The effect of 5-HT 1A receptor ligands in a chronic mild stress model of depression

Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Neuropharmacology (Impact Factor: 5.11). 11/1995; 34(10):1305-10. DOI: 10.1016/0028-3908(95)00102-C
Source: PubMed

ABSTRACT Antidepressant properties of 5-HT1A receptor ligands (the full agonist 8-OH-DPAT, the partial agonists ipsapirone and buspirone, and the selective antagonist WAY 100135) were studied in a chronic mild stress model of depression. In this model, rats subjected to a variety of mild stressors for a prolonged period of time show a substantial decrease in the consumption of a 1% sucrose solution (anhedonia), an effect being sensitive to repeated treatment with antidepressant drugs. In the present study we found that the stress-induced deficit in the sucrose intake was gradually reversed by chronic (3-5 weeks) administration of buspirone (2.5 and 5 mg/kg, i.p., b.i.d.) or WAY 100135 (10 mg/kg, s.c., b.i.d.), but not 8-OH-DPAT (0.5 mg/kg, s.c., b.i.d.) or ipsapirone (5 mg/kg i.p., b.i.d.). The magnitude of the effect of buspirone and WAY 100135 was comparable to that observed following similar administration of the antidepressant drugs imipramine (10 mg/kg i.p.) or citalopram (10 mg/kg i.p.). Increases in the sucrose intake following chronic treatment with buspirone, WAY 100135, imipramine and citalopram were specific to the stressed animals; the behaviour of control non-stressed animals was unchanged by any drug. These results suggest that buspirone and WAY 100135 may have antidepressant properties. Possible links between the anti-anhedonic effect of these drugs and their interaction with 5-HT1A receptors and/or the dopamine system are discussed.

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Available from: Mariusz Papp, Sep 26, 2015
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    • "Fluoxetine (Jindal et al. 2013; Muscat et al. 1992; Mutlu et al. 2012), maprotiline (Muscat et al. 1992), minaserin (Cheeta et al. 1994), imipramine (Marston et al. 2011; Norman et al. 2012; Papp et al. 1996; Przegalinski et al. 1995), buspirone (Papp et al. 1996; Przegalinski et al. 1995), ipsapirone (Przegalinski et al. 1995), agomelatine (Bourin et al. 2004; Dagyte et al. 2011), risperidon (Marston et al. 2011), citalopram (Herrera-Perez et al. 2010; Przegalinski et al. 1995), escitalopram (Christensen et al. 2012), tianeptine (Mutlu et al. 2012) Social stress— repeated defeat "
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    ABSTRACT: Modelling of complex psychiatric disorders, e.g., depression and schizophrenia, in animals is a major challenge, since they are characterized by certain disturbances in functions that are absolutely unique to humans. Furthermore, we still have not identified the genetic and neurobiological mechanisms, nor do we know precisely the circuits in the brain that function abnormally in mood and psychotic disorders. Consequently, the pharmacological treatments used are mostly variations on a theme that was started more than 50 years ago. Thus, progress in novel drug development with improved therapeutic efficacy would benefit greatly from improved animal models. Here, we review the available animal models of depression and schizophrenia and focus on the way that they respond to various types of potential candidate molecules, such as novel antidepressant or antipsychotic drugs, as an index of predictive validity. We conclude that the generation of convincing and useful animal models of mental illnesses could be a bridge to success in drug discovery.
    Cell and Tissue Research 08/2013; DOI:10.1007/s00441-013-1692-9 · 3.57 Impact Factor
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    • "BUS showed reversal of stress induced deficit in the sucrose intake (anhedonia), a major symptom of depression.[14] Further it exhibited significant anxiolytic activity in Vogel's and the open-field tests and novelty-suppressed feeding in food-deprived rats.[1516] It indicated significant mood regulating activity of BUS possibly by modulating 5-HT1A receptors in brain areas. "
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    ABSTRACT: Depression is a neurological disorder characterized by sad mood, loss of pleasure, agitation and retardation. Though most relevant neuronal pathophysiology is characterized by decrease in monoamine namely; serotonin (5-HT), dopamine, noradrenaline level in central areas regulating mood and behavior, it inadequately explains the exact mechanism involved. Buspirone (BUS), a partial 5-HT1A receptor agonist has shown promising anti-depressant and anxiolytic properties in various pre-clinical and clinical studies, but the molecular and cellular mechanisms are still unclear. The aim of this study was to investigate, in vivo, the role of hypothalamic-pituitary-adrenal (HPA) axis dysregulation in pathophysiology of depression-related disorders and the anti-depressant like activity of BUS. To simulate HPA axis dysregulation, rats were subjected to bilateral adrenalectomy (ADX). We have analyzed effect of BUS (10 mg/kg, i.p.) in ADX and sham rats using open field, sucrose consumption, elevated plus maze and hyper-emotionality tests. In all animal models tested, ADX rats exhibited significant depressive and anxiogenic states while BUS was effective in reversing the psychological diseased condition developed. Taken together, these data showed a prominent role of HPA axis in depression and neuronal mechanism of BUS as anti-depressant and anxiolytic agent. Moreover, our findings suggest that BUS can be a better candidate for stress related depression and anxiety.
    Indian Journal of Psychological Medicine 07/2013; 35(3):290-8. DOI:10.4103/0253-7176.119501
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    • "The 5-HT 1A receptor agonists produce AD-like effects in rats responding under the DRL 72-s schedule (O'Donnell et al. 2005). Chronic treatment with the partial agonist buspirone produced AD-like effects in the CMS paradigm (Przegalinski et al. 1995) and chronic flesinoxan produced AD-like effects in the OB model (Cryan et al. 1997). Chronic administration of the 5-HT 1A receptor agonists 8-OH-DPAT or buspirone also reduces approach latencies in the NIH test and increases neurogenesis and survival of new neurons in the dentate gyrus after chronic treatment in rats and mice and (Banasr et al. 2004; Bodnoff et al. 1989; Santarelli et al. 2003). "
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    ABSTRACT: Serotonin reuptake inhibitors (SSRIs) are effective in treating depression. Given the existence of different families and subtypes of 5-HT receptors, multiple 5-HT receptors may be involved in the antidepressant-like behavioral effects of SSRIs. Behavioral pharmacology studies investigating the role of 5-HT receptor subtypes in producing or blocking the effects of SSRIs were reviewed. Few animal behavior tests were available to support the original development of SSRIs. Since their development, a number of behavioral tests and models of depression have been developed that are sensitive to the effects of SSRIs, as well as to other types of antidepressant treatments. The rationale for the development and use of these tests is reviewed. Behavioral effects similar to those of SSRIs (antidepressant-like) have been produced by agonists at 5-HT(1A), 5-HT(1B), 5-HT(2C), 5-HT(4), and 5-HT(6) receptors. Also, antagonists at 5-HT(2A), 5-HT(2C), 5-HT(3), 5-HT(6), and 5-HT(7) receptors have been reported to produce antidepressant-like responses. Although it seems paradoxical that both agonists and antagonists at particular 5-HT receptors can produce antidepressant-like effects, they probably involve diverse neurochemical mechanisms. The behavioral effects of SSRIs and other antidepressants may also be augmented when 5-HT receptor agonists or antagonists are given in combination. The involvement of 5-HT receptors in the antidepressant-like effects of SSRIs is complex and involves the orchestration of stimulation and blockade at different 5-HT receptor subtypes. Individual 5-HT receptors provide opportunities for the development of a newer generation of antidepressants that may be more beneficial and effective than SSRIs.
    Psychopharmacology 02/2011; 213(2-3):265-87. DOI:10.1007/s00213-010-2097-z · 3.88 Impact Factor
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