RESUMO
Most depressed patients don't respond to their first drug treatment, and the reasons for this treatment resistance remain enigmatic. Human studies implicate a polymorphism in the promoter of the serotonin-1A (5-HT(1A)) receptor gene in increased susceptibility to depression and decreased treatment response. Here we develop a new strategy to manipulate 5-HT(1A) autoreceptors in raphe nuclei without affecting 5-HT(1A) heteroreceptors, generating mice with higher (1A-High) or lower (1A-Low) autoreceptor levels. We show that this robustly affects raphe firing rates, but has no effect on either basal forebrain serotonin levels or conflict-anxiety measures. However, compared to 1A-Low mice, 1A-High mice show a blunted physiological response to acute stress, increased behavioral despair, and no behavioral response to antidepressant, modeling patients with the 5-HT(1A) risk allele. Furthermore, reducing 5-HT(1A) autoreceptor levels prior to antidepressant treatment is sufficient to convert nonresponders into responders. These results establish a causal relationship between 5-HT(1A) autoreceptor levels, resilience under stress, and response to antidepressants.
Assuntos
Antidepressivos , Autorreceptores/metabolismo , Fluoxetina , Neurônios/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/metabolismo , Estresse Psicológico/metabolismo , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Autorreceptores/genética , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/fisiopatologia , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Humanos , Camundongos , Camundongos Transgênicos , Neurônios/citologia , Neurônios/fisiologia , Técnicas de Patch-Clamp , Polimorfismo Genético , Núcleos da Rafe/citologia , Núcleos da Rafe/metabolismo , Receptor 5-HT1A de Serotonina/genética , Serotonina/metabolismoRESUMO
The Wistar-Kyoto (WKY) rat is stress sensitive and exhibits depressive-like behavior. The locus coeruleus (LC)-norepinephrine and dorsal raphe (DR)-serotonin systems mediate certain aspects of the stress response and have been implicated in depression. Microarray technology was used to identify gene expression differences in the LC and DR between WKY vs Sprague-Dawley (SD) rats that might account for the WKY phenotype. RNA was isolated from microdissected LC and DR, amplified, and hybridized to microarrays (1 array/subject, n = 4/group). Significance of microarray (SAM) analysis revealed increased expression of 66 genes in the LC and 19 genes in the DR and decreased expression of 33 genes in the DR of WKY rats. Hierarchical clustering identified differences in gene expression profiles of WKY vs SD rats that generally concurred with SAM. Notably, genes that encoded for enzymes involved in norepinephrine turnover, amino-acid receptors, and certain G-protein-coupled receptors were elevated in the LC of WKY rats. The DR of WKY rats showed decreased expression of genes encoding several potassium channels and neurofilament genes. The chromosomal locations of 15 genes that were differentially expressed in WKY rats were near loci identified as contributing to depressive-like behaviors in the rat. The specific genes revealed by the present analysis as being differentially expressed in WKY rats may contribute to their unique behavioral profile and suggest targets that confer susceptibility to stress-related psychiatric disorders.
