fluvoxamine and flesinoxan

Recently, a new putative animal model of anxiety, "light-enhanced startle" was introduced. By placing a rat in a brightly lit environment, which is a naturally aversive stimulus to rats, the amplitude of the startle response to a startle-eliciting noise burst is increased.. The present study aimed to determine the predictive validity of the light-enhanced startle as a putative model for anxiety.. The effects of the GABA(A)-benzodiazepine receptor agonist chlordiazepoxide (CDP), the 5-HT1A receptor agonist flesinoxan and the specific 5-HT reuptake inhibitor fluvoxamine on light-enhanced startle were studied.. Both CDP and flesinoxan decreased startle potentiation, whereas fluvoxamine was devoid of any effects on potentiation. Effects on baseline startle amplitude were only seen after CDP administration.. The present experiment provides evidence for the predictive validity of the light-enhanced startle as an animal model for anxiety. Due to the use of an unconditioned anxiogenic stimulus, the light-enhanced startle offers several benefits over animal models that depend on conditioning. Drug effects can be ascribed more directly to effects on anxiety, as opposed to memory retrieval and, as shown in this study, non-specific drug effects can easily be detected without the interference of contextual fear.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Chlordiazepoxide; Darkness; Disease Models, Animal; Fluvoxamine; Light; Male; Piperazines; Rats; Rats, Wistar; Reflex, Startle

The present study investigated the acute effects of flesinoxan (a selective 5-HT(1A) receptor agonist), fluvoxamine (a selective serotonin reuptake inhibitor) and their co-administration on the expression of conditioned freezing, and index of anxiety in rats. This study also examined the acute effects of fluvoxamine and flesinoxan following chronic flesinoxan or chronic fluvoxamine on the expression of conditioned freezing. Acute administration of flesinoxan (s.c.; 0.1-3 mg/kg) reduced freezing dose dependently, and fluvoxamine (i.p.) at a high dose (60 mg/kg) reduced freezing significantly. Acute co-administration of fluvoxamine (30 mg/kg) and flesinoxan (0.3 mg/kg) showed an additive inhibitory effect on freezing. Chronic flesinoxan treatment (0.3 mg/kg, for 13 days) did not affect the inhibitory effect of acute flesinoxan treatment, but enhanced that of acute fluvoxamine (30 mg/kg) on conditioned freezing. Chronic fluvoxamine treatment (30 mg/kg, for 13 days) enhanced the inhibitory effect of acute fluvoxamine (30 mg/kg) and the inhibitory effect of acute flesinoxan (0.3 mg/kg) on conditioned freezing. These results suggest that co-administration of a selective serotonin reuptake inhibitor and a 5-HT(1A) receptor agonist is useful for the treatment of anxiety disorders.

Topics: Analysis of Variance; Animals; Behavior, Animal; Conditioning, Psychological; Dose-Response Relationship, Drug; Fear; Fluvoxamine; Male; Motor Activity; Piperazines; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin Receptor Agonists

Twelve homing pigeons were trained to discriminate the 5-HT1A receptor agonist flesinoxan (0.25 mg/kg p.o.) from its vehicle in a fixed ratio (FR) 30 two-key operant drug discrimination procedure. Tests for generalization and antagonism showed that compounds with agonistic action at the 5-HT1A receptor, such as 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), buspirone and ipsapirone all substituted for the flesinoxan cue. Compounds with mixed agonistic action at the 5-HT(1A/1B) receptor fully (eltoprazine) or partially (RU24969 (5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl-1H-indole)) substituted for flesinoxan. TFMPP (1-(3-trifluoromethylphenyl)piperazine) and mCPP (1-(3-chlorophenyl)piperazine), both acting at the 5-HT(1B/2C) receptor, did not substitute for flesinoxan, neither did the selective 5-HT re-uptake inhibitor fluvoxamine. The results of the antagonism tests showed that the 5-HT1A receptor antagonists NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine), WAY 100635 ((N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-he xane-carboxamide) and the newly developed DU125530 (2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl ]butyl]-1,2-benzisothiazol-3(2H)-one-1,1-dioxide) fully (more than 80%) blocked the flesinoxan cue without having substantial effects when given alone. WAY100135 (N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide ), (+/-)-pindolol and (S)-UH-301 ((S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin) all partially antagonized the flesinoxan cue. However, both WAY100135 as well as (+/-)-pindolol also partially substituted for flesinoxan in generalization tests. NAN190, (S)-UH-301, WAY100635 and DU125530 were without any activity in the generalization test at the doses tested. The putative 5-HT1A receptor antagonist S15535 (4-benzodioxan-5-yl) 1-(indan-2-yl)piperazine) was identified as a full agonist in the present procedure. Taken together these results suggest that the flesinoxan cue in pigeons is mediated by the 5-HT1A receptor and that DU125530 acts as a full antagonist on the 5-HT1A receptor.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Buspirone; Columbidae; Discrimination Learning; Fluvoxamine; Indoles; Pindolol; Piperazines; Pyridines; Pyrimidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Antagonists; Serotonin Receptor Agonists; Thiazoles

The fear-potentiated startle response paradigm is used to investigate anxiolytic properties of drugs. The first objective of the present study was to further investigate the predictive validity of this paradigm. The anxiolytics chlordiazepoxide (2.5-10 mg/ kg IP) and oxazepam (1-10 mg/kg PO) and the putative anxiolytic flesinoxan (1-10 mg/kg PO) decreased startle potentiation dose-dependently, indicating an anxiolytic effect. The antidepressant fluvoxamine (5-20 mg/kg PO) did not affect startle potentiation. Ideally, anxiolytic drugs attenuate startle potentiation without affecting control startle levels, although some studies report altered control startle amplitudes. The second objective was to investigate whether different effects on control startle amplitudes are related to different startle devices. Therefore, the drugs were tested in two laboratories. Results showed no significant differences between laboratories, indicating that equipment is not a critical factor in the drug-induced alteration of control startle levels. In an additional experiment, it was shown that flesinoxan (10 mg/kg PO) did not affect strychnine-induced startle potentiation, supporting the idea that the attenuating effect of flesinoxan on the fear-potentiated startle response is due to its anxiolytic properties. Thus, the fear-potentiated startle response paradigm appears a valid and reliable model for anxiolytic properties of drugs.

Topics: Animals; Anti-Anxiety Agents; Chlordiazepoxide; Dose-Response Relationship, Drug; Fear; Fluvoxamine; Male; Oxazepam; Piperazines; Rats; Rats, Wistar; Reflex, Startle

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)

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Behavior, Animal; Desipramine; Diazepam; Electroshock; Fluvoxamine; Male; Motor Activity; Noise; Piperazines; Rats; Rats, Wistar; Serotonin Receptor Agonists; Stress, Psychological