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M Jessa

Publications and source records attributed to M Jessa.

14 recordsLinked to original sources
PubMed1997

Benzodiazepine-GABAA receptor complex ligands in two models of anxiety.

In the present study, the actions of several compounds with different intrinsic activities and BDZ receptor selectivity were examined in two well established animal models of anxiety: the open field test (OFT) and Vogel's punished drinking text (VT). Full agonists at the BDZ GABAA receptor (midazolam and diazepam) showed anxiolytic-like effects in both tests; however, the doses necessary to disinhibit animal behavior controlled by fear were higher in the VT than in the OFT. None of the partial BDZ receptor agonists studied (bretazenil, Ro 19-8022 and abecarnil) diminished neophobia-like behavior of rats in the OFT, and their sedative influence on gross behavior prevailed. On the other hand, all three drugs produced a clear-cut anxiolytic effect in the VT. A selective BDZ, receptor subtype full agonist (zolpidem) had a similar profile of action to that of partial agonists with an even stronger sedative effect in the OFT. Alpidem (a selective BDZ1 receptor partial agonist) did not reveal any anxiolytic action in either test. Flumazenil (an antagonist at the BDZ-GABAA receptors) also produced no effect in the OFT, or the VT. An inverse BDZ receptor agonist, beta-carboline-3-carboxylate methyl ester (beta-CCM), evoked an anxiogenic-like response in the OFT, but not in the VT. In summary, it appeared that partial agonists and selective ligands at BDZ1 receptors revealed less advantageous anxiolytic-like action than did full allosteric GABAA receptor modulators. This study also indicates the test dependent profiles of action of BDZ-GABAA receptor ligands. It also indirectly suggests a different neurobiological background underlying the applied tests.

Analysis of Variance↗
PubMed1997

Anxiolytic activity of glycine-B antagonists and partial agonists--no relation to intrinsic activity in the patch clamp.

On the basis of animal models, anxiety was one of the first suggested clinical applications of partial agonists of the glycineB site coupled to the NMDA receptor. It is not certain, however, whether these findings can be extended to full glycineB antagonists and what is the relation between intrinsic activity (degree of NMDA receptor antagonism) and anxiolytic effect. In the present study several NMDA receptor antagonists, including several glycineB antagonists/partial agonists, were tested for anxiolytic activity in the Vogel conflict test and the elevated plus-maze. Additionally, the intrinsic activities of the glycineB partial agonists used [ACPC, (R,+)-HA-966 and D-cycloserine] were compared in patch-clamp experiments in cultured neurones. In the plus-maze the most striking increase in the time spent in open arms (index of anxiolytic effect) was seen after diazepam and D-cycloserine (at doses that did not change locomotion). Also reliable (dose-dependent), although weaker, anxiolytic activity was produced by the uncompetitive NMDA receptor antagonist (+)MK-801 and the competitive antagonist CGP 39551. Modest anxiolytic-like effect in the plus-maze was also observed after the glycineB antagonist L-701,324 and the partial agonist (+,R)-HA-966. Uncompetitive antagonists memantine and amantadine, the glycineB partial agonist ACPC (up to 600 mg/kg) or the full antagonists MRZ 2/570, MRZ 2/571 and MRZ 2/576 had no effect. In the Vogel conflict test neither memantine, nor any of the full glycineB antagonists tested (L-701,324 and MRZ 2/576), showed anxiolytic activity. Patch-clamp studies revealed that the intrinsic activity of (+,R)-HA-966, D-cycloserine and ACPC was 13, 57 and 92%, respectively, as compared to that of glycine itself (100%). In conclusion, for the agents tested there is no clear relation between the levels of intrinsic activity, i.e. degree of NMDA receptor inhibition, and anxiolytic activity. Moreover, L-701,324 and MRZ-type glycineB full antagonists do not exchibit anxiolytic activity in the elevated plus-maze and Vogel conflict test.

Animals↗
PubMed1997

The behavioral effects of NMDA antagonists in serotonin depleted rats.

The influence of serotonin (5-HT) depletion (5,7-dihydroxytryptamine, 5,7-DHT, 250.0 micrograms, ICV), on behavioral effects of non-competitive (MK-801) and competitive (CGP 37849) NMDA antagonists, was examined in rats. 5,7-DHT induced very potent and long lasting decrease in the 5-HT concentration in the brainstem and limbic forebrain. One week after 5,7-DHT administration, dopamine metabolism was found enhanced in the brainstem. The lesion did not change rat baseline motor and exploratory activity, but it significantly disinhibited animals' behavior suppressed by shock, in the Vogel test. Serotonin depletion revealed locomotor stimulating effect of MK-801, administered IP at the doses of 0.05 and 0.2 mg/kg. However, no change in striatal dopamine metabolism was detected in rats injected with the same dose of MK-801 (0.2 mg/kg), and examined one week after serotonergic denervation. Serotonergic lesions antagonized both enhancements of exploratory behavior, and motor suppression produced by the dose of 1.0 and 10.0 mg/kg of CGP 37849, respectively. Thus, 5,7-DHT-induced lesions influenced in a complex way the effects of NMDA antagonists. It is reasoned, that enhancement of motor stimulating effects of MK-801 in neurotoxin pretreated animals, reflects synergistic disinhibition of activity of dopaminergic neurons by MK-801 and serotonin depletion. On the other hand, antagonism of CGP 37849-caused motor depression can be explained by the lowering influence of 5,7-DHT on serotonin content. It is known that the release of serotonin is strongly stimulated by higher doses of CGP 37849, and takes part in the expression of some symptoms of the serotonin-like syndrome, including motor disturbances.

2-Amino-5-phosphonovalerate↗
PubMed1996

The effects of repeated administration of diazepam, MK-801 and CGP 37849 on rat behavior in two models of anxiety.

The effects of repeated administration of diazepam, MK-801 and CGP 37849 on rat behavior in the Vogel conflict test, and in the open field test of neophobia, were studied in rats. The drugs were given at doses active acutely, for 5 days, the last dose was administered 30 or 60 min prior to testing. It appeared that diazepam and MK-801 treated animals showed clear-cut signs of behavioral tolerance and motor sensitization, respectively. CGP 37849 was characterized by the best pharmacological profile, in that on repeated administration the drug not only retained its anxiolytic-like potency in the Vogel test, but even enhanced rat exploratory behavior in a new environment, independently of changes in animal motor activity. Repeated injections of the examined agents did not cause any significant modifications in monoamine levels and their turnover rates, in the striatum and limbic forebrain. It is concluded that the new class of competitive NMDA receptor antagonists, exemplified by CGP 37849, is the most promising candidate for clinical trials in anxiety disorders.

2-Amino-5-phosphonovalerate↗
PubMed1996

Central serotonergic system and mechanism of anxiolytic action.

The results clearly indicate that the hippocampus, rather than nucleus accumbens is involved in mediating anxiolytic-like effects of the 5-HT1A receptor agonists. Furthermore, hippocampal postsynaptic 5-HT1A receptors may account for the anti-emotional influence of this groups of drugs. As far as the 5-HT3 receptor antagonists are concerned, it was more difficult to localize their central anti-anxiety like action. More clear and unequirocal effects could be observed after intra-accumbens, rather than after intrahippocampal injections of tropisetron and ondansetron.

Animals↗
PubMed1994

The effect of serotonin depletion and intra-hippocampal midazolam on rat behavior in the Vogel conflict test.

The effect of intra-hippocampal (dentate gyrus) microinjections of the benzodiazepine, midazolam (10 micrograms per site, bilaterally), was examined in the Vogel conflict test in serotonin depleted rats (pretreated with p-chlorophenylalanine). p-Chlorophenylalanine and midazolam, when given separately, significantly disinhibited rat conflict behavior. Midazolam retained its anticonflict potency in the p-chlorophenylalanine pretreated animals. These and other data indicate: (i) the specific involvement of limbic serotonin in emotional control, (ii) a dissociation of the effects of serotonin depletion and intra-hippocampal benzodiazepine on conflict behavior, and (iii) the important role of the hippocampus in processing emotional input.

Animals↗
PubMed1994

Antidepressant treatment and limbic serotonergic mechanisms regulating rat locomotor activity.

The effects of chronic administration of desipramine, citalopram, and electroconvulsive shocks (ECS) on changes in rat motility after intraaccumbens (NAS) injections of selective serotonergic drugs were studied in intact and 5.7-DHT lesioned animals. It was shown that local injections of 8-OHDPAT and DOI-HCl depressed rat locomotor activity. Their effects appeared to be mediated postsynaptically, and could be antagonized by NAN-190 and ritanserin, respectively. Chronic but not acute pretreatment of rats with antidepressants (21 days long; the experiment was performed 24 h after the last dose) as well as repeated ECS (shocks were applied five times every second day), antagonized behavioral depression after 8-OHDPAT and DOI-HCl. The influence of antidepressant treatment was prevented by serotonergic lesions. Chronic administration of antidepressants and ECS did not equivocally affect the levels or metabolism of 5-HT, dopamine, and noradrenaline in the rat limbic forebrain. It is concluded that the present data indicate diminished activity of 5-HT systems related to the 5-HT1A and 5-HT2 receptors in the limbic nucleus, after chronic antidepressant treatment. This effect of drugs and ECS concerns nervous processes linked with the function of postsynaptically localized 5-HT receptor subtypes, and it probably depends on intact presynaptic 5-HT innervation.

5,7-Dihydroxytryptamine↗
PubMed1994

Effects of antagonists at the NMDA receptor complex in two models of anxiety.

The effects of an antagonist at the strychnine insensitive glycine site (5,7-dichlorokynurenic acid, i.c.v.), and of noncompetitive (MK-801, i.p.) and competitive (CGP 37849, i.p.; CGP 39551, i.p.; AP-7, i.c.v.) NMDA antagonists were compared with diazepam (i.p.) in two animal models of anxiety (the open field exploratory behavior of non-habituated rats, and the Vogel conflict test). All drugs when applied in appropriate doses increased punished drinking in the Vogel test, without producing any significant changes in free drinking and the stimulus threshold at their lowest anticonflict doses. The effective doses were as follows: diazepam 1.5 and 2.5 mg/kg; MK-801 0.005 and 0.01 mg/kg; CGP 39551 5.0 and 20.0 mg/kg; CGP 37849 1.0 and 2.5 mg/kg; 5,7-dichlorokynurenic acid 5.0 microgram (i.c.v.); AP-7 0.5 microgram (i.c.v.). In the open field diazepam (0.05 mg/kg), MK-801 (0.1 mg/kg), CGP 37849 (0.01, 0.1, 1.0 mg/kg), and AP-7 2.5 micrograms (i.c.v.) significantly increased exploratory activity in the central sectors of the open field (anti-neophobic reaction), without changing motor activity of the rat. MK-801 at the highest tested dose of 0.2 mg/kg significantly stimulated animal locomotor activity. CGP 37849 in the largest dose examined (10 mg/kg) significantly depressed the motor behavior of rats. Overall, it appeared that different NMDA antagonists showed an anxiolytic-like profile, similar to that of the benzodiazepine diazepam. Among different NMDA receptor complex antagonists studied, CGP 37849 was characterized by the largest distinction between the doses showing an anxiolytic-like action in the open field test, and changing rat motor behavior.

2-Amino-5-phosphonovalerate↗
PubMedDate not supplied

Neonatal treatment with 5,7-dihydroxytryptamine induces decrease in alcohol drinking in adult animals.

It has long been suggested that serotonin (5-HT) neurotransmitter system activity is associated with ethanol (ETOH) intake and dependence. The authors studied the effects of neonatal 5,7-dihydroxytryptamine (5,7-DHT) lesions on voluntary alcohol drinking in adult Wistar rats. At 3 days after birth animals were pretreated with desipramine (DMI) and then given a bilateral injection of 5,7-DHT into lateral ventricles. Afterwards, the rats were kept under standard laboratory conditions until at least 2 months of age following which they were tested. 5,7-DHT induced a marked and permanent decrease in brain 5-HT content, measured in the prefrontal cortex, hippocampus and striatum, but did not modify noradrenaline content in these structures. Lesioned animals, both males and females displayed lower preference for ETOH than sham-lesioned animals. Total fluid intake was significantly higher in 5,7-DHT-lesioned than sham-lesioned rats. A significant decrease in body weight was observed in 5,7-DHT-treated rats. This effect was not caused by a significant change in food intake. Both groups showed high preference for a 0.1% saccharin. In conclusion, the present results demonstrated that neonatal treatment with 5,7-DHT evoked long-lasting neurochemical changes and reduction of ETOH intake in adult rats. Neonatally 5,7-DHT-treated rats may be considered as a suitable model in further research on the relationship between the function of central 5-HT system and alcohol intake and dependence.

5,7-Dihydroxytryptamine↗
PubMedDate not supplied

Studies on antidepressant action of a new oxazolidinone derivative AS-8.

On the basis of previous laboratory studies AS-8 was suggested to possess antidepressant-like activity. Forced swim test, learned helplessness and conflict Vogel's test were performed after three prior administrations of AS-8 (24, 5 and 1 h before the test). The data have shown that AS-8 produces moderate antidepressant effect but did not induce anxiolytic-like action. Biochemical data revealed increased brain 5-HT and 5-HIAA levels following AS-8 administration. The combined treatment of rats with AS-8 (100 mg/kg) and amitriptyline (5 mg/kg) or desipramine (1.25 mg/kg) significantly stimulated active behavior in the forced swim test above the level obtained with each of the drug given separately. The present data suggest the potential antidepressant efficacy of AS-8 in conjunction with small doses of tricyclic antidepressants.

Amitriptyline↗
PubMedDate not supplied

Anxiolytic-like action of intra-hippocampally administered NMDA antagonists in rats.

The effects of intra-hippocampally administered NMDA receptor antagonists MK-801, and AP-7 on rat behavior in the Vogel's and open field tests of anxiety were examined. MK-801 and AP-7 given locally stimulated at the same time rat exploratory and motor activities, in the open field. In the Vogel's test, both compounds attenuated the suppressive effect of shock on drinking, in a dose-range not affecting rat motility. It is concluded that hippocampal NMDA innervation may play a role in the control of motor activity. Furthermore, the Vogel's test data indicate more selective involvement of hippocampal NMDA innervation in processing of fear-related signals.

2-Amino-5-phosphonovalerate↗
PubMedDate not supplied

Antagonism of behavioral effects of electroconvulsive shock but not those of desipramine by the selective 5-HT-3 receptor antagonist, ondansetron.

The influence of ondansetron (ON) on desipramine (DMI) and electroconvulsive shock (ECS) effects in the open field (OFT) and forced swim test (FST) were studied in Wistar male rats. ON failed to influence the action of DMI but abolished stimulatory effect of ECS in the OFT and, in the lower dose (0.01 mg/kg) reduced ECS action in the FST. This result suggests that 5-HT-3 receptors are involved in behavioral effects of ECS but not DMI.

Animals↗