Effects of repeated treatment with 5-HT1A agonists on active avoidance responding in the rat

The behavioural effects of the serotonin 1A receptor (5-HT_1A) agonist anxiolytics are generally examined after acute administration. The present study examined the effects of these substances during repeated treatment in the two-way active avoidance (Conditioned Avoidance Response, CAR) procedure. Previously it has been found that the prototypical 5-HT_1A receptor agonist, 8-OH-DPAT, increases avoidance, apparently by increasing general activity, after repeated administration but not on acute administration. In the present study, it was demonstrated that this increase in activity can be blocked by the 5-HT_1A receptor antagonists (–)alprenolol (also beta adrenergic antagonist) and (S)-UH-301, but not by the non-selective 5-HT antagonist metergoline. The relatively full 5-HT_1A agonist, flesinoxan, and the partial 5-HT_1A agonist, ipsapirone, had qualitatively similar effects to 8-OH-DPAT, although the effect of ipsapirone was clearly smaller in magnitude. Buspirone, the 5-HT_1A partial agonist/dopamine D₂ antagonist, markedly decreased activity, and thus avoidance of the shocks, in a manner similar to the antipsychotic drug, haloperidol. However, when the hypothermic effects of these compounds were investigated after acute administration, buspirone induced a strong hypothermic response in rats, like 8-OH-DPAT, whereas haloperidol had no effect. With the exception of buspirone, the effectiveness of these compounds in increasing activity in the CAR test appears to be related to their agonist efficacy at the 5-HT_1A receptor. Similarities between the effects of these compounds and previously reported results with serotonin-depleting agents (Tenen 1967; Breese et al. 1974) suggest that the net effect of 5-HT_1A agonists after repeated administration is to produce a functional reduction in 5-HT activity. The activity suppressing action of buspirone indicates that the dopamine antagonist activity of buspirone predominates in this procedure.     

Serotonin1A receptor agonists induce Fos protein expression in the locus coeruleus of the conscious rat

The azapirones, which are partial agonists of the serotonin (5-HT)_1A receptor, possess anxiolytic activity. These agents may act at the pre- or postsynaptic 5-HT_1A receptors, and involve the noradrenergic system. To determine whether these drugs activate noradrenergic neurons via 5-HT_1A receptors, we have evaluated the expression of the immediate early gene c-fos in the locus coeruleus. Tandospirone and ipsapirone each induced expression of Fos protein in the noradrenergic neurons of the locus coeruleus of conscious rats. This effect was reversed by pretreatment with (+)-WAY100135, a specific 5-HT_1A antagonist. These results clearly demonstrate that azapirones activate noradrenergic neurons via 5-HT_1A receptors.     

Behavioural and pharmacological characterisation of the canopy stretched attend posture test as a model of anxiety in mice and rats

The behavioural element, stretched attend posture (SAP), is an important component of the “risk-assessment” repertoire of defensive behaviour in rodents. The present experimental paradigm was devised as a novel and simple method of eliciting high levels of SAP in mice and rats. The SAP test apparatus comprised an elevated black Perspex circular platform. A smaller clear red Perspex circular “Canopy” was supported directly above the platform by a central pillar, thus dividing the platform into an inner, dimly lit covered zone and an outer, brightly lit exposed zone. In both the rat and mouse version of this model, vehicle-treated animals exhibited a marked preference for exploring the covered zone and also exhibited high baseline levels of SAP, particularly at the covered zone boundary whilst they investigated the exposed zone. In the mouse SAP test, the benzodiazepine receptor agonists, diazepam (0.5 mg/kg SC) and chlordiazepoxide (2 mg/kg SC), and the 5-HT_1A receptor agonists, buspirone (1 and 3 mg/kg SC), ipsapirone (3 mg/kg SC) and 8-OH-DPAT (0.2 mg/kg SC), all significantly decreased the frequency of SAP without impairing motor activity. In the rat SAP test, diazepam (0.5 mg/kg SC) significantly decreased, whilst the anxiogenic 5-HT_2C/1B receptor agonist, mCPP (0.25 and 0.5 mg/kg SC), significantly increased, the frequency of SAP. Ipsapirone (3 mg/kg SC) induced a non-specific behavioural inhibition. These data suggest that the “Canopy” SAP test is a useful paradigm to investigate risk assessment behaviour in both rats and mice, and may provide a sensitive novel rodent model of anxiety. Received: 11 October 1996/Final version: 18 February 1997     

Prevention of the analgesic consequences of social defeat in male mice by 5-HT1A anxiolytics,buspirone, gepirone and ipsapirone

Behavioural and pharmacological studies have suggested that anxiety may be an important factor in the initiation of non-opioid analgesia in defeated male mice. In the present study, the effects of three 5-HT_1A anxiolytics (buspirone, ipsapirone and gepirone) on basal nociception and defeat analgesia were examined. Results show that the analgesic consequences of social defeat were potently blocked by all three compounds, with a rank-order potency (minimum effective doses) of ipsapirone (0.05 mg/kg) > gepirone (0.1 mg/kg) > buspirone (0.5 mg/kg). These inhibitory effects on defeat analgesia were observed in the absence of intrinsic activity on basal nociception (tail-flick assay). When administered alone, (-)pindolol produced biphasic effects on defeat analgesia with enhancement at 0.5 mg/kg and inhibition at 5.0 mg/kg. Lower doses of (-)pindolol (0.05 and 0.25 mg/kg) which did not affect defeat analgesia when administered alone, totally blocked the inhibitory effects of ipsapirone (0.5 mg/kg). Data are discussed in relation to the involvement of 5-HT_1A receptor mechanisms in this adaptive form of pain inhibition.     

Long-term fluoxetine treatment decreases 5-HT1A receptor responsivity in obsessive-compulsive disorder

Fluoxetine (FLX) is a selective serotonin (5-HT) reuptake inhibitor with therapeutic benefit in patients with obsessive-compulsive disorder (OCD). To evaluate the effect of chronic FLX treatment on 5-HT_1A receptor responsivity, hypothermic, neuroendocrine, and behavioral responses to the selective 5-HT_1A receptor ligand ipsapirone (IPS) were examined in patients with primary OCD. A single dose of 0.3 mg/kg of IPS or placebo were given under double-blind, random-assignment conditions to ten patients before and during FLX treatment. The ability of IPS to induce hypothermia and ACTH/cortisol release was significantly attenuated during chronic FLX as compared to the pretreatment IPS challenge. The behavioral effects of IPS, though minimal, were less pronounced during FLX treatment. While FLX was effective in reducing the severity of OC symptoms, no significant correlation between attenuation of 5-HT_1A receptor-mediated functional measures and FLX-induced improvement in OC symptoms was detected. These findings are consistent with the development of adaptive hyporesponsivity of the 5-HT_1A receptor-effector system complex possibly involving subsensitivity of the 5-HT_1A receptor itself and/or decreased functional activity of the postreceptor signal transduction. Modulation of 5-HT_1A receptor-effector system function may be critical to the antidepressant/anti-OC efficacy of 5-HT reuptake inhibitors.Part of this work was presented at the 17th Congress of the CINP, Kyoto, Japan, September 10–14, 1990     

Complex effects of age and gender on hypothermic,adrenocorticotrophic hormone and cortisol responses to ipsapirone challenge in normal subjects

The effects of a challenge dose of the 5-HT_1A agonist, ipsapirone (0.3 mg per kg body weight), or placebo on body temperature and on adrenocorticotrophic hormone (ACTH) and cortisol release, were examined in 30 normal subjects (14 males, 19–74 years and 16 females, 22–69 years) using a randomized, double blind design. Irrespective of age or gender, ipsapirone induced a significant reduction in body temperature relative to placebo and a significant increase in ACTH and cortisol release. Maximal temperature reduction by ipsapirone was significantly blunted in older subjects and was inversely related to age. There was no gender difference in the hypothermic response to ipsapirone. ACTH and cortisol responses showed an opposite impact of aging in males and females. Whereas both responses diminished with age in male subjects, they increased with age in females. The cortisol response of older females was significantly larger than that of all the other subjects. Adverse effects of ipsapirone were also more marked in elderly females and were correlated with ACTH and cortisol responses. These findings should be taken into consideration in the use of ipsapirone and other 5-HT_1A agonists as challenge procedures for studying central serotonergic function in depression and other disorders. Careful matching of control and experimental subjects is indicated so as to avoid spurious results which reflect the effects of age and gender rather than the pathophysiology of the disorders being investigated.     

Anxiolytic effect of the 5-HT1A compounds 8-hydroxy-2-(di-n-propylamino) tetralin and ipsapirone in the social interaction paradigm: Evidence of a presynaptic action

This study analyses at which site, pre- or postsynaptic, the 5-HT_1A ligands—8-hydroxy-2(dl-n-propyilamino)tetralin (8-OH-DPAT) and ipsapirone—induce their amdoytic action. The experimental anxiety was assessed in the social interaction test. An anxioyfic action was observed after the systemic administration of 8-OH-DPAT (025 and 0.5 mg/kg and ipsapirone (5 but not 10 mg/kg). In 5,7-dihydroxytrpytamine (5,7-DHT, 150 μg/10 μl) lesioned rats the arodoytie effect of 8-OH-DPAT and ipsapirone was not observed, suggesting a presynaptic action of these drugs.dnVs. When directly injected into the dorsal raphe nucleus 8-OH-DPAT (0.1 μgμl) and ipsapirone (0.2 μg/μl), both compounds produce an)dolytic effects. At same doses, these drugs lacked an effect after their intrahippocampal infusion. All data strongly suggest that both drugs act presynaptically to reduce the anxiety levels in the social interaction paradigm.     

Evidence for the involvement of the 5-HT1A receptor in the anxiolytic action of indorenate and ipsapirone

The systemic injection of diazepam (0.5 and 1.0 mg/kg), indorenate (5 and 10 mg/kg) and ipsapirone (2.5 and 5.0 mg/kg) reduced anxiety as tested in an exploratory avoidance model in mice. The injection of pindolol (2.0 mg/kg), alprenolol (5.0 mg/kg) or methiotepin (0.25 mg/kg) effectively prevented the anxiolytic action of indorenate and ipsapirone. The combined treatment of the antagonists with indorenate or ipsapirone did not reduce the motor activity, therefore suggesting that the inhibition of exploratory behaviour, after such combinations, was not mediated through a general motor impairment. Neither diazepam nor indorenate alone modified the motor activity; ipsapirone (5 and 2.5 mg/kg), however, reduced ambulation. This reduction was also prevented by administering pindolol, alprenolol or methiotepin. These observations suggest that the anxiolytic actions of indorenate and ipsapirone are mediated via stimulation of the 5-HT1A like receptor subtype.     

Evidence for a postsynaptic action of the serotonergic anxiolytics: Ipsapirone, indorenate and buspirone

In the present experiment we analyzed whether the antianxiety action of the serotonergic 1A agonists buspirone (5 mg/kg), ipsapirone (5 mg/kg), indorenate (5 mg/kg), and 8-OH-DPAT (0.5 mg/kg) were mediated through the stimulation of pre- or postsynaptic serotonergic receptors. The experimental anxiety values were determined with the burying behavior test, where a reduction in the cumulative time of burying behavior was interpreted as a reduction in anxiety. To that purpose we analyzed the putative anxiolytic action of these drugs in animals with lesion of the serotonergic fibers after the intracerebroventricular (ICV) injection of 5,7-dihydroxytyptamine (5,7-DHT, 10 or 150 micrograms/10 microliters). The neurochemical analysis shows that these treatments produce a statistically significant reduction in 5-HT and 5-HIAA levels in various brain areas. The results of the behavioral experiments reveal that buspirone, ipsapirone, and indorenate produced exactly the same reduction in burying behavior in lesioned animals as compared with control rats. The reduction in burying behavior produced by 8-OH-DPAT was effectively prevented by the lesion with 5,7-DHT. These data suggest that the anxiolytic effect of buspirone, ipsapirone, and indorenate is mediated via the stimulation of postsynaptic receptors, while the somatodendritic receptors are involved in the antianxiety effect of 8-OH-DPAT.