Mesolimbic dopamine D_{2} receptor plasticity contributes to stress resilience in rats subjected to chronic mild stress

RATIONALE: Few studies have investigated neurobiological and biochemical differences between stress-resilient and stress-vulnerable experimental animals. OBJECTIVES: We investigated alterations in mesolimbic dopamine D(2) receptor density and mRNA expression level in stressed rats at two time points, i.e. after 2 and 5 weeks of chronic mild stress (CMS). METHODS: We used the chronic mild stress paradigm because it is a well-established animal model of depression. Two groups of stressed rats were distinguished during CMS experiments: (1) stress reactive (70 %), which displayed a decrease in the drinking of a palatable sucrose solution during the stress regimen, and (2) stress resilient (30 %), which exhibited an unaltered drinking profile when compared with the unchallenged control group. [(3)H]Domperidone was used as a ligand to label dopamine D(2) receptors, and a mixture of three specific oligonucleotides was used to evaluate dopamine D(2) receptor mRNA changes in various regions of the rat brain. RESULTS: CMS strongly affected the mesolimbic dopamine circuit in stress-resilient group after 2 weeks and stress-reactive group of rats after 5 weeks which exhibited a decrease in the level of dopamine D(2) receptor protein without alterations in D(2) mRNA expression. Stress-resilient animals, but not stress-reactive animals, effectively adapted to the extended stress and coped with it. The increase in D(2) mRNA expression returned the dopamine D(2) receptor density to control levels in stress-resilient rats after 5 weeks of CMS, but not in stress-reactive animals. CONCLUSIONS: These results clearly demonstrate that, despite earlier blunting, the activation of dopamine receptor biosynthesis in the dopamine mesoaccumbens system in stress-resilient rats is involved in active coping with stressful experiences, and it exhibits a delay in time

Chronic mild stress alters the somatostatin receptors in the rat brain

RATIONALE: The involvement of somatostatin (SST) and its receptors in the pathophysiology of depression and stress has been evidenced by numerous studies. OBJECTIVES: The purpose of the present study was to find whether chronic mild stress (CMS), an animal model of depression, affects the SST receptors in the rat brain and pituitary, as well as the level of SST in plasma. METHODS: In CMS model, rats were subjected to 2 weeks of stress and behaviorally characterized using the sucrose consumption test into differently reacting groups based on their response to stress, i.e., stress-reactive (anhedonic), stress-non-reactive (resilient), and invert-reactive rats (characterized by excessive sucrose intake). We measured specific binding of [(125)I]Tyr(3)-Octreotide, expression of mRNA encoding sst2R receptors in the rat brains, expression of SST and its receptors in rat pituitary, and the level of SST in the plasma. RESULTS: The obtained results show decreases in binding of [(125)I]Tyr(3)-Octreotide in most of rat brain regions upon CMS and no significant differences between three stressed groups of animals, except for significant up-regulation of sst2 receptor in medial habenula (MHb) in the stress-reactive group. In the same group of animals, significant increase in plasma SST level was observed. CONCLUSIONS: There are two particularly sensitive sites distinguishing the response to stress in CMS model. In the brain, it is MHb, while on the periphery this predictor is SST level in plasma. These changes may broaden an understanding of the mechanisms involved in the stress response and point to the intriguing role of MHb

The miRNome of Depression

Depression is an effect of complex interactions between genetic, epigenetic and environmental factors. It is well established that stress responses are associated with multiple modest and often dynamic molecular changes in the homeostatic balance, rather than with a single genetic factor that has a strong phenotypic penetration. As depression is a multifaceted phenotype, it is important to study biochemical pathways that can regulate the overall allostasis of the brain. One such biological system that has the potential to fine-tune a multitude of diverse molecular processes is RNA interference (RNAi). RNAi is an epigenetic process showing a very low level of evolutionary diversity, and relies on the posttranscriptional regulation of gene expression using, in the case of mammals, primarily short (17–23 nucleotides) noncoding RNA transcripts called microRNAs (miRNA). In this review, our objective was to examine, summarize and discuss recent advances in the field of biomedical and clinical research on the role of miRNA-mediated regulation of gene expression in the development of depression. We focused on studies investigating post-mortem brain tissue of individuals with depression, as well as research aiming to elucidate the biomarker potential of miRNAs in depression and antidepressant response