Behavioural PharmacologySONU20176289, a compound combining partial dopamine D2 receptor agonism with specific serotonin reuptake inhibitor activity, affects neuroplasticity in an animal model for depression
Introduction
Increasing evidence has led to the view that the leading theory of the etiology of depression, the “monoamine hypothesis”, does not fully explain this complex disorder. More recent theories suggest that disturbed neuroplasticity, including impaired cytogenesis, may be the basis for depressive disorders (Castren, 2005, Pittenger and Duman, 2008). In the present study we investigated the efficacy of the novel compound SONU20176289 in preventing or treating changes in neuroplasticity in the chronic psychosocial stress model of depression in male tree shrews. SONU20176289 is a compound combining partial agonism at the dopamine D2 receptor with selective serotonin reuptake inhibitor (SSRI) activity. The rationale behind a combination of these two activities is a potentially increased therapeutic efficacy in depressive/anxiety syndromes such as social anxiety disorder, obsessive compulsive disorder and bipolar disorder. Most depressive and anxiety disorders are currently treated with SSRIs. Recent evidence shows a potential beneficial effect of dopamine agonist augmentation of SSRI or tricyclic antidepressant treatment in patients with resistant major depression (Lattanti et al., 2002, Cassano et al., 2004), as a mood stabilizer treatment in bipolar depression (Goldberg et al., 2004) and as monotherapy in bipolar depression (Zarate et al., 2004). Thus, a compound combining SSRI activity with partial agonism at the dopamine D2 receptor could be an improvement upon the existing treatment of anxiety and depressive disorders, as it would not only increase extracellular serotonin (5-HT) levels but also modulate the dopaminergic system.
Converging observations suggest a link between stress, depression, excitatory amino acids and antidepressant treatment. Stress is associated with the risk of developing depression (Kendler et al., 1999), and in rats stress increases the release of glutamate in the prefrontal cortex (Moghaddam, 1993). Major depression is associated with a decrease in cortical blood flow and glucose metabolism in the prefrontal cortex, which is at least partly due to a reduction in cortical volume (Drevets et al., 1997). In line with the in vivo findings, post mortem histological analyses of specific subregions in the frontal cortex demonstrated reductions in neuronal size and glial cell density in depressed patients (Rajkowska and Miguel-Hidalgo, 2007).
In recent years, our group has described and validated a model of chronic social defeat in male tree shrews which has high validity for research on the pathophysiology of depression (Fuchs and Flügge, 2002, Fuchs et al., 2005). We treated animals with SONU20176289 for a clinically relevant period of four weeks. The oral drug application started after one week of repeated social defeat and the psychosocial stress continued during the whole treatment period. Urinary noradrenaline as a marker for neurosympathetic tone, was monitored throughout. After this period, brain metabolite concentrations were assessed in vivo by localized proton magnetic resonance spectroscopy, and adult dentate gyrus cell proliferation was determined post mortem.
We had previously shown that chronic treatment with the tricyclic antidepressant imipramine reduces glutamate release in rat prefrontal cortex and increases the expression of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor GluR2 subunit in this area (Michael-Titus et al., 2000, Nazir et al., 2002). Therefore, we analysed the expression of the GluR2 subunit in the prefrontal cortex in control, stressed, and antidepressant treated tree shrews post mortem.
Section snippets
Animals, experimental design, and drug treatment
All experiments were carried out on tree shrews (Tupaia belangeri), which are considered to be phylogenetically closely related to primates (Martin, 1990). Experimentally naive adult male tree shrews were obtained from the breeding colony at the German Primate Center (Göttingen, Germany). Animals were housed individually on a 12 h/12 h light/dark cycle and with free access to food and water. All treatments were performed during the day (activity period, lights on). Animal experiments were
Endocrine parameters
The intensity of psychosocial stress in subordinate tree shrews was demonstrated by an immediate and sustained activation of the neurosympathetic tone, as indicated by the pronounced and significant elevation of urinary noradrenaline excretion both in the Stress and Stress + SONU groups (Fig. 2). One-way ANOVA revealed a significant difference between the four groups for each week between the 2nd and 6th week (Week 2: F(3,20) = 15.26; P < 0.01; Week 3: F(3,20) = 18.51; P < 0.01; Week 4: F(3,20) = 9.39; P <
Discussion
In the present study we employed the chronic social defeat paradigm to model human depression. We treated the animals with a novel potential antidepressant compound, combining a dopamine D2 receptor partial agonist with SSRI activity, and investigated the effect of stress and drug treatment on indicators of neuroplasticity. As contemporary theories put emphasis on altered neuroplasticity as a potential neurobiological basis of depression (Castren, 2005, Pittenger and Duman, 2008), we analysed
Acknowledgments
The present study has been partially supported by Solvay Pharmaceuticals, Weesp, The Netherlands. The analysis of concentrations of urinary norepinephrine and creatinine was performed at KCL Bioanalysis b.v., Leeuwarden, The Netherlands. We thank Jan Berk for his help. The analysis of serum testosterone concentrations was performed in the Department of Reproductive Biology of the German Primate Center, Göttingen, Germany. We are grateful to Dr. M. Heistermann for his help.
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