Comparison of chronic physical and emotional social defeat stress effects on mesocorticolimbic circuit activation and voluntary consumption of morphine.

Chronic social defeat stress (CSDS) is a well-established rodent model of depression that induces persistent social avoidance. CSDS triggers molecular adaptations throughout the mesocorticolimbic reward circuit, including changes in the activity of dopamine neurons in the ventral tegmental area (VTA), that may also influence drug reward. One limitation of traditional, physical CSDS (PS) is that injury complicates the study of opiate drugs like morphine. Thus, we sought to characterize a variation of CSDS, termed emotional CSDS (ES), that eliminates this confound. We assessed the effect of PS and ES on mesocorticolimbic circuit activation, VTA gene expression, and morphine intake. We found that PS and ES similarly induced ΔFosB in the hippocampus, but only PS significantly increased ΔFosB expression in the prefrontal cortex and striatum. In contrast, cFos expression was similarly reduced by both PS and ES. Interestingly, we found that PS and ES similarly increased voluntary morphine consumption immediately following stress, despite differences in the magnitude of the depressive phenotype and striatal ΔFosB expression at this time point. Combined, these data suggest that both stress paradigms may be useful for investigation of stress-induced changes in drug behavior.

Multivariate permutation analysis associates multiple polymorphisms with subphenotypes of major depression.

Unipolar major depressive disorder (MDD) is a prevalent, disabling condition with multiple genetic and environmental factors impacting disease risk. The diagnosis of MDD relies on a cumulative measure derived from multiple trait dimensions and alone is limited in elucidating MDD genetic determinants. We and others have proposed that MDD may be better dissected using paradigms that assess how specific genes associate with component features of MDD. This within-disease design requires both a well-phenotyped cohort and a robust statistical approach that retains power with multiple tests of genetic association. In the present study, common polymorphic variants of genes related to central monoaminergic and cholinergic pathways that previous studies align with functional change in vitro or depression associations in vivo were genotyped in 110 individuals with unipolar MDD. Subphenotypic characteristics were examined using responses to individual items assessed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM IV), the 17-item Hamilton Rating Scale for Depression (HAM-D) and the NEO Five Factor Inventory. Multivariate Permutation Testing (MPT) was used to infer genotype-phenotype relationships underlying dimensional findings within clinical categories. MPT analyses show significant associations of the norepinephrine transporter (NET, SLC6A2) -182 T/C (rs2242446) with recurrent depression [odds ratio, OR = 4.15 (1.91-9.02)], NET -3081 A/T (rs28386840) with increase in appetite [OR = 3.58 (1.53-8.39)] and the presynaptic choline transporter (CHT, SLC5A7) Ile89Val (rs1013940) with HAM-D-17 total score {i.e. overall depression severity [OR = 2.74 (1.05-7.18)]}. These relationships illustrate an approach to the elucidation of gene influences on trait components of MDD and with replication, may help identify MDD subpopulations that can benefit from more targeted pharmacotherapy.