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Serotonin 1A (5-HT1A) receptors in brain play an important role in cognitive and integrative functions, as well as emotional states. Decreased brain-derived neurotrophic factor (BDNF) expression and/or function, particularly in hippocampus, are implicated in the pathophysiology of stress-related disorders such as major depression. BDNF+/- mice are more vulnerable to stress than wild-type mice, exhibiting behavioural despair after mild handling stress. We examined the effect of mild handling stress on 5-HT1A receptor function, as measured by 8-OH-DPAT stimulated [35S]GTPγS binding, in BDNF+/- mice and mice with a forebrain-specific reduction in BDNF (embryonic BDNF inducible knockout mice). Our data show a remarkable sensitivity of hippocampal 5-HT1A receptors to mild stress and a deficiency in BDNF. Other 5-HT1A receptor populations, specifically in frontal cortex and dorsal raphe, were resistant to the combined detrimental effects of mild stress and reductions in BDNF expression. Decreases in hippocampal 5-HT1A receptor function induced by mild stress in BDNF-deficient mice were prevented by administration of the selective serotonin reuptake inhibitor fluoxetine, which increased activation of TrkB, the high affinity receptor for BDNF, in wild-type and BDNF+/- mice. In hippocampal cultures, BDNF increased the capacity of 5-HT1A receptors to activate G proteins, an effect eliminated by the knockout of TrkB, confirming TrkB activation increases 5-HTlA receptor function. The mechanisms underlying the sensitivity of hippocampal 5-HT1A receptors to mild stress and decreased BDNF expression remain to be elucidated and may have important implications for the emotional and cognitive impairments associated with stress-related mental illness. [ABSTRACT FROM AUTHOR]

There is generally a two-three week delay in obtaining therapeutic effectiveness with antidepressants, which has been attributed to compensatory changes in neurotransmitter systems. One example is the desensitization of somatodendritic 5-HT1A autoreceptors in the DRN following chronic SSRI administration. Treatment of rats for 14 days with the SSRI fluoxetine (10 mg/kg, i.p.) results in a decrease in the efficacy of the 5-HT1A receptor agonist 8-OH-DPAT to stimulate [35S]GTPγS binding in the DRN [Emax (%above basal): saline-treated = 44 ± 5.5; fluoxetine-treated = 31.1 ± 4.4]. In contrast, chronic administration of the SSRIs citalopram (18 mg/kg/day, 14 days) or sertraline (10 mg/kg/day, 21 days) via osmotic minipump did not result in changes in the efficacy or potency of 8-OH-DPAT to stimulate [35S]GTPγS binding. The binding of [³H]8-OH-DPAT to the coupled, high-affinity agonist state of the receptor was unaltered by these treatments. Thus, not all SSRIs when administered chronically decrease the capacity of 5-HT1A receptors to activate G-proteins in the DRN. We hypothesize that the mechanism by which chronic fluoxetine administration decreases the capacity of 5-HT1A receptors to activate G-proteins in the DRN is due to phosphorylation of G proteins. Because fluoxetine has moderate affinity for the norepinephrine transporter (Kd=119-473nM), we propose that chronic fluoxetine treatment may result in activation of alpha-1 noradrenergic receptors in the DRN. Phosphorylation of Gα by PKC inhibits signal transduction via Gαi, to which 5-HT1A receptors are coupled. [ABSTRACT FROM AUTHOR]