Biomedical subjects

J Mos

Publications and source records attributed to J Mos.

At least 19 recordsLinked to original sources

PubMed1995

The corticosterone-enhancing effects of the 5-HT1A receptor antagonist, (S)-UH301, are not mediated by the 5-HT1A receptor.

We tried to antagonize the endocrine and behavioural changes induced by the selective 5-HT1A receptor agonist, flesinoxan, with the putative 5-HT1A receptor antagonist, (S)-UH301 ((S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin). The interaction of (S)-UH301 (3 and 10 mg/kg s.c.) with flesinoxan (3 mg/kg s.c.) showed no antagonistic effects of (S)-UH301 on flesinoxan-induced corticosterone secretion. In fact, like flesinoxan (1 and 3 mg/kg s.c.), (S)-UH301 (3 and 10 mg/kg s.c.) itself dose dependently increased plasma corticosterone levels. Unlike flesinoxan, (S)-UH301 did not induce hyperglycemia, lower lip retraction and flat body posture. Moreover, flesinoxan-induced hyperglycemia and behavioural changes were effectively antagonized by (S)-UH301, showing potent 5-HT1A receptor antagonistic effects of (S)-UH301. Therefore we conclude that (S)-UH301 is a potent 5-HT1A receptor antagonist and that the (S)-UH301-induced corticosterone secretion is mediated by a non-5-HT1A receptor mechanism.

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

PubMed1995

Conditioned ultrasonic distress vocalizations in adult male rats as a behavioural paradigm for screening anti-panic drugs.

Rats may produce ultrasonic vocalizations (USV) in threatening situations. USV of adult male rats in association with aversive stimulation was evaluated as a screening method for anxiolytic drugs. The triazolobenzodiazepine alprazolam, the 5-HT uptake inhibitors fluvoxamine and clomipramine, the mixed 5-HT/NA uptake inhibitor imipramine, the full 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan, the partial 5-HT1A receptor agonists buspirone, ipsapirone and BMY 7378, the alpha 2-adrenoceptor agonist clonidine and the alpha 2-adrenoceptor antagonist yohimbine reduced conditioned USV. The classical benzodiazepines (BZD) diazepam and chlordiazepoxide were ineffective or had a very low potency to decrease USV. The partial BZD receptor agonists bretazenil, alpidem and zolpidem, the BZD receptor antagonist flumazenil, the NA uptake inhibitors desipramine and maprotiline, and the 5-HT3 receptor antagonist ondansetron had no effect on conditioned USV. The dopamine-D2 receptor antagonist haloperidol reduced USV at a very high dose. In separate experiments the effects of these drugs on locomotor activity were assessed. There was, however, no direct relationship between effects on motor behaviour and USV. In conclusion, the sensitivity of conditioned USV to 5-HT uptake inhibitors and alprazolam versus the insensitivity to classical benzodiazepines and NA uptake inhibitors provides a very interesting profile, which closely resembles the psychopharmacology of panic disorder. Also the face validity of conditioned USV towards situational panic attacks is high. We therefore propose conditioned USV in adult male rats as a novel behavioural paradigm to screen for anti-panic drugs.

Animals↗

PubMed1994

Adrenoceptors and dopamine receptors are not involved in the discriminative stimulus effect of the 5-HT1A receptor agonist flesinoxan.

Using a two-lever operant drug discrimination procedure, rats were trained to discriminate the 5-HT1A receptor agonist, flesinoxan (0.5 mg/kg i.p.), from saline. Hereafter, several non-serotonergic drugs were tested in generalization and antagonism tests. The flesinoxan stimulus did not generalize to the stimuli of either the alpha 1-adrenoceptor antagonist, prazosin, the alpha 2-adrenoceptor agonist, clonidine, the dopamine receptor agonist, apomorphine, the dopamine receptor antagonists, haloperidol and pimozide, the benzodiazepine receptor agonist, chlordiazepoxide, nor to the peripherally acting vasodilator, hydralazine. In antagonism studies, prazosin, haloperidol, pimozide and the alpha 2-adrenoceptor antagonist, idazoxan, failed to block the flesinoxan stimulus. In substitution tests, however, flesinoxan partially generalized to idazoxan and completely to the alpha 2-adrenoceptor antagonist, yohimbine. The affinities of yohimbine and idazoxan for the 5-HT1A receptor may explain the latter result. The present findings suggest that the central mechanism through which flesinoxan exerts its discriminative stimulus effects does not involve alpha 1- and alpha 2-adrenoceptors, dopamine and benzodiazepine receptors. Finally, the results with the blood pressure lowering agents, hydralazine, clonidine and prazosin do not support the suggestion that the centrally mediated blood pressure lowering effects of flesinoxan contribute to its internal stimulus effect.

Animals↗

PubMed1994

Serenics.

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Aggression↗

PubMed1994

(S)-UH301, a silent 5-HT1A receptor antagonist, enhances plasma corticosterone levels in the rat.

The putative silent 5-HT1A receptor antagonist (S)-UH301 (S-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin) dose-dependently enhanced (3 to 10 mg/kg, sc) plasma corticosterone levels in undisturbed rats, an effect shared with 5-HT1A receptor agonists. (S)-UH301 did not influence plasma glucose levels. This unexpected finding may be indicative of a partial 5-HT1A-receptor agonistic effect of (S)-UH301, or reveals a hitherto unknown mechanism of action in (S)-UH301.

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

PubMed1994

New animal models of anxiety.

In an attempt to develop new animal models of anxiety with face and predictive validity for the spectrum of human anxiety disorders, two new animal paradigms have been described, stress-induced hyperthermia (SIH) in mice and ultrasonic pup vocalizations (UV) in rats. In SIH mice develop enhanced body temperature in anticipation of an aversive event. This SIH can be antagonized by benzodiazepines, alcohol and 5-HT1A receptor agonists, but not by specific 5-HT reuptake inhibitors (SSRIs) or 5-HT3 receptor antagonists. When rat pups are separated from their mother and littermates they produce ultrasonic sounds, indicative of a separation distress. Benzodiazepines, 5-HT1A receptor agonists and SSRIs decrease this calling, whereas 5-HT3 receptor antagonists have no effect. Antidepressants in general do not decrease pup calling because in contrast to the SSRIs, noradrenergic uptake blockers enhance calling. These two animal models of anxiety can be added to the range of anxiety models and will be of help in predicting new putative anxiolytic drugs.

Animals↗

PubMed1992

The effects of intraventricular administration of eltoprazine, 1-(3-trifluoromethylphenyl)piperazine hydrochloride and 8-hydroxy-2-(di-n-propylamino)tetralin on resident intruder aggression in the rat.

Various serotonergic agents may reduce aggression in rats, but how they act in different parts of the brain is unknown. This study attempted to unravel part of this question by application of different serotonergic ligands into the lateral ventricle (i.c.v.) of male rats (resident-intruder aggression). 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin; 1 and 10 micrograms), a specific 5-HT1A agonist, affected neither aggression nor any other behaviour. The mixed 5-HT1A,B,C agonist, TFMPP (1-(3-trifluoromethylphenyl)piperazine hydrochloride), and the 5-HT1A/1B agonist, eltoprazine ((1-(2,3)-dihydro-1,4-benzodioxin-5-yl)piperazine hydrochloride), suppressed aggression at i.c.v. doses of 10 and 30 micrograms. This reduction was not caused by sedation. These data suggest a role of postsynaptic 5-HT1B receptors in mediating the anti-aggressive effects of mixed 5-HT1 agonists.

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

PubMed1992

Effects of anxiolytic and antidepressant drugs on long-lasting behavioural deficits resulting from one short stress experience in male rats.

Exposure of male Wistar rats to one single session of ten inescapable footshocks induces changes in the behavioural responses to environmental stimuli as measured in the "noise test" 14 days later. Shocked (S) rats showed decreased locomotion and rearing during the first 3 min of exposure to a novel environment compared to control (C) rats. When the 85 dB background noise was switched off a marked immobility response emerged in S rats, concomitant with a further decrease in locomotion and rearing. In response to noise off, C rats showed hardly any immobility and a much smaller reduction in locomotion and rearing compared to S rats. These long-lasting changes in behaviour were not reversed by acute treatment with the antidepressants fluvoxamine (3.0-30.0 mg/kg) and desmethylimipramine (DMI, 2.5-10.0 mg/kg) injected IP 30 min before the noise test on day 14 following the shock session. Chronic treatment (day 1 to day 14) with fluvoxamine or DMI did not reverse the behavioural deficits induced by shock exposure. Diazepam (0.6-5.0 mg/kg) administered acutely only reversed the effects of shock on locomotion during the first 3 min of the noise test. Chronic treatment with diazepam normalized the shock-induced decrease in locomotion and attenuated the rearing decrease during the first 3 min of the test, and partially restored shock-induced changes in behavioural response to switching off the noise. The most potent drug in this study was the 5-HT1A receptor agonist flesinoxan (0.3-3.0 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Inescapable footshocks induce progressive and long-lasting behavioural changes in male rats.

Long-term behavioural consequences of exposure to a brief (15 min) session of inescapable footshocks (10 x 6 s, 1 mA) were investigated in male rats. The time course of the effects of inescapable footshocks was assessed by studying the behaviour of groups of rats at different post-stress intervals. Footshocked rats (S) did not differ from control (C) rats (exposed to the shock box for 15 min) in their behavioural response to an open field whether tested 1 h or 4 h post-stress. However, one day after shocks, S rats showed less locomotion and rearing, and more immobility and attention as compared to C rats. At 7 days or 14 days post-stress, S rats exhibited decreased locomotion, rearing, sniffing, and grooming, and increased immobility, attention, and defecation relative to C rats. In a second experiment, we investigated whether footshocks affect the behavioural response to a sudden drop in background noise during exposure to a novel environment. At 21 days post-stress, S rats showed a markedly enhanced immobility response to this stimulus as compared to C rats. In order to investigate whether rats could be exposed repeatedly to the open field without affecting the differences in behaviour between the two treatment groups, C and S rats were tested in an open field for the first time at 7 days post-stress, which yielded the typical effects of footshocks. When these rats were exposed to a second open-field test one week later, the behavioural responses of C and S rats were not different.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Characterization of stress-induced long-term behavioural changes in rats: evidence in favor of anxiety.

Recently, we reported that rats exposed to one brief session of inescapable footshocks showed a gradually developing and long-lasting decrease in behavioural activity and an increase in defecation in an open field. The aim of the present study was to further characterize the long-lasting changes in behavioural responsiveness to environmental stimuli. For this purpose, behavioural paradigms validated as tools in the preclinical study of the psychobiology of depression were used. Footshocked rats (S) showed a decreased response latency in an one-way avoidance-escape task and decreased immobility in a forced swim test as compared to nonshocked control rats (C) 14 days after shock exposure. These S rats showed decreased behavioural activity and increased defecation as compared to the C rats in an open field test carried out 28 days after footshock exposure. In addition, footshock exposure did not affect the preference for or consumption of a 0.05% saccharin solution on a long-term basis, although a decreased consumption of this solution was evident in S rats on day 1 postshock. These S rats showed an exaggerated immobility response to a sudden reduction in background noise level compared to C rats while placed in a novel environment on day 11 postshock. We conclude that the long-term effects of one short session of inescapable footshocks are not compatible with what is supposed to represent behavioural manifestations of depression in animals. It is argued that the common denominator of shock-induced long-lasting changes is increased behavioural defensiveness, which is more likely related to increased fear and/or anxiety.

Animals↗

PubMed1992

Effect of group size on social organization in rats with restricted access to food.

In groups of rats subjected to a experimental design in which access to the feeder was made difficult, a behavioural differentiation developed. Some rats brought back food pellets to the cage (carrier rats) while the others stayed in the home cage (noncarrier rats). We compared the social organization underlying the adoption of these roles in groups of three and six rats. Reducing group size increased the incidence of carrier rats, leading to a smaller number of differentiated groups. However, differentiated groups seemed to adapt to the situation in the same way as the groups of six rats. In both cases, carriers could be distinguished from noncarriers by their way of obtaining food and by how food possession stopped. Moreover, behavioural variables generally exhibited better stability in small groups and noncarrier/carrier rat relations were more extensive, resulting in more typical organization. The potential use of such groups for pharmacological studies is discussed.

Animals↗

PubMed1992

Rodent models of aggressive behavior and serotonergic drugs.

Various models of rodent agonistic behaviour are described, which differentiate between offensive and defensive/flight models. Particular attention is given to one male and one female paradigm for offensive aggression, viz. resident-intruder or territorial (RI) and maternal aggression (MA). After an overview of the serotonin (5-HT) system in the CNS, a description is given of the ligands available. Subsequently the effects of various drugs affecting serotonergic transmission in the RI- and MA-paradigms are described. The 5-HT1A agonists buspirone, ipsapirone and 8-OH-DPAT decreased aggression in RI and MA, but simultaneously led to a marked decrease in social interest and activity, indicative of a non-specific anti-aggressive profile. Non-selective 5-HT1 agonists, such as RU 24969, eltoprazine (DU 28853), and TFMPP reduced aggression quite specific and did not decrease social interest or exploration, but sometimes even increased these behaviours. In RI and MA the behavioural effects of these drugs were roughly similar. In contrast, MA was more sensitive to the treatment with the 5-HT reuptake blocker fluvoxamine, which blocked RI aggression only non-specifically at the highest dose. DOI, a 5-HT2 and 5-HT1C agonist, decreased aggressive behaviour and increased inactivity, without affecting social interest and exploration in RI as well as MA. This was, however, accompanied by 'wet dog shaking', characteristic of 5-HT2-receptor stimulation. The non-specific 5-HT agonist (and 5-HT3 antagonist) quipazine also induced 'wet dog shaking' at doses which suppressed aggression, social interest and exploration but increased inactive behaviours (sitting and lying). The discussion attempts to delineate a role for 5-HT receptor subtype involvement in the modulation of aggression, with the restrictions we clearly face with regard to the lack of specific serotonergic agonists and antagonists for certain receptor subtypes. By and large, male and female rats react similarly to treatment with serotonergic drugs stressing the consistent role of 5-HT in different forms of aggression.

Aggression↗

PubMed1992

Corticosteroid receptor plasticity in the central nervous system of various rat models.

The action of corticosteroids in the central nervous system (CNS) is mediated by two distinct corticosteroid receptors: the mineralocorticoid and glucocorticoid receptors (MR and GR respectively). Using an established in vitro binding assay system, MR and GR binding parameters were determined in the hippocampal, hypothalamic and pituitary cytosol of various rat models. In the (pharmaco-)genetically selected rat lines, the apomorphine susceptible (APO-SUS) rats showed a significant increase in the hippocampal and pituitary MR binding capacities (but not affinity) compared to those in the apomorphine-unsusceptible (APO-UNSUS) rats. In immunologically-altered Lewis (LEW/N) rats and in spontaneously hypertensive rats (SHR), increased hippocampal MR capacity (but not affinity) and hypothalamic MR capacity were observed compared to their respective control, Wistar (WIST) and Wistar Kyoto (WKY) rats. In addition, compared to WKY rats, SHR rats also showed a much greater pituitary but lesser hypothalamic GR binding capacity. In rats subjected to alteration in environmental conditions, the long-term effects of a short inescapable stress resulted in a significant increase in both hippocampal MR and GR while the pituitary and hypothalamic MR and GR do not differ in the stress and control groups. In rats subjected to a defeat test, a decrease in hippocampal MR and GR was observed 3 weeks (but not 1 week) later.

Animals↗

PubMed1992

Discriminative stimulus properties of the serotonergic compound eltoprazine.

The 5-hydroxytryptamine-1a/1b (5-HT1a/1b) agonist eltoprazine is the main representative of the so-called "serenics," a group of drugs sharing a specific antiaggressive activity. Rats were trained to discriminate an i.p. dose of 0.5 mg/kg of eltoprazine from saline in a two-lever operant drug discrimination task using a fixed ratio 10 schedule of food reinforcement. The cue of eltoprazine was found to be dose and time dependent. The eltoprazine stimulus generalized to the structurally related experimental drug fluprazine, the mixed 5-HT1a/1b agonist 5-methoxy-3-(1,2,3,6-tetrahydropyridinyl)-1H indole, (RU 24969), the 5-HT1b/1c agonist 1-[3-(trifluoromethyl)phenyl]piperazine, (TFMPP), the 5-HT1a agonist 8-hydroxy-2-(di-n-propylamino)tetralin-HB, (8-OH-DPAT), and the beta adrenergic/5-HT1 antagonists (+/-)-pindolol and (+/-)-propranolol. The eltoprazine cue partially generalized to the cues of the 5-HT1a agonists flesinoxan and buspirone, (m-CPP), the 5-HT1b/1c agonist 1,3-chlorophenyl-piperazine dihydrochloride and the 5-HT1c/2 antagonist mesulergine, and did not generalize to the 5-HT2/1c agonist DOI. During tests of antagonism, neither mesulergine, the nonspecific 5-HT antagonist methysergide, the 5-HT2 antagonist ketanserin, the 5-HT3 antagonist tropisetron (ICS 205-930), nor (+/-)-pindolol and (+/-)-propranolol attenuated the stimulus effect of eltoprazine. The specific beta adrenergic antagonist timolol did not substitute for eltoprazine. The present data show that eltoprazine can serve as a discriminative stimulus in rats and suggest that specifically 5-HT1 (i.e., 5-HT1a and 5-HT1b) receptors are involved in the stimulus properties of eltoprazine.(ABSTRACT TRUNCATED AT 250 WORDS)

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

PubMed1991

Adult partner preference and sexual behavior of male rats affected by perinatal endocrine manipulations.

Intact adult male rats, in which aromatization of testosterone to estradiol was prevented pre- and/or neonatally by ATD (1,4,6-androstatriene-3,17-dione), were repeatedly tested for partner preference behavior (choice: estrous female vs active male). In consecutive tests increasing preference scores for the female were found. Neonatal ATD males showed significantly lower preference scores for an estrous female than controls or prenatal ATD males. Prenatal ATD caused preference scores only slightly lower than those of controls. Ejaculation frequencies were markedly reduced or even absent in neonatal ATD males. Prenatal ATD treatment only had no or a moderately lowering effect on ejaculation frequency. Lordosis behavior of adult intact males was more facilitated following neonatal ATD treatment than following prenatal ATD treatment. In a number of tests the serotonergic drug 8-OH-DPAT was injected prior to testing for sexual partner preference and copulatory behavior. DPAT significantly increased preference for an estrous female in all groups of males when interaction was possible, but had no effect when sexual interaction was prevented by wire mesh. DPAT was able to increase the number of ejaculators in nonejaculating groups (i.e., perinatally ATD-treated males). "Premature ejaculations," i.e., ejaculations with the first intromission, were frequently observed with DPAT treatment in all groups of males. In conclusion, the availability of neonatal estrogen (derived from testosterone) organizes, at least partially, the preference for an estrous female normally shown by adult male rats. The lack of neonatal estrogen causes males to be less masculinized, both in partner preference behavior and ejaculatory behavior, and less defeminized in lordosis behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Postsynaptic 5-HT1 receptors and offensive aggression in rats: a combined behavioural and autoradiographic study with eltoprazine.

The present study was designed to assess whether the antiaggressive effects of eltoprazine are mediated via presynaptic and/or postsynaptic 5-HT1 receptors. We describe the effects of central 5-HT depletion 1) on the behaviour of resident TMD-S3 rats in a territorial situation, 2) on the efficacy of eltoprazine to inhibit offensive aggression, and 3) on the 5-HT1A, 5-HT1B and 5-HT1C receptor binding in brains of rats previously used in behavioural studies. Male resident rats were given combined 5,7-dihydroxytryptamine (5,7-DHT) injections into the dorsal and median raphe nuclei. Two to four weeks after the lesions, rats were confronted with an intruder Wiser rat in their home cage for a 10-min period. The 5,7-DHT treatment resulted in a modest reduction of offensive behaviour, while having no effects on other social and nonsocial behaviours. Oral administration of eltoprazine (1 mg/kg) specifically reduced offensive aggression in both sham- and 5,7-DHT-lesioned animals, leaving social interest and exploration intact or even increasing it. A low dose (0.3 mg/kg) of eltoprazine did not affect the behavioural repertoire of sham-operated rats, whereas this dose significantly reduced offense behaviours in the 5,7-DHT-lesioned residents. Quantitative autoradiographic studies 5 weeks after 5,7-DHT treatment revealed a significant increase in radioligand binding to 5-HT1A, 5-HT1B and 5-HT1C sites in many brain regions studied, except for the raphe nuclei where [3H]8-OH-DPAT binding to 5-HT1A sites was markedly reduced. The concentrations of 5-HT and 5-HIAA in frontal cortex were reduced to approximately 10% of controls. The results indicate that serotonin has a stimulatory rather than an inhibitory influence on offensive aggressive behaviour. Central 5-HT depletion does not prevent the antiaggressive effects of eltoprazine, indicating a role for postsynaptic 5-HT1 receptors in the modulation of offensive aggression. The 5,7-DHT-induced overall upregulation of 5-HT1A, 5-HT1B and 5-HT1C binding sites suggests that these three receptor subtypes receive a tonic serotonergic influence. It is conceivable that this postsynaptic 5-HT1 receptor supersensitivity is reflected by the increased efficacy of eltoprazine to inhibit offensive aggression.

5,7-Dihydroxytryptamine↗

PubMed1991

Sex behavior of male and female Wistar rats affected by the serotonin agonist 8-OH-DPAT.

Four experiments were carried out to test the stimulatory effects of 8-OH-DPAT on various aspects of "masculine" sexual behavior of male and female rats and on the sexual attractivity of male rats. In Experiment 1 8-OH-DPAT (0.2 mg/kg) stimulated ejaculation frequency in middle-aged (approx. 15 months old) males, both sexually inactive and active subjects. There was a coinciding decrease in total number of mounts, intromissions, intromissions to first ejaculation and latency to first ejaculation. In Experiment 2 the effects of two doses (0.2 and 0.4 mg/kg) 8-OH-DPAT on the first ejaculation cycle were investigated. Especially, the higher dose made a high percentage (45-55%) of males to ejaculate "prematurely," i.e., at the first or second intromission. Latency to ejaculation decreased. With the higher dose, 25-35% of the males ejaculated extravaginally. In Experiment 3 8-OH-DPAT did not make males more attractive for an estrous female than saline-treated males, as judged by the time spent in their vicinity. However, estrous females received much more ejaculations from the tethered 8-OH-DPAT males, with the lowest latencies to first ejaculation, than from the saline-treated males. In Experiment 4 8-OH-DPAT stimulated mounting behavior in female rats only when they were long-term treated with testosterone. In that condition also shortest latencies to first mount were found with 8-OH-DPAT treatment.

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

PubMed1991

Ethopharmacological studies of anxiolytics and aggression.

This paper presents examples of the application of ethopharmacology to the study of aggression. Low doses of benzodiazepines may increase aggression under appropriate conditions. In various animal models in male and female rats and mice the aggression enhancing effects are particularly marked when aggression is inhibited by internal or external events. It is therefore suggested that benzodiazepines have no direct effect on aggression, but modulate inhibitory factors which regulate aggression.

Aggression↗