Regional Serotonin Metabolism under Basal and Restraint Stress Conditions in the Brain of Transgenic Mice with Impaired Glucocorticoid Receptor Function

Abstract

Transgenic (TG) mice deficient in glucocorticoid receptors (GR) were used in order to study the effects of a reduced GR function on adrenocorticotropin hormone and corticosterone plasma levels and on serotonin metabolism in different brain areas under basal resting conditions, after a 30-min restraint stress and 60 min after the end of the restraint stress. There was no difference in basal or stress-induced levels of either adrenocorticotropin hormone or corticosterone in control and TG mice, but the return of adrenocorticotropin hormone to basal values after the end of the stress was delayed in TG mice. Under basal conditions, the ratio 5-hydroxyindoleacetic acid/5-hydroxytryptamine was decreased only in the hippocampus of TG mice compared to controls. In the brain stem, the ratio 5-hydroxyindoleacetic acid/5-hydroxytryptamine increased compared to basal values after a 30-min restraint stress and values were still high 60 min after the end of the restraint stress in both control and TG mice. In the hippocampus, the ratio 5-hydroxyindoleacetic acid/5-hydroxytryptamine increased at the end of the stress and returned to basal levels 60 min later in control mice, whereas there was no change at the end of the stress but an increase 60 min later in TG mice. Finally there was no change in serotonin metabolism in the cortex, striatum or hypothalamus in either group or situation. Our results support the hypothesis of a tonic activation of serotonin turnover by corticosterone through GR in the mouse hippocampus. Moreover, stress-induced stimulation of serotonin metabolism in the brain stem and hippocampus appears to be delayed in TG mice compared to control mice. These results are particularly relevant for mood disorders such as depression where alterations of serotoninergic transmission might be secondary to an impairment of GR functions.

Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways

“…These mice exhibit deficits in spatial learning, enhanced responses to novelty and decreased locomotion in familiar environments [6]. These mice also exhibit changes in mesolimbic dopaminergic [26] and raphehippocampal serotonergic neurotransmission [27,28], as well as disrupted hippocampal long-term potentiation [29]. In addition, they show differences in binding to 5-HT 1 and 5-HT 2 receptors in hippocampal areas containing both glucocorticoid and mineralocorticoid receptors [30].…”

Central 5-Hydroxytryptamine-2A Receptor Expression in Transgenic Mice Bearing a Glucocorticoid Receptor Antisense

“…In these transgenic mice, Farisse et al [19]have demonstrated, under basal conditions, that hippocampal concentrations of 5-HT are similar to those found in control (B6C/3F1) mice. The 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) as well as the turnover of 5-HT, estimated with the 5-HIAA/5-HT ratio, was lower in the hippocampus of transgenic animals [19].…”

“…The 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) as well as the turnover of 5-HT, estimated with the 5-HIAA/5-HT ratio, was lower in the hippocampus of transgenic animals [19]. However, no difference in 5-HT and 5-HIAA levels or their ratio was found in the cortex, striatum or hypothalamus of transgenic compared to control mice [19].…”

“…The 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) as well as the turnover of 5-HT, estimated with the 5-HIAA/5-HT ratio, was lower in the hippocampus of transgenic animals [19]. However, no difference in 5-HT and 5-HIAA levels or their ratio was found in the cortex, striatum or hypothalamus of transgenic compared to control mice [19]. Hence, in the present study and in the data of Farisse et al [19], 5-HT transmission is only altered in the hippocampus of transgenic mice, and in the striatum, cortex and hypothalamus it is the same as in control mice.…”

“…To investigate the role of glucocorticoid receptors in the regulation of the 5-HT 2A receptors, we used a transgenic mouse bearing a transgene coding for a glucocorticoid receptor antisense mRNA. This transgenic mouse has a 30–70% reduction in glucocorticoid receptor mRNA levels in the hypothalamus, hippocampus and cortex [18]as well as an altered 5-HT metabolism under basal and restraint stress conditions [19]. …”