On antidepressant effects of running and SSRI : Focus on hippocampus and striatal dopamine pathways

Sammanfattning: Considering the heterogeneous character of depression, it seems likely that many brain regions are involved mediating the diverse symptoms of depression. For example, the mesolimbic DA system has a central function for motivational behaviors and pleasure seeking, and it is possible that malfunctioning of brain reward systems could be an underlying mechanism of the anhedonia experienced in depressive illness. The hippocampal formation is essential for learning and memory and depressed patients often suffer of cognitive disturbances. Image studies have shown that there is shrinkage of the hippocampal formation in depressed patients. In this thesis we have used an animal model of depression, the Flinders Sensitive Line strain (FSL), to analyze the effects of physical activity, which has antidepressant effect in humans, and the SSRI-type drug escitalopram. Special focus has been on the brain reward pathways and the hippocampus. To monitor depressive-like behavior we have used Porsolt´s swim test, which can discriminate between a norepinephrine-like and serotonin-like mediated antidepressant responses. We also examined how environmental factors can modulate the response to antidepressant treatments. When comparing the antidepressant response of wheel running to the response of escitalopram we found the following: Wheel running had an antidepressant norepinephrine-like effect in the Porsolt swim test in FSL rats. Escitalopram had a serotonergic-like antidepressant response in the Porsolt swim test in single housed FSL rats with a running-wheel as cage enrichment (barely used for running). In contrast, escitalopram did not have an antidepressant-like effect in single housed FSL rats without a running-wheel as cage enrichment. Thus environmental factors can facilitate the antidepressant action of escitalopram. Major depression in humans is associated with shrinkage of hippocampus. In this thesis we noted that the “depressed” FSL strain had lower adult hippocampal cell proliferation than the “non-depressed” FRL strain. Interestingly, wheel running normalized this mismatch. Moreover, wheel running, and escitalopram with or without access to running wheels increased the survival of newly proliferated cells. Thus decreased hippocampal cell proliferation could be one factor that contributes hippocampal shrinkage in depressed patients and antidepressant treatment could have the capacity to normalize this. However, the newly proliferated cells require a diverse cocktail of regulatory molecules to differentiate and migrate into deeper layers and send out axons that integrate into functional neuronal networks. In this thesis we have analyzed the levels of mRNAs encoding the neuropeptide tyrosine (NPY) and one of its receptor Y1 and the Brain Derived Neurotrophic Factor (BDNF), which are factors with a putative role in these processes. We found that escitalopram, running and a combination of these two increased the number of newly proliferated hippocampal BrdU-immunoreactive cells. NPY mRNA was elevated by running and the combined treatment and correlated positively to the number of newly proliferated cells and climbing behavior in the Porsolt swim test (noradrenergic response). Running elevated BDNF mRNA and correlated positively to climbing. Y1 receptor mRNA was elevated by running and the combined treatment and correlated to swimming in the Porsolt swim test (serotonergic response). Escitalopram alone did not regulate any of the molecules analyzed. Thus, different patterns of hippocampal NPY, Y1, BDNF mRNAs correlated to the norepinephrinergic and serotonergic PST response suggesting different mechanisms to achieve an antidepressant-like response by the treatments. Finally we analyzed the effect of the mild stress of social isolation in female FSL rats and SD controls with focus on hippocampus and on the dopamine D2 receptor in brain reward pathways. We demonstrated that socially isolated but not group housed FSL rats had lower dopamine D2 receptor mRNA levels compared to “non-depressed” Sprague Dawley rats. Our findings of decreased dopamine D2 receptor levels in socially isolated FSL rats suggest that low D2 receptor expression may play a role in the pathophysiology of depression. Analysis of the hippocampus in the same model revealed that social isolation increased newly proliferated BrdU-immunoreactive cells in the FSL rats whereas it had no impact on the number of cells in the Sprague Dawley strain. Group housed “depressed” Flinders rats had a lower expression of mRNAs encoding BDNF, NPY and the serotonin 5HT2A receptor than Sprague Dawley, however social isolation down regulated these molecules in Sprague Dawley rats and washed-out the differences between the two strains. To summarize, our finding support that physical activity has a comparable antidepressant effect as a SSRI-type drug and that the drug is dependent on the environmental context. Moreover, we have found a complex regulation of the patterns of hippocampal cell proliferation and regulation of different receptor and neuropeptide mRNAs in hippocampus and brain reward pathways that could have a major impact for depression and antidepressant treatments.