SONU20176289, a compound combining partial dopamine D(2) receptor agonism with specific serotonin reuptake inhibitor activity, affects neuroplasticity in an animal model for depression.
We investigated the efficacy of SONU20176289, a member of a group of novel phenylpiperazine derivatives with a mixed dopamine D(2) 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 D(2) receptor agonism with SSRI activity may serve as an effective tool in the treatment of depressive/anxiety syndromes.
Michael-Titus
Adina T
AT
Neuroscience Centre, Institute of Cell and Molecular Science, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary, University of London, London E1 2AT, UK.
Albert
Monika
M
Michael
Gregory J
GJ
Michaelis
Thomas
T
Watanabe
Takashi
T
Frahm
Jens
J
Pudovkina
Olga
O
van der Hart
Marieke G C
MG
Hesselink
Mayke B
MB
Fuchs
Eberhard
E
Czéh
Boldizsár
B
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000494:pharmacology; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects; D003863:Depression / Q000523:psychology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects*; D009638:Norepinephrine / Q000652:urine; D010879:Piperazines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D012931:Social Environment; D013315:Stress, Psychological / Q000188:drug therapy / Q000523:psychology; D013737:Testis / Q000187:drug effects / Q000254:growth & development; D013739:Testosterone / Q000378:metabolism; D014418:Tupaiidae
D000964:Antimetabolites, Antineoplastic; D001973:Bromodeoxyuridine; D018491:Dopamine Agonists; D007211:Indoles; D009638:Norepinephrine; D010879:Piperazines; D018091:Receptors, AMPA; D017448:Receptors, Dopamine D2; D017367:Selective Serotonin Reuptake Inhibitors; D013739:Testosterone; C533830:SONU20176289; C104722:glutamate receptor ionotropic, AMPA 2