The Signature of the Serotonin System in the Chronic Corticosterone Depression Model: A Study with [18F] MPPF, [18F] Altanserin and [11C] DASB

Introduction For more than six decades abnormalities in the serotonin system have been proposed to play a key role in the pathophysiology of major depressive disorder (MDD). An interesting pathway would be the role of a dysregulated hypothalamic-pituitary-adrenal (HPA) axis, seen in patients suffering from MDD, in the disturbed serotonergic neurotransmission. The present study aimed to further explore this role of the serotonergic system in the corticosterone (CORT) rodent depression model. Methods The CORT depression model was induced by means of chronic CORT administration (40 mg/kg) to male Long-Evans rats during three weeks. CORT-induced effects were investigated on the behavioral level, the total body weight and the plasma corticosterone levels, and compared to a healthy control group (N=18). Furthermore, in both the CORT and the control group, non-invasive imaging was performed using three positron emission tomography (PET) radiotracers. These included [18F]-2’-methoxyphenyl-(N-2’-pyridinyl)-p-fluoro-benzamidoethyipiperazine ([18F] MPPF), [18F] altanserin and 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile ([11C] DASB), which allowed quantification of the binding potential (BPND) on the 5-HT1A receptor, the 5-HT2A receptor, and the serotonin transporter, respectively. Results The chronic CORT administration resulted in significantly lowered body weight, significantly elevated plasma corticosterone levels, and induced depression-like behavior. Compared to the control group, induction of the CORT depression model resulted in significantly decreased BPND of [18F] MPPF in the medial prefrontal cortex and anterior cingulate cortex (ACC). At the 5-HT2A receptor level, the [18F] altanserin BPND was significantly increased in all of the cortical regions of interest except for the ACC. No significant differences in regional BPND of [11C] DASB were detected. Conclusion This extended study with three radio-ligands emphasizes the potential influence of a dysregulated HPA-axis on the serotonin system. Furthermore, these results indicate the relevance and reliability of the corticosterone depression model in the investigation of the mode of action for current and novel antidepressant therapies on the 5-HT1A and 5-HT2A receptors.