Behavioural Pharmacology
SONU20176289, a compound combining partial dopamine D2 receptor agonism with specific serotonin reuptake inhibitor activity, affects neuroplasticity in an animal model for depression

https://doi.org/10.1016/j.ejphar.2008.09.006Get rights and content

Abstract

We investigated the efficacy of SONU20176289, a member of a group of novel phenylpiperazine derivatives with a mixed dopamine D2 receptor partial agonist and specific serotonin reuptake inhibitor (SSRI) activity, in a chronic stress model of depression in male tree shrews. Animals were subjected to a 7-day period of psychosocial stress before treatment for 28 days with SONU20176289 (6 mg/kg/day, p.o.), during which stress was maintained. Stress reduced the in vivo brain concentrations of N-acetyl-aspartate, total creatine, and choline-containing compounds, as measured by localized proton magnetic resonance spectroscopy. Post mortem analyses revealed a reduced adult dentate cell proliferation and a decreased GluR2 expression in the prefrontal cortex. All these alterations were prevented by concomitant administration of SONU20176289. The results provide further support to the concept that antidepressant treatments may act by normalizing disturbed neuroplasticity, and indicate that combining dopamine D2 receptor agonism with SSRI activity may serve as an effective tool in the treatment of depressive/anxiety syndromes.

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.

References (70)

  • KrausC. et al.

    Physiological suppression of sexual function of subordinate males: a subtle form of intrasexual competition among male sifakas (Propithecus verreauxi)?

    Physiol. Behav.

    (1999)
  • LyooI.K. et al.

    Magnetic resonance spectroscopy: current and future applications in psychiatric research

    Biol. Psychiatry

    (2002)
  • Michael-TitusA.T. et al.

    Imipramine and phenelzine decrease glutamate overflow in the prefrontal cortex — a possible mechanism of neuroprotection in major depression?

    Neuroscience

    (2000)
  • PalmioJ. et al.

    Changes in plasma amino acids after electroconvulsive therapy of depressed patients

    Psychiatry Res.

    (2005)
  • SemkovaI. et al.

    Neuroprotective effect of 5-HT1A receptor agonist Bay X 3702 demonstrated in vitro and in vivo

    Eur. J. Pharmacol.

    (1998)
  • TanakaH. et al.

    The AMPAR subunit GluR2: still front and center-stage

    Brain Res.

    (2000)
  • TrullasR. et al.

    Functional antagonists at the NMDA receptor complex exhibit antidepressant actions

    Eur. J. Pharmacol.

    (1990)
  • ZarateC.A. et al.

    Pramipexole for bipolar II depression: a placebo-controlled proof of concept study

    Biol. Psychiatry

    (2004)
  • AbercrombieE.D. et al.

    Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex

    J. Neurochem.

    (1989)
  • BanasrM. et al.

    Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone

    Neuropsychopharmacology

    (2004)
  • BeneytoM. et al.

    Cortical AMPA and kainate receptor subunit expression in schizophrenia, bipolar disorder and major depressive disorder

    Soc. Neurosci. USA Abstr. Nr.

    (2002)
  • BlackM.D.

    Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data

    Psychopharmacology

    (2005)
  • BrandA. et al.

    Multinuclear NMR studies on the energy metabolism of glial and neuronal cells

    Dev. Neurosci.

    (1993)
  • CassanoP. et al.

    Pramipexole in treatment-resistant depression: an extended follow-up

    Depress. Anxiety

    (2004)
  • CastrenE.

    Is mood chemistry?

    Nat. Rev. Neurosci.

    (2005)
  • ChoudaryP.V. et al.

    Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression

    Proc. Natl. Acad. Sci. U. S. A.

    (2005)
  • CzéhB. et al.

    Stress-induced changes in cerebral metabolites, hippocampal volume and cell proliferation are prevented by antidepressant treatment with tianeptine

    Proc. Natl. Acad. Sci. U. S. A.

    (2001)
  • CzéhB. et al.

    Chronic stress decreases the number of parvalbumin-immunoreactive interneurons in the hippocampus: prevention by treatment with a substance P receptor (NK1) antagonist

    Neuropsychopharmacology

    (2005)
  • CzéhB. et al.

    Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment

    Neuropsychopharmacology

    (2006)
  • CzéhB. et al.

    Chronic social stress inhibits cell proliferation in the adult medial prefrontal cortex: hemispheric asymmetry and reversal by fluoxetine treatment

    Neuropsychopharmacology

    (2007)
  • DivacI. et al.

    Converging projections from the mediodorsal thalamic nucleus and mesencephalic dopaminergic neurons in the neocortex in three species

    J. Comp. Neurol.

    (1978)
  • DrevetsW.C. et al.

    Subgenual prefrontal cortex abnormalities in mood disorders

    Nature

    (1997)
  • EncinasJ.M. et al.

    Fluoxetine targets early progenitor cells in the adult brain

    Proc. Natl. Acad. Sci. U. S. A.

    (2006)
  • FischerH.D. et al.

    Gonadal response to psychosocial stress in male tree shrews (Tupaia belangeri) morphometry of testis, epididymis and prostate

    Andrologia

    (1985)
  • FlüggeG. et al.

    5HT1A-receptors and behaviour under chronic stress: selective counteraction by testosterone

    Eur. J. Neurosci.

    (1998)
  • Cited by (14)

    • The possible beneficial effects of creatine for the management of depression

      2019, Progress in Neuro-Psychopharmacology and Biological Psychiatry
      Citation Excerpt :

      In mice exposed to the forced swim test (FST), total creatine concentrations in the left dorsolateral prefrontal cortex were significantly decreased and this alteration was abolished by desipramine administration (Kim et al., 2010). In male tree shrews subjected to chronic stress model of depression, the brain levels of total creatine were also reduced (Czeh et al., 2001; Michael-Titus et al., 2008), a finding accompanied by reduced cell proliferation rate in the dentate gyrus of the hippocampus (Fuchs et al., 2004). Moreover, serial application of restraint stress, forced swim, and ether exposure, a rat model of post traumatic stress disorder, decreased creatine concentrations in the rat medial prefrontal cortex (Knox et al., 2010).

    • Adipocytokine signaling is altered in flinders sensitive line rats, and adiponectin correlates in humans with some symptoms of depression

      2013, Pharmacology Biochemistry and Behavior
      Citation Excerpt :

      Early life stress may underlie the reduced hippocampal volumes observed in some patients with MDD (see Frodl and O'Keane, in press for review). Efficacious antidepressant treatments function in part, by normalizing disturbed neuroplasticity (Michael-Titus et al., 2008) and facilitating axonal and dendritic sprouting (Vaidya et al., 1999) — processes that can help restore synaptic connections within the neuropil. Although the role of hippocampal neurogenesis in the development and persistence of depression is not completely understood, its requirement for antidepressant efficacy is well accepted (Lewitus et al., 2009; Santarelli et al., 2003; Malberg et al., 2000).

    • Sex-specific antidepressant effects of dietary creatine with and without sub-acute fluoxetine in rats

      2012, Pharmacology Biochemistry and Behavior
      Citation Excerpt :

      Drugs prescribed to treat depression, such as paroxetine, fluoxetine, and imipramine, alter brain- and mitochondrial-type creatine kinases in the prefrontal cortex, hippocampus, and striatum (Agostinho et al., 2009; Assis et al., 2009; Santos et al., 2009), areas of the brain known to be involved with depression (Drevets et al., 2008; Maletic et al., 2007). Additionally, antidepressant drugs increase creatine and phosphocreatine concentrations in the prefrontal cortex and hippocampus in animal models of depression (Kim et al., 2010; Czéh et al., 2001; Michael-Titus et al., 2008). It is hypothesized that increased phosphocreatine stores and creatine kinase activity attenuate metabolic impairments associated with depression by increasing the rate of ATP replenishment and accordingly improving neuronal integrity or function (Agostinho et al., 2009; Kim et al., 2010; Santos et al., 2009).

    • Sertoli cell therapy: A novel possible treatment strategy for treatment-resistant major depressive disorder

      2011, Medical Hypotheses
      Citation Excerpt :

      Reduced neuropil sizes in patients with depression may account for the decreased hippocampal volumes observed in imaging studies [29,123]. Further, efficacious antidepressant treatments function, in part, by normalizing disturbed neuroplasticity [124] and facilitating axonal and dendritic sprouting [125]—processes that can help restore synaptic connections within the neuropil. Targeted Sertoli cell-based therapy is hypothesized to increase hippocampal neurogenesis by secreting immunoprotective and trophic factors (e.g., TGF-β, GDNF) ([52]; Table 2).

    View all citing articles on Scopus
    View full text