In vivo efflux of serotonin in the dorsal raphe nucleus of 5-HT1A receptor knockout mice

In the dorsal raphe nucleus (DR), extracellular serotonin (5-HT) regulates serotonergic transmission through 5-HT1A autoreceptors. In this work we used in vivo microdialysis to examine the effects of stressful and pharmacological challenges on DR 5-HT efflux in 5-HT1A receptor knockout (5-HT1A-/-) mice and their wild-type counterparts (5-HT1A+/+). Baseline 5-HT concentrations did not differ between both lines of mice, which is consistent with a lack of tonic control of 5-HT1A autoreceptors on DR 5-HT release. (R)-(+)-8-Hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT, 0.5 mg/kg) reduced 5-HT levels to 30% of basal values in 5-HT1A+/+ mice, but not in 5-HT1A-/- mice. The selective 5-HT1B receptor agonist 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (CP 93129, 300 micro m) reduced dialysate 5-HT to the same extent (30-40% of baseline) in the two genotypes, which suggests a lack of compensatory changes in 5-HT1B receptors in the DR of such mutant mice. Both a saline injection and handling for 3 min increased DR dialysate 5-HT in mutants, but not in 5-HT1A+/+ mice. Fluoxetine (5 and 20 mg/kg) elevated 5-HT in a dose-dependent manner in both genotypes. However, this effect was markedly more pronounced in the 5-HT1A-/- mice. The increased responsiveness of the extracellular 5-HT in the DR of 5-HT1A receptor knockout mice reflects a lack of the autoinhibitory control exerted by 5-HT1A autoreceptors.     

Developmental plasticity of HPA and fear responses in rats: a critical review of the maternal mediation hypothesis

Developmental plasticity of HPA and fear responses in rats has been proposed to be mediated by environment-dependent variation in active maternal care. Here, we review this maternal mediation hypothesis based on the postnatal manipulation literature and on our own recent research in rats. We show that developmental plasticity of HPA and fear responses in rats cannot be explained by a linear single-factor model based on environment-dependent variation in active maternal care. However, by adding environmental stress as a second factor to the model, we were able to explain the variation in HPA and fear responses induced by postnatal manipulations. In this two-factor model, active maternal care and environmental stress (as induced, e.g., by long maternal separations or maternal food restriction) exert independent, yet opposing, effects on HPA reactivity and fearfulness in the offspring. This accounts well for the finding that completely safe and stable, as well as, highly stressful maternal environments result in high HPA reactivity and fearfulness compared to moderately challenging maternal environments. Furthermore, it suggests that the downregulation of the HPA system in response to stressful maternal environments could reflect adaptive developmental plasticity based on the increasing costs of high stress reactivity with increasingly stressful conditions. By contrast, high levels of environmental stress induced by environmental adversity might constrain such adaptive plasticity, resulting in non-adaptive or even pathological outcomes. Alternatively, however, developmental plasticity of HPA and fear responses in rats might be a function of maternal HPA activation (e.g., levels of circulating maternal glucocorticoid hormones). Thus, implying a U-shaped relationship between maternal HPA activation and HPA reactivity and fearfulness in the offspring, increasing maternal HPA activation with increasing environmental adversity would explain the effects of postnatal manipulations equally well. This raises the possibility that variation in active maternal care is an epiphenomenon, rather than a causal factor in developmental plasticity of HPA and fear responses in rats. Developmental plasticity of HPA and fear responses in rats and other animals has important implications for the design of animal experiments and for the well-being of experimental animals, both of which depend on the exact underlying mechanism(s). Importantly, however, more naturalistic approaches are needed to elucidate the adaptive significance of environment-dependent variation of HPA reactivity and fearfulness in view of discriminating between effects reflecting adaptive plasticity, phenotypic mismatch and pathological outcomes, respectively.