piperidines and ipsapirone

Topics: Analysis of Variance; Animals; Antidepressive Agents; Clomipramine; Clorgyline; Fluvoxamine; Frontal Lobe; Hydroxyindoleacetic Acid; Imipramine; Microdialysis; Monoamine Oxidase Inhibitors; Piperidines; Pyrimidines; Raphe Nuclei; Rats; Serotonin; Stereotaxic Techniques; Tranylcypromine; Tryptophan

In order to investigate whether protein malnutrition in early life causes lasting changes in reactivity to anxiolytic drugs, exploration of the elevated plus-maze was used. Rat dams during lactation (21 days) and pups after weaning until day 49 of life were fed on 8% casein diet (M rats), while their well-nourished controls received 25% casein (W rats). From day 50 on all animals ate the same balanced diet. Experiments started on day 70. Under the non-drug condition, M rats tended to explore the open arms of the maze relatively more than W rats. Diazepam (0.5-5 mg/kg, IP) dose-dependently increased the percentage of open/total arm entries without significantly affecting the total number of arm entries in W rats. This selective anxiolytic effect of diazepam was considerably smaller in M rats. Ipsapirone (0.5-5 mg/kg) caused a similar though less pronounced anxiolytic effect in W rats, whereas the drug decreased both the % open/total and total arm entries in M rats. In contrast, ritanserin (0.05-1 mg/kg) significantly increased the % open/total arm entries in M rats only, though not in a dose-dependent way. Isamoltane (2.5-20 mg/kg) was ineffective on both M and W rats. These results indicate that early protein malnutrition causes long-lasting alterations in brain systems regulating emotional behaviour.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Diazepam; Dose-Response Relationship, Drug; Exploratory Behavior; Male; Piperidines; Propanolamines; Protein-Energy Malnutrition; Pyrimidines; Rats; Rats, Inbred Strains; Ritanserin

The effect of oxaprotiline (OXA) enantiomers--of which (+)-OXA inhibits noradrenaline (NA) uptake, whereas (-)-OXA does not--on the secretion of adrenocorticotropin hormone (ACTH) and corticosterone was studied in rats. Both enantiomers dose-dependently and with a similar potency increased the plasma level of ACTH and corticosterone, the effect of (-)-OXA on corticosterone being of a longer duration. The stimulation of ACTH secretion and the inability of (+)- and (-)-OXA to increase the plasma corticosterone concentration in animals pretreated with dexamethasone indicate that secretion of the latter hormone results from the action of the enantiomers at a level superior to the adrenal cortex, i.e. the hypothalamus/pituitary. The corticosterone response to (+)- or (-)-OXA was not modified in rats with a selective lesion of NA nerve endings induced by the neurotoxin DSP-4, nor was it affected by the selective alpha 1-antagonist prazosin, the selective alpha 2-antagonist yohimbine, the mixed alpha 1/alpha 2-antagonist phentolamine, the selective dopamine (D2) receptor antagonist sulpiride and the non-selective 5-hydroxytryptamine (5-HT) receptor antagonist metergoline. These results indicate that neither the NA system nor D2 and 5-HT receptors are involved in the hormonal response to the OXA enantiomers. Although the (+)- and (-)-OXA-induced stimulation of corticosterone secretion was not antagonized by diazepam, ipsapirone, naloxone, or propranolol, it cannot be excluded that both these enantiomers act as non-specific stressors.

Topics: Adrenergic alpha-Antagonists; Adrenocorticotropic Hormone; Animals; Antidepressive Agents; Benzylamines; Corticosterone; Dexamethasone; Diazepam; Dose-Response Relationship, Drug; Male; Maprotiline; Metergoline; Naloxone; Piperidines; Pyrimidines; Radioimmunoassay; Rats; Rats, Inbred Strains; Serotonin Antagonists; Stereoisomerism; Sulpiride; Sympathomimetics

In order to investigate whether early malnutrition causes lasting changes in the reactivity to anxiolytic drugs, rat dams during lactation (21 days) and pups after weaning until the 49th day of life were fed on 8% casein diet (M rats), while their well-nourished controls received 25% casein (W rats). From day 50 on all animals ate the same balanced diet. Experiments started on the 91st day. Rats deprived for 22 hours drank water containing either 1.8% or 2.7% sodium chloride for 30 min in a test chamber, total intake being measured. Dose-effect curves for diazepam (0.5-5.0 mg/kg, IP), as well as for the nonbenzodiazepine anxiolytics ipsapirone (0.5-5.0 mg/kg), ritanserin (0.05-1.0 mg/kg) and isamoltane (2.5-20.0 mg/kg) were determined in M as well as in W rats. Diazepam and ipsapirone dose-dependently released drinking suppressed by either salt concentration in W rats, but caused little or no effect in M rats. Ritanserin and isamoltane were ineffective in both groups. These and previously reported results show that early protein malnutrition markedly reduces anticonflict effects of anxiolytics, indicating long-lasting impairment of neuronal systems underlying emotional behavior.

Topics: Animals; Anti-Anxiety Agents; Body Weight; Diazepam; Diet; Dose-Response Relationship, Drug; Hypertonic Solutions; Lactation; Male; Piperidines; Propanolamines; Protein-Energy Malnutrition; Pyrimidines; Rats; Rats, Inbred Strains; Ritanserin

The proposed anxioselective drug, buspirone, interacts with 5HT1 receptors. An analogue, MJ 13805, produces a 5HT behavioural syndrome blocked by central 5HT pathway lesion. Both compounds inhibit 5HT neurone firing. An association of any such action with models of anxiety is not yet possible. Several compounds selective for 5HT receptor sub-types have been tested in models of anxiety. Ritanserin, a selective 5HT2 antagonist, shows activity in an emergence test but not conflict models. Preliminary clinical reports indicate qualitatively different anxiolytic activity from that of benzodiazepines. TVXQ 7821 is selective for 5HT1 receptors and has shown activity in several models of anxiety. 8OHDPAT and RU 24969 are 5HT1 agonists, selective for 5HT1A and 5HT1B sites respectively. 8OHDPAT released punished drinking but reversed a similar effect of PCPA. Its mode of action remains unclear. RU 24969 has shown no marked anxiolytic-like activity in food or water-motivated conflicts. Further studies are necessary before associating modulation of central 5HT systems with anxiolytic activity, either in animal models or patients.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Buspirone; Disease Models, Animal; Piperidines; Pyrimidines; Receptors, Serotonin; Ritanserin; Serotonin; Serotonin Antagonists; Social Behavior

The abilities of the putative non-benzodiazepine anxiolytic compound TVX Q 7821 in comparison to 5-HT and the 5-HT2 receptor antagonist ketanserin to displace 3H-5-HT from its binding sites in various regions of calf brain were studied. Binding affinities and capacities for 3H-5-HT were determined using membranes from different calf brain regions. Competition experiments with radiolabelled 3H-ketanserin using rat prefrontal cortex membranes were also performed. High affinity 3H-5-HT binding was found in all calf brain areas examined, with the hippocampus having the highest density of binding sites. TVX Q 7821 was a potent displacer (Ki-value 10 nmol/l) of 3H-5-HT binding in hippocampal membranes but not in membranes from other brain regions. No high affinity binding of TVX Q 7821 was found to the 5-HT receptors labelled with 3H-ketanserin. It is concluded, that TVX Q 7821 may bind preferentially to a special subtype of the 5-HT1 recognition site. Furthermore the results suggest that these sites may be involved in the mechanism of the anxiolytic action of TVX Q 7821.

Topics: Animals; Binding, Competitive; Cattle; Hippocampus; Ketanserin; Kinetics; Membranes; Piperidines; Pyrimidines; Rats; Receptors, Serotonin