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  • 1
    Electronic Resource
    Electronic Resource
    5-HT1A Receptor Agonist Flesinoxan Enhances Fos Immunoreactivity in Rat Central Amygdala, Bed Nucleus of the Stria Terminalis and Hypothalamus (1996)
    Oxford, UK : Blackwell Publishing Ltd
    European journal of neuroscience 8 (1996), S. 0 
    Details
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 5-Hydroxytryptamine-1A (5-HT1A) receptor agonists, including flesinoxan, reduce anxiety and activate the hypothalamus-pituitary-adrenal (HPA) axis under basal conditions. In order to investigate the underlying neural mechanisms we investigated immunoreactivity for the immediate early gene protein product Fos (Fos-ir) in rat brains 1 h after flesinoxan treatment (0.0, 0.3 or 3.0 mg/kg p.0.). Typically, 5-HT1A receptor-containing brain areas, such as the dorsal raphe nuclei, hippocampus, septum, diagonal band and the cortical and basomedial amygdala, do not show Fos-ir. Apparently, binding of flesinoxan at the 5-HT1A receptor does not directly lead to activation of c-fos in the cell, probably due to its negative coupling to adenylate cyclase. However, in typically non-5HTlA receptor-containing brain areas Fos-ir is increased due to flesinoxan treatment, as in the paraventricular nucleus of the hypothalamus (PVN), the dorsolateral part of the bed nucleus of the stria terminalis (BNSTd1) and the central amygdala (CeA). Flesinoxan-treated rats also exhibited higher plasma corticosterone levels than vehicle-treated animals, which suggests the involvement of corticotropin-releasing hormone (CRH) or vasopressin in the hypothalamus. After double immunolabelling (Fos/CRH or Fos/vasopressin), every CRH neuron detected in the PVN also contained Fos. Moreover, a significant correlation existed between the number of Fos-ir neurons in the PVN and the plasma corticosterone level. Hardly any Fos/ vasopressin double labelling was visible in the PVN. Accordingly, flesinoxan exerts its activating effects on the HPA axis via CRH neurons in the PVN. These effects are transsynaptically mediated by other brain areas, such as the CeA and BNSTdl, which also show increased Fos-ir.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1460-9568.1996.tb01197.x
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  • 2
    Electronic Resource
    Electronic Resource
    Predictive validity of the potentiated startle response as a behavioral model for anxiolytic drugs (1995)
    Springer
    Psychopharmacology 118 (1995), S. 150-154 
    Details
    ISSN: 1432-2072
    Keywords: Anxiety ; Fear-potentiated startle ; Behavioral models ; Predictive validity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The fear-potentiated startle (PSR) paradigm is a putative behavioral model for the determination of anxiolytic properties of drugs. The present study further investigated the predictive validity of the model. Predictive validity is high, when only drugs clinically used as anxiolytics attenuate PSR dose dependently. Results showed that startle potentiation decreased dose dependently after the administration of the anxiolytics CDP (2.5–10 mg/kg, IP) and alprazolam (1–3 mg/kg, IP). After administration of the clinically non-anxiolytic drugs amitriptyline (2.5–10 mg/kg, IP), carbamazepine (5–20 mg/kg, IP), fentanyl (0.0025–0.04 mg/kg, SC), naloxone (2.5–10 mg/kg, IP), nicotine (0.4–1.6 mg/kg, IP), alcohol (500–2000 mg/kg, IP), andd-amphetamine (0.6–2.4 mg/kg, IP), a dose-dependent decrease in startle potentiation was not found. The PSR correctly discriminated most of the drugs tested in clinically anxiolytic and clinically non-anxiolytic drugs. However, haloperidol behaved as a false positive, and results of nicotine and alcohol were at variance with results reported by others.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02245833
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  • 3
    Electronic Resource
    Electronic Resource
    Fear-potentiated startle response is remarkably similar in two laboratories (1996)
    Springer
    Psychopharmacology 126 (1996), S. 104-109 
    Details
    ISSN: 1432-2072
    Keywords: Anxiety ; Fear-potentiated startle response ; Predictive validity ; Reliability ; Oxazepam ; Flesinoxan ; Fluvoxamine ; Strychnine-potentiated startle response
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02246344
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  • 4
    Electronic Resource
    Electronic Resource
    Stimulus properties of fluvoxamine in a conditioned taste aversion procedure (1998)
    Springer
    Psychopharmacology 140 (1998), S. 496-502 
    Details
    ISSN: 1432-2072
    Keywords: Key words Serotonin (5-HT) reuptake inhibitor ; Fluvoxamine ; Fluoxetine ; Stimulus properties ; Conditioned taste aversion ; 5-HT1A receptor ; 5-HT2C receptor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A conditioned taste aversion (CTA) procedure in mice was used to investigate the stimulus effects of the serotonin reuptake inhibitors (SSRIs) fluvoxamine and fluoxetine. Fluvoxamine elicited a reliable CTA (ED50 = 24 mg/kg, SC) and a number of drugs were tested as pre-exposure drugs. Pre-exposure to the serotonin (5-HT)1A receptor agonists flesinoxan and ±-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) prevented the CTA induced by fluvoxamine (50 mg/kg, SC). Pre-exposure with the 5-HT2C receptor agonist MK 212 [6-chloro-2(1-piperazinyl)pyrazine] partially prevented the fluvoxamine-induced CTA, pre-exposure with the 5-HT2A/2C receptor agonist DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl] did not prevent the CTA induced by fluvoxamine. Flesinoxan pre-exposure also prevented the taste aversion induced by fluoxetine (10 mg/kg, SC) completely. This contrasts previous results obtained with fluoxetine, where was found that its stimulus is primarily mediated by 5-HT2C, and to a lesser degree by 5-HT1A receptors. Therefore, we compared the two SSRIs directly. Pre-exposure to fluvoxamine prevented the fluoxetine-induced CTA, whereas pre-exposure to fluoxetine only partially prevented the fluvoxamine-induced CTA. We conclude that 5-HT1A receptors are involved in the stimulus properties of both fluvoxamine and fluoxetine, that 5-HT2C receptors are involved in fluvoxamine and especially fluoxetine, and , based primarily on the cross-comparison tests, that the two SSRIs have somewhat different stimulus properties.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050794
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  • 5
    Electronic Resource
    Electronic Resource
    Reduction of guinea pig pup isolation calls by anxiolytic and antidepressant drugs (1996)
    Springer
    Psychopharmacology 128 (1996), S. 31-38 
    Details
    ISSN: 1432-2072
    Keywords: Key words Distress vocalizations ; Guinea pig pup ; Anxiolytics ; Antidepressants ; Benzodiazepines ; 5-HT1A receptor ligands ; 5-HT uptake inhibitors ; NA uptake inhibitor ; 5-CT ; 5-HT1D receptor ; Alcohol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Guinea pigs possess central 5-HT1D receptors similar to humans but different from rats and mice. In order to study the role of this receptor on animal behaviour, it may be of interest to develop a paradigm measuring affective states in the guinea pig. Therefore we assessed the effects of a variety of psychotropic drugs on guinea pig pup isolation calls. Anxiolytic compounds such as the benzodiazepine receptor agonists diazepam and alprazolam, the full 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan, and alcohol reduced isolation calling by the guinea pig pup. Moreover, mixed antidepressant/anxiolytic compounds like the 5-HT uptake inhibitors fluvoxamine and clomipramine or the MAO-inhibitor clorgyline as well as the antidepressant NA uptake inhibitors desipramine and maprotiline suppressed vocalizations. The 5-HT1D/1A receptor agonist 5-CT was also very effective in reducing separation calls. Remarkably, the partial 5-HT1A receptor agonists buspirone and BMY 7378 did not affect calling. The neuroleptic haloperidol, the psychostimulant d-amphetamine, the putative anxiogenics DMCM and m-CPP and the putative anxiolytics ondansetron and CI-988 had no effect on isolation calls of guinea pig pups. We propose this paradigm could be helpful to assess behavioural effects of anxiolytic and antidepressant drugs in a species different from rat or mouse, and in which the effects of 5-HT1D receptor ligands may possibly be established.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050106
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  • 6
    Electronic Resource
    Electronic Resource
    The effects of 5-HT1A receptor agonists, 5-HT1A receptor antagonists and their interaction on the fear-potentiated startle response (1998)
    Springer
    Psychopharmacology 139 (1998), S. 383-390 
    Details
    ISSN: 1432-2072
    Keywords: Key words Anxiety ; Fear-potentiated startle response ; 8-OH-DPAT ; Flesinoxan ; WAY 100 ; 635 ; (±)-Pindolol ; DU 125 ; 530 ; Lower lip retraction ; 5-HT1A receptor agonist ; 5-HT1A receptor antagonist ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The present study investigated whether the anxiolytic effect of 5-HT1A receptor agonists on the fear-potentiated startle response could be antagonized by 5-HT1A receptor antagonists. Therefore, control and fear-potentiated startle amplitudes were measured after co-administration of vehicle, flesinoxan (10 mg/kg PO) or 8-OH-DPAT (0.3 mg/kg SC) and DU 125,530 (0, 1, 3 and 10 mg/kg SC), (±)-pindolol (0, 3, 10 and 30 mg/kg SC) or WAY 100,635 (0, 0.1, 0.3 and 1 mg/kg SC). Unexpectedly, the three antagonists themselves as measured in the vehicle-pretreatment groups dose-dependently decreased startle potentiation. Further, DU 125,530 and WAY 100,635 were able to reverse the attenuating effect of 8-OH-DPAT, while no antagonism of the flesinoxan effect on startle potentiation was found. In contrast, both the flesinoxan- and 8-OH-DPAT-induced lower lip retraction were antagonized by DU 125,530 and WAY 100,635, but not by (±)-pindolol. The findings of the present study suggest that drugs acting on 5-HT1A receptors differentially affect lower lip retraction and startle potentiation probably mediated by different neuronal populations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050729
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  • 7
    Electronic Resource
    Electronic Resource
    The ambivalent behaviour “stretched approach posture” in the rat as a paradigm to characterize anxiolytic drugs (1995)
    Springer
    Psychopharmacology 121 (1995), S. 81-90 
    Details
    ISSN: 1432-2072
    Keywords: Stretched approach posture ; Ambivalent behaviour ; Intention movements ; Ethological observation ; Rat ; Anxiety disorders ; Benzodiazepines ; 5-HT1A receptor agonists ; 5-HT uptake inhibitors ; Clonidine ; Clorgyline ; Anxiogenic drugs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of various psychotropic drugs on the ambivalent behaviour “stretched approach posture” (SAP) in the rat was assessed. SAP was elicited after a mild startle reaction due to physical contact with an electrified prod at one end of a straight runway. Using ethological observation methods, SAP as well as intention movements, prod contact, crossings, rearing, exploration, grooming and immobility were recorded. The benzodiazepine receptor agonists chlordiazepoxide, diazepam and alprazolam, the 5-HT1A receptor agonists flesinoxan and ipsapirone and the 5-HT uptake inhibitor clomipramine selectively (no effect on crossings) reduced SAP. Except for alprazolam, these drugs also reduced intention movements. In addition, chlordiazepoxide and diazepam enhanced prod contact. Reductions of SAP and intentions with concomitant reductions of crossings (nonspecific anti-ambivalent effects) were established for the α2-adrenoceptor agonist clonidine and the MAO inhibitor clorgyline. The 5-HT uptake inhibitor fluvoxamine suppressed intention movements, but not SAP. The mixed 5-HT/NA uptake inhibitor imipramine did not significantly affect SAP or intentions, but reduced crossings. The 5-HT2C/1B receptor agonist m-CPP, the inverse BZD receptor agonists FG 7142 and DMCM, and the α2-adrenoceptor antagonist yohimbine, to all of which putative anxiogenic effects have been ascribed, had no effect on SAP directed towards the prod. m-CPP, however, produced an increase in the stretched posture directed away from the prod (SAwayP). FG 7142 reduced intentions while strongly enhancing immobility (freezing). SAwayP and/or freezing may possibly reflect anxiogenic properties of drugs. The putative anxiogenic drug pentylenetetrazol false positively reduced SAP while increasing exploration. The dopamine-D2 receptor antagonist haloperidol and the catecholamine releaserdl-amphetamine had no effect on ambivalent behaviour. The muscarine receptor antagonist scopolamine reduced SAP and intentions while stimulating crossings. Finally, the 5-HT2C receptor antagonist ritanserine, the CCKA receptor antagonist devazepide, the CCKB receptor antagonist L-365.260 and the strychnine-insensitive glycine site antagonist 7-Cl-kynurenic acid were without effect on the behaviours in this paradigm using single doses. In conclusion, SAP and intention movements were reduced selectively by anxiolytic agents from different classes, including benzodiazepine receptor agonists, 5-HT1A receptor agonists and a 5-HT uptake inhibitor, whereas an α2-adrenoceptor agonist and a MAO inhibitor reduced SAP non-selectively. SAP in relation to other behaviours may therefore serve as a valuable paradigm to characterize anxiolytic drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02245594
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  • 8
    Electronic Resource
    Electronic Resource
    Conditioned ultrasonic distress vocalizations in adult male rats as a behavioural paradigm for screening anti-panic drugs (1995)
    Springer
    Psychopharmacology 117 (1995), S. 32-40 
    Details
    ISSN: 1432-2072
    Keywords: Ultrasonic distress vocalizations ; Adult rat ; Anxiety ; Panic disorder ; Situational panic attack ; Alprazolam ; 5-HT uptake inhibitor ; Fluvoxamine ; Clomipramine ; Imipramine ; Diazepam ; Chlordiazepoxide ; Benzodiazepine ; 5-HT1A receptor agonist ; NA uptake inhibitor ; Dopamine-D2 receptor antagonist
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 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, theα 2-adrenoceptor agonist clonidine and theα 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02245095
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