of R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine (SB-258741), a specific 5-HT(7) receptor antagonist, in three models for positive symptoms, D-amphetamine-induced hyperactivity and D-amphetamine- and phencyclidine (PCP)-disrupted prepulse inhibition (PPI) in rats, with the aim of investigating the role of this receptor in the clinical effect of antipsychotics. We also tested this compound in a model for negative symptoms, PCP-disrupted social interaction (SIT) in rats. Induction of side effects by this compound was evaluated by testing its potency to reduce spontaneous motility and to induce catalepsy in rats. The effect of SB-258741 was compared to risperidone in all models. This study showed that SB-258741 had no beneficial effect on PCP-disrupted SIT. SB-258741 did not reverse D-amphetamine-disrupted PPI; however, it dose-dependently normalised PCP-disrupted PPI. SB-258741 antagonised D-amphetamine-induced hyperactivity but reduced motility of rats at similar doses. Thus, this specific 5-HT(7) receptor antagonist brought a clear positive outcome in only one model for positive symptoms of schizophrenia and had no beneficial effect in the model for negative symptoms. Consequently, it is clear that SB-258741 affects the PPI phenomenon but is not expected to have an antipsychotic effect on its own in clinic.

Animals↗

PubMed2001

Induction of tolerance to the suppressant effect of the neurotensin analogue NT69L on amphetamine-induced hyperactivity.

Although several studies have indicated that neurotensin administered acutely has several pharmacological properties common with those of antipsychotic drugs, the effects of repeated exposure to neurotensin receptor agonism have been less well characterised. Here, we investigated the effect of the novel neurotensin-(8-13) analogue NT69L [(N-methyl-Arg), Lys, Pro, L-neo-Trp, tert-Leu, Leu] in animal models sensitive to central neurotensin receptor stimulation as well as in predictive models for antipsychotic activity and motor side-effect liability. Acute injection of NT69L (0.19-6.1 micromol/kg, s.c./i.p.) caused hypothermia (>2.5 degrees C) and reduction in spontaneous locomotor activity but failed to induce catalepsy. Furthermore, NT69L (0.10 micromol/kg, s.c.) counteracted the hyperlocomotion elicited by amphetamine (0.5 mg/kg, s.c.). However, repeated injections of NT69L (0.19 micromol/kg, s.c. for 6 days, twice daily) significantly reduced its effect on spontaneous locomotor activity and completely abolished its effect on amphetamine-elicited hyperactivity. Our data obtained after single injections of NT69L indicate that this drug stimulates central neurotensin receptors after peripheral administration and collectively support the notion that neurotensin receptor agonism is associated with an attractive pre-clinical profile as regards both antipsychotic activity and motor side-effect liability. However, the present results also indicate that repeated neurotensin receptor stimulation may cause a desensitisation of neurotensin receptor mediated effects.

Amphetamine↗

PubMed2000

Intracranial self-stimulation and sucrose intake differ as hedonic measures following chronic mild stress: interstrain and interindividual differences.

The present study was designed to assess the utility of sucrose intake and intracranial self-stimulation (ICSS) as hedonic measures for chronic mild stress (CMS) induced behavioural deficits. Wistar and PVG hooded rats were exposed to a variety of mild stressors, e.g. periods of food and/or water deprivation, soiled cage, light/dark reversal, confinement to small cages and pairing, during 6-9 weeks. The intake of 1% sucrose solution was significantly reduced in stressed PVG hooded rats compared to control animals. The sucrose intake in stressed Wistar rats remained unaltered, indicating that CMS-induced decreases in sucrose intake are strain dependent. However, sucrose intake has in our experience been shown to be unreliable as the observed decreases following CMS were inconsistent over time. ICSS behaviour was evaluated from rate/frequency functions by determining the frequency that supported 50% of maximal response rate. Neither the Wistar nor the PVG hooded rats showed an overall decrease in ICSS behaviour following CMS. However, the ICSS measures revealed interindividual differences in both rat strains. In the stress groups a subgroup (14 +/- 2.4%) of rats progressively exhibited an attenuated ICSS behaviour. These findings may reflect the interindividual variability observed in humans as stress does not invariably lead to depression. The model may in its present form be used to study the pathophysiology of depressive disorders. However, the utility of the CMS model to study antidepressant drug actions has to be questioned. Our results show there is a need for rat strains in which there is a greater sensitivity for detecting stress effects. It emphasises the fact that replication of CMS-induced decreases in ICSS behaviour can be as problematic as inducing decreases in sucrose intake.

Animals↗

PubMed2000

In-vivo assessment of 5-HT2A and 5-HT2C antagonistic properties of newer antipsychotics.

The effects of serotonin (5-HT) receptor ligands on the MK 212 (6-chloro-2[1-piperazinyl]pyrazine) discriminative stimulus and quipazine-induced head twitches were studied in rats. 5-HT1A (8-OH-DPAT) and preferential 5-HT2A (DOI) receptor agonists did not generalize to the discriminative stimulus. The 5-HT2B/2C-receptor antagonist, SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2 ,3-f]indole), and the 5-HT2A/2C-receptor antagonist, ritanserin, acted as potent antagonists, whereas the 5-HT2A-receptor antagonist, MDL 100.151 ([(+/-)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4- piperidine-methanol), produced minor and inconsistent inhibition. SB 206553 was a weak antagonist against quipazine-induced head twitches, whereas MDL 100.151 and ritanserin were potent antagonists. This suggests that the MK 212 discriminative stimulus is mediated by 5-HT2C receptors, while quipazine-induced head twitches are mediated primarily by 5-HT2A receptors. The effects on quipazine-induced head twitches were comparable to previously published effects on the DOI discriminative stimulus. 5-HT2A- and 5-HT2C-receptor antagonistic potencies of clozapine, olanzapine, risperidone, sertindole and ziprasidone were compared in the same models. Clozapine showed similar potencies in both models, while sertindole, olanzapine and risperidone inhibited quipazine-induced effects more potently than the MK 212 discriminative stimulus. Ziprasidone exerted a minor preference for 5-HT2A- compared to 5-HT2C-receptor-mediated effects. The ratio between in vivo inhibitory potencies at 5-HT2A and 5-HT2C receptors did not correlate with corresponding ratios from in-vitro affinity and ex-vivo occupancy studies in the literature.

Animals↗

PubMed1998

In vivo muscarinic cholinergic mediated effects of Lu 25-109, a M1 agonist and M2/M3 antagonist in vitro.

Lu 25-109 [5-(2-ethyl-2H-tetrazol-5-yl)-1,2,3,6-tetrahydro-1-methylpyridine] , has M agonistic and M2/M3 antagonistic effects at muscarinic receptors in vitro; a pharmacological profile that may be beneficial in treatment of Alzheimer's disease. In the present study, we compare functional in vivo effects of Lu 25-109 and reference compounds in animal models of muscarinic cholinergic function. Lu 25-109 substituted completely for the discriminative stimulus effects of (-)-7-methyl-3-(2-propynyloxy)-4,5,6,7-tetrahydroisothiazolo -[4, 5-c]pyridine (Lu 26-046), a partial M1/M2 agonist, but only weakly for the effects of the non-selective M1/M2/M3 agonist 3-methoxy-4,5,6,7-tetrahydro-isoxazolo[4, 5-c] pyridine (O-Me-THPO). Lu 25-109 did not reverse O-Me-THPO-induced discriminative stimulus. Tacrine did not substitute for any of the training drugs. Lu 25-109 did not substitute in (-)-nicotine trained rats. Lu 25-109 did not antagonize oxotremorine-induced hypothermia, tremor and salivation in mice and antagonized physostigmine-induced lethality with low potency. Unlike non-selective muscarinic agonists and acetylcholinesterase inhibitors, Lu 25-109 did not induce hypothermia, tremor or salivation in mice. Spontaneous locomotor activity and motor co-ordination were inhibited only at high doses. Lu 25-109 had no effect on mean blood pressure in anaesthetized rats. Lu 25-109 and O-Me-THPO produced a significant increase in heart rate. The maximum increase was 37%. In anaesthetized cats, increasing i.v. doses of Lu 25-109 were without effect on the mean blood pressure, except for a short lasting (<2 min) depressor effect following the IV injection. Furthermore, Lu 25-109 did not attenuate the reflex mechanisms restoring blood pressure following orthostasis in cats. In conclusion, the drug discrimination studies suggest a unique activity profile of Lu 25-109, and the in vivo profile suggests none or a very low frequency of unwanted cholinergic mediated effects.

Animals↗

PubMed1998

Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence.

The pharmacological properties of the novel antipsychotic drugs (APDs) risperidone, sertindole, olanzapine, quetiapine, ziprasidone, remoxipride, and amperozide are reviewed and compared with haloperidol and clozapine. Focus is made on their receptor profiles, their effects in animal models used for evaluation of antipsychotic activity, and extrapyramidal side effects (EPS). In addition, the contrasting actions of these compounds on animal models of cognition, anxiety, and depression are briefly reviewed. The available evidence indicates that novel APDs and clozapine can be differentiated from haloperidol, particularly in models of EPS and cognitive side effects. However, among the group of novel APDs there are many individual differences in models reflecting limbic versus striatal inhibition of dopamine function: clozapine and sertindole show the largest limbic selectivity, followed by quetiapine, ziprasidone, olanzapine and remoxipride, whereas risperidone in many respects has a profile that resembles haloperidol. To date, the results of clinical studies have confirmed the predictions of lower incidence or absence of EPS after administration of novel APDs in doses which demonstrate antipsychotic efficacy.

Animals↗

PubMed1998

Pharmacological differentiation of classical and novel antipsychotics.

The symptoms of schizophrenia are treated through the blockade of mesolimbic and mesocortical dopamine activity. However, if dopamine activity in the nigrostriatal region is also blocked, extrapyramidal syndromes (EPS) are induced, and EPS are a major cause of noncompliance. It is therefore important for antipsychotic drugs with selective pharmacological profiles to be developed. Animal models for limbic selectivity and dose-response separation between behavioural and pharmacological parameters, which are analogous to EPS and antipsychotic effects, can now be used to differentiate between novel antipsychotics with few or no EPS and classical antipsychotics. Schizophrenic patients also often experience cognitive dysfunction, and it is important that antipsychotic drugs are developed that do not exacerbate this. Again, animal models can be used to give an indication of whether a compound has any effect on cognition. Both behavioural and electrophysiological rat models indicate that novel antipsychotic drugs, such as sertindole, but not classical antipsychotic drugs, such as haloperidol, demonstrate marked limbic selectivity. Nonhuman primate models of EPS show that the novel antipsychotics have a much greater separation between dose-response curves for antipsychotic effect and the development of EPS. The Morris water maze confirmed that sertindole does not adversely affect spatial learning or memory in rats. This paper reports on the differentiation between classical and novel antipsychotics using animal models.

Animals↗

PubMed1997

Differentiation of classical and novel antipsychotics using animal models.

The criteria that have been used to differentiate classical and atypical antipsychotics include measures of neurological and cognitive side effects and therapeutic effects. Novel antipsychotic compounds with few or no extrapyramidal syndromes (EPS) can be differentiated from classical neuroleptics by a number of animal models for limbic selectivity and dose-response separation between behavioral and pharmacological parameters analogous to EPS and antipsychotic effects. The results obtained using these models seem to be concordant with clinical findings. Moreover, animal models expand our understanding of the pharmacological mechanisms responsible for EPS and for the therapeutic effects of antipsychotics, and they allow an examination of the possible effects of new compounds on cognition. Here we review a number of key reports on the differentiation of classical and novel antipsychotics using animal models.

Animals↗

PubMed1997

The selective sigma2-ligand Lu 28-179 has potent anxiolytic-like effects in rodents.

The anxiolytic potential of the selective sigma2 ligand 1-[4-[1-(4-Fluorophenyl)-1H-indol-3-yl]-1-butyl]spiro[isobenzofuran-1(3H),4-piperidine] [corrected] (Lu 28-179) was assessed in various animal models of anxiety in rodents. Lu 28-179 facilitated the exploratory behavior of mice and rats in the black and white two-compartment box over a large dose range. In the rat, the minimal effective dose (MED) was 0.18 nmol/kg (0.1 microg/kg), and in the mouse, the MED was 0.00018 nmol/kg (0.1 ng/kg). The anxiolytic-like effect was maintained after treatment with 1 microg/kg/day for up to 14 days, and no anxiogenic-like effects were seen upon withdrawal from repeated treatment. Lu 28-179 increased the time that pairs of rats spent in active social interaction (unfamiliar high-light conditions), MED = 0.1 ng/kg. Daily treatment with Lu 28-179 (1.8 nmol/kg = 1 microg/kg/day) for up to 4 weeks increased the social interaction time significantly compared with controls, and no anxiogenic-like effects were seen upon withdrawal. Furthermore, Lu 28-179 reversed shock-induced suppression of drinking in the rat (MED = 18,000 nmol/kg = 10 mg/kg). Lu 28-179 did not inhibit footshock-induced ultrasonic vocalization in the rat or isolation-induced aggressive behavior in the mouse. Lu 28-179 was over 100 times more potent than diazepam in the rat and mouse black and white test box and the rat social interaction test, whereas the potency of Lu 28-179 was comparable to that of lorazepam in reversal of shock-induced suppression of drinking. Lu 28-179 neither induced sedation nor impaired motor coordination, even at high doses (70,000 nmol/kg = 40 mg/kg). In conclusion, Lu 28-179 exerts potent and long-lasting anxiolytic-like effects in rodents without inducing sedation and withdrawal anxiogenesis.

Animals↗

PubMed1996

Assessment of relative efficacies of 5-HT1A receptor ligands by means of in vivo animal models.

We have evaluated the effects of ligands with varying efficacies at beta-adrenoceptors and 5-HT1A receptors in three in vivo models reflecting pre- and/or postsynaptic 5-HT1A receptor activation. Forepaw treading in rats is mediated by postsynaptic 5-HT1A receptors, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamin)tetralin)-induced discriminative stimulus is predominantly mediated by postsynaptic, but presynaptic 5-HT1A receptors might also be involved, and footshock-induced ultrasonic vocalization involves predominantly presynaptic 5-HT1A receptors. In vitro receptor binding studies demonstrated high beta-adrenoceptor and 5-HT1A receptor affinity of (-)-penbutolol, high beta-adrenoceptor and 60 times lower 5-HT1A receptor affinity of (+)-penbutolol, high beta-adrenoceptor affinity and about 100 times lower 5-HT1A receptor affinity of pindolol and (-)-tertatolol, only affinity for beta-adrenoceptors of metoprolol and ICI 118,551 (erythro-D,L-1-(7-methylindan-4-yloxy)-3-isopropylamine-b utan-2-ol, and only affinity for 5-HT1A receptors of WAY 100.635 ((N-[2-[4- (2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclo-hexane-carboxamide). (-)-Penbutolol, (-)-tertatolol, pindolol and WAY 100.635 antagonized 5-MeODMT-induced (5-methoxy-N, N-dimethyltryptamine) forepaw treading in rats, and (+)-penbutolol, ICI 118,551 and metoprolol were inactive. (-)-Penbutolol, WAY 100.635 and (-)-tertatolol antagonized 8-OH-DPAT-induced discriminative stimulus in rats, pindolol and metoprolol showed a mixed antagonistic and agonistic profile. Pindolol antagonized footshock-induced ultrasonic vocalization in rats, tertatolol inhibited maximum 36% and WAY 100.635, (-)-penbutolol, (+)-penbutolol, metroprolol and ICI 118,551 were inactive. (-)-Penbutolol and WAY 100.635 reversed 8-OH-DPAT-induced inhibition of ultrasonic vocalization completely, (-)-tertatolol reversed maximum 52% and (+)-penbutolol and pindolol were inactive. It is concluded, that efficacies at 5-HT1A receptors can be estimated by applying a battery of in vivo test models that involve post- and presynaptic receptors to a variable degree. The in vivo ranking order of efficacy at 5-HT1A receptors was: WAY 100.635 = (-)-penbutolol < (-)-tertatolol < pindolol.

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

PubMed1996

The antiaggressive potency of (-)-penbutolol involves both 5-HT1A and 5-HT1B receptors and beta-adrenoceptors.

The relative importance of 5-HT1A and beta-adrenergic activities in the antiaggressive effects of (-)-penbutolol was studied in male mice. (-)-Penbutolol had high affinity for 5-HT1A receptors and beta-adrenoceptors, and antagonized the 5-methoxy-N,N-dimethyltryptamine (5-MeODMT)-induced 5-HT syndrome and the 8-hydroxy-2-(di-n-propylamin)tetralin (8-OH-DPAT)-induced discriminatory stimulus in rats. (-)-Penbutolol abolished aggressive behaviour (ED50 = 56 mumol/kg), and reversed the antiaggressive effects of 8-OH-DPAT and 1-(3-trifluoromethylphenyl)piperazine (TFMPP) (ED50 = 8.1 and 2.1 mumol/kg, respectively). (N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl-N-(2-pyridinyl) cyclohexanecarboxamide (WAY 100635) reversed the antiaggressive effects of 8-OH-DPAT (ED50 = 0.012 mumol/kg), but did not affect the antiaggressive effects of TFMPP. The antiaggressive effect of a submaximal dose of 8-OH-DPAT was markedly potentiated by beta-adrenoceptor antagonists without 5-HT1A receptor affinity, whereas (-)-penbutolol was effective at only one dose (4.5 mumol/kg). In conclusion, the 5-HT1A receptor antagonistic potency of (-)-penbutolol in aggressive mice is attenuated by beta-adrenoceptor-induced facilitation of serotonergic neurotransmission.

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

PubMed1996

Inhibitory effects on the discriminative stimulus properties of D-amphetamine by classical and newer antipsychotics do not correlate with antipsychotic activity. Relation to effects on the reward system?

Classical antipsychotics exemplified by haloperidol (0.30), fluphenazine (0.070) and cis(Z)-flupentixol (0.088; ED50 values in mumol/kg are given in parentheses for all compounds) potently block the discriminative stimulus properties of D-amphetamine (1.0 mg/kg, IP) in rats. Newer antipsychotics have very different profiles: clozapine (7.2) and olanzapine (5.9) induce dose-dependent inhibition, while risperidone (> 6.1) and remoxipride (> 47) show weak inhibitory effects and sertindole (> 23), seroquel (> 20), amperozide (> 2.9) and the putative antipsychotic MDL 100151 (> 13; racemate with MDL 100907 as the active enantiomer) are ineffective. Antagonists of alpha 1-adrenoceptors (prazosin; > 6.0), 5-HT2A/2C (ritanserin; > 2.6) and histamine H1 receptors (mepyramine; > 50) are ineffective. Sertindole (0.076), risperidone (0.23), clozapine (0.39), olanzapine (0.088), MDL 100151 (0.0082), fluphenazine (0.13) and ritanserin (0.12) are potent inhibitors of the discriminative stimulus induced by the 5-HT2A/2C agonist DOI (0.63 mg/kg, IP), while haloperidol (approximately 0.4), cis(Z)-flupentixol (approximately 0.04), amperozide (approximately 0.5) and prazosin (> 12) show partial inhibition and remoxipride (> 23) and mepyramine (> 25) are ineffective. The results indicate that inhibition of D-amphetamine discrimination does not correlate with antipsychotic activity of newer antipsychotics, as has previously been suggested in the literature. Furthermore, the inhibitory potencies against D-amphetamine-induced discrimination (present study) and hypermotility (previous study in the same strain of rats) do not correlate either for several of the newer antipsychotics (e.g. for sertindole, risperidone, seroquel and remoxipride). The discrepancies cannot solely be explained by additional pharmacological effects of these compounds, e.g. 5-HT2 receptor blockade. The D-amphetamine discrimination is documented to depend on increased limbic dopamine function which in humans is associated with increased euphoria. Based on these results, it is hypothesized that D-amphetamine discrimination rather than a model for antipsychotic activity may reflect dysphoric or anhedonic activity.

Amphetamine↗

PubMed1995

Enhanced D1 affinity in a series of piperazine ring substituted 1-piperazino-3-arylindans with potential atypical antipsychotic activity.

A study of the effect of aromatic substitution on D1 and D2 affinity in a series of previously reported trans-1-piperazino-3-phenylindans shows similar structure-activity relationships for the two receptor sites. 6-Substituted derivatives have affinity for both receptors, and 6-chloro-or 6-fluoro-substituted derivatives show preference for D1 receptors. D1 affinity and selectivity are significantly increased in a series of new piperazine ring substituted derivatives. Potent D1 and D2 antagonism in vivo are confined to derivatives with relatively small substituents in the 2-position of the piperazine ring (e.g. 2-methyl,2,2-dimethyl, 2-spirocyclobutyl or 2-spirocyclopentyl). Consequently, the effect of aromatic substitution is examined in a series of 1-(2,2-dimethylpiperazino)-3-arylindans. All these compounds except the 4-, 5-, 7- and 4'-chloro-substituted derivatives have potent D1 affinity (IC50's below 10 nM) and the majority of the compounds antagonize SK&F 38393-induced circling in 6-OHDA-lesioned rats with ED50 values about 1 mumol/kg. In vitro all compounds show preference for D1 receptors, but in vivo they are equally effective as D1 and D2 antagonists. The compounds have high affinity for 5-HT2 receptors and selected compounds show high affinity for alpha 1 adrenoceptors. Furthermore, a subgroup consisting of (-)-38, (-)-39, (-)-41, and (-)-54 does not induce catalepsy in rats. These compounds have the potential of being "atypical" antipsychotics and have consequently been selected for further studies. The non-receptor-blocking enantiomers are shown to be inhibitors of DA and NE uptake in accordance with previous observations in compounds unsubstituted in the piperazine ring. Two compounds, (+)-38 and (+)-40, block DA uptake with IC50 values below 10 nM. Finally, the observed structure-activity relationships are discussed in relation to previously published pharmacophore models for D2 and 5-HT2 receptors. It is concluded that the piperazine substituents might induce a different binding mode at the dopamine receptor sites, perhaps only at the D1 receptor site.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1995

Differentiation of in vivo effects of AMPA and NMDA receptor ligands using drug discrimination methods and convulsant/anticonvulsant activity.

The discriminative stimulus properties of the AMPA ((RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid) receptor agonist ATPA ((RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propionic acid) and NMDA (N-methyl-D-aspartic acid) in rats have been characterized. It is suggested that the cues are mediated by separate mechanisms in the central nervous system. The ATPA cue is not mimicked by NMDA or an NMDA receptor agonist, and is inhibited by the AMPA receptor antagonist (R)-APPA ((R)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid) but not the AMPA receptor antagonist ATOA ((RS)-2-amino-3-(3-carboxymethoxy-5-tert-butylisoxazol-4-yl)propio nic acid) or the NMDA receptor antagonist CPP ((RS)-3-(2-carboxypiperazin-4-yl)propyl)phosphonic acid). The ATPA cue is not mimicked by AMPA which is believed not to penetrate the blood-brain barrier. In contrast, ATPA does not generalize to the NMDA cue, which is mimicked by some NMDA receptor agonists (tetrazol-5-yl-glycine and AMAA ((RS)-2-amino-2-(3-hydroxy-5-methylisoxazol-4-yl)acetic acid)) and is inhibited by the NMDA receptor antagonist CPP. Highly potent convulsant activity was demonstrated in mice with all AMPA and NMDA receptor agonists after intracerebroventricular (i.c.v.) injection, whereas weaker or no effects were found after subcutaneous (s.c.) or intravenous injection. Only (RS)-tetrazol-5-yl-glycine had a potent effect after s.c. administration. I.c.v. ATOA and CPP inhibited convulsions induced by i.c.v. injection of AMPA or NMDA, while (R)-APPA was ineffective. These results indicate that there are differences in the structure-activity relations in the drug discrimination and convulsant/anticonvulsant models, even when effects after i.c.v. and s.c. injection are taken into consideration. The convulsion models are rapid tests which can give an indication of central nervous system penetration, but are less pharmacologically specific with respect to differentiation between AMPA and NMDA ligands where cue models demonstrate clear differences in effects of ligands with selectivity for receptor subtypes.

Animals↗

PubMed1995

Differential effects of classical and newer antipsychotics on the hypermotility induced by two dose levels of D-amphetamine.

The inhibitory effects of a variety of established and putative antipsychotic compounds on the hypermotility induced by D-amphetamine at two dose levels (0.5 and 2.0 mg/kg) have been studied. Classical antipsychotics (haloperidol, fluphenazine and cis(Z)-flupentixol) and the selective dopamine D2 receptor antagonist remoxipride inhibit hypermotility in the two conditions with similar potencies, whereas sertindole, clozapine, risperidone, ziprasidone and olanzapine preferentially inhibit the effect of the low dose of D-amphetamine (selectivity ratios between 6.5 and 18). Seroquel, amperozide and the selective 5-HT2A receptor antagonist MDL 100.151 ((+/-)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-p iperidine - methanol) have no effect on D-amphetamine 2.0 mg/kg, but inhibit the response to D-amphetamine 0.5 mg/kg. The alpha 1-adrenoceptor antagonist prazosin inhibits the motility response to D-amphetamine 0.5 mg/kg with slightly higher potency than that to D-amphetamine 2.0 mg/kg, whereas the 5-HT2A/2C receptor antagonist ritanserin selectively inhibits the effect of D-amphetamine 0.5 mg/kg. The histamine H1 receptor antagonist mepyramine is ineffective in both models. All compounds, except remoxipride, MDL 100.151 and ritanserin (which are ineffective) inhibit spontaneous locomotor activity at dose levels close to those inhibiting the response to D-amphetamine 2.0 mg/kg. Prazosin has partial inhibitory effect. In conclusion, dopamine antagonism has similar inhibitory effect on hyperactivity induced by low and high D-amphetamine dosages, alpha 1-adrenoceptor antagonism also contributes to both effects, whereas 5-HT2 receptor antagonism selectively interacts with the low D-amphetamine dose. This indicates that the responses to D-amphetamine 0.5 and 2.0 mg/kg are differently modulated by these neurotransmitters.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Stereospecific and selective 5-HT2 antagonism in a series of 5-substituted trans-1-piperazino-3-phenylindans.

A study of the effect of aromatic substitution on 5-HT2, D2, and alpha 1 receptor affinity in a subseries of new and previously synthesized 1-piperazino-3-phenylindans indicated that high 5-HT2 selectivity could be obtained in 5-substituted derivatives. Accordingly, a series of 5-substituted derivatives was synthesized with the goal of obtaining stereospecific and selective, centrally acting 5-HT2 antagonists. This goal was fulfilled in 5-chloro- or 5-fluoro-substituted compounds with 2-(3-alkyl-2-oxoimidazolidin-1-yl)ethyl- or 2-(tetrahydro-2-oxo-1H-pyrimidin-1-yl)ethylpiperazine substituents, as well as in their imidazolidine-2-thione or pyrimidine-2-thione analogues. The most interesting derivatives were resolved either directly via diastereomeric salts or by syntheses from resolved starting materials. Optical purity was determined by a 1H NMR method, using the chiral shift reagent (R)-(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol. The compound (-)-trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden++ +-1- yl]piperazin-1-yl]ethyl]-3-isopropyl-2-imidazolidinone ((-)-20) had the overall best profile with a high stereoselectivity (eudismic ratio: 68) and a high selectivity versus D2 and alpha 1 receptors (affinity ratios 182 and 191, respectively). It had a potent central effect but was shorter-acting than the tetrahydropyrimidinone or thione derivatives ((-)-39, (+)-40, (-)-41, and (+)-42). The observed activities of the compounds are settled in perspective in relation to a recently proposed D2 receptor interaction model. While there are no indications so far that trans-1-piperazino-3-phenylindans interact with D2 and 5-HT2 receptors in different conformations, the present study shows important differences in aromatic substitution effects. Only 5-HT2 receptors are able to accommodate a 5-substituent in the indan benzene ring, thus allowing syntheses of highly selective compounds.

Animals↗

PubMed1993

The role of serotonergic mechanisms in inhibition of isolation-induced aggression in male mice.

The role of serotonergic (5-HT) receptor subtypes in mediation of aggressive behaviour in isolated male mice has been studied. Increase of attack latency was used as a simple measure of antiaggressive behaviour. 5-HT1A agonists (BAY R 1531, 8-OHDPAT, flesinoxan, gepirone, 5MeO DMT, buspirone, ipsapirone, BMY 14802) completely inhibit the aggressive behaviour irrespective of their intrinsic activities. Also the putative antagonists spiroxatrine and NAN 190 as well as the non-selective 5-HT1 agonists RU 24969, TFMPP, mCPP and eltoprazine have an antiaggressive effect. The mixed 5-HT1A and beta-adrenoceptor antagonists (-)-alprenolol and pindolol are ineffective and do not inhibit the effect of 8-OHDPAT. Neither does the non-selective 5-HT antagonist metergoline. The antiaggressive effect correlates with 5-HT1A receptor affinity in vitro and with generalization to the 8-OHDPAT-induced discriminative stimulus. The selective 5-HT uptake inhibitor citalopram does not inhibit aggressive behaviour. The 5-HT2 agonist DOI has an antiaggressive effect only at high doses, whereas the 5-HT2 antagonist ritanserin and the 5-HT3 antagonist ondansetron are ineffective. Prazosin (alpha 1-adrenoceptor antagonist), clonidine (alpha 2-adrenoceptor agonist), clenbuterol (beta-adrenoceptor agonist), ketanserin (5-HT2 receptor and alpha 1-adrenoceptor antagonist), clozapine and (-)-octoclothepin (dopamine (DA), 5-HT2 receptor and alpha 1-adrenoceptor antagonist) all show an antiaggressive effect. SCH 23390 (DA D1 receptor antagonist) and emonapride (DA D2 receptor antagonist) are ineffective. In conclusion, 5-HT1A receptors are involved in mediation of isolation-induced aggressive behaviour in mice. The involvement of other 5-HT receptor subtypes needs further clarification. The adrenergic system may also be involved.(ABSTRACT TRUNCATED AT 250 WORDS)

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