Differential Effects of Three Acute Stressors on the Serotonin 5-HT_1A Receptor System in Rat Brain

Abstract

The effects of different acute stressors on circulating corticosterone levels, 5-HT _1A receptors and 5-HT_1A mRNA levels were measured in male Sprague-Dawley rats. Two hours restraint stress, short swim stress (15 min) and long swim stress (30 min) increased circulating corticosterone levels 10-, 13- and 18-fold, respectively, when measured immediately after termination of the stress. Each stressor produced a unique profile of changes in 5-HT_1A receptors measured in coronal sections 24 h after the termination of stress with the antagonist [¹²⁵I]-4-(2’-methoxyphenyl)-1-[2’-(n-2’’-pyridinyl)-p-iodobenzamido]ethylpiperazine and the agonist [³H]-8-hydroxy-2-(di-n-propylamino)tetralin. Restraint stress produced decreases in antagonist binding in the CA3 region and dentate gyms; agonist binding was decreased only in the dentate gyms. Despite the larger elevation in circulating corticosterone level measured after short swim stress, no changes in agonist or antagonist binding were detected after this stressor. In contrast, the long swim stress increased antagonist binding in the CA2 region and in layers IV–VI of the cortex; agonist binding was also increased in all regions of the hippocampus and in layers I–VI of the cortex. Thus, restraint and long swim stress produce opposite effects on 5-HT _1A receptor expression in different subregions of the hippocampus. Analysis of presynaptic 5-HT_1A receptors in the raphe nuclei revealed an increase in antagonist binding in the dorsal raphe following long swim stress. No change in the level of 5-HT_1A mRNA measured in adjacent sections was detected following any of the stressors. The role of corticosteroid receptors in these stress-induced alterations of 5-HT_1A receptors and the potential significance of these alterations in the context of affective disorders are discussed.

Prolonged corticosterone treatment alters the responsiveness of 5-HT 1A receptors to 8-OH-DPAT in rat CA1 hippocampal neurons

“…The present study showed that repeated treatment with a high dose of corticosterone, which induced a persistent elevation of blood level of this hormone (20.5-59.2 µg/dl), comparable to those (41.5-75.3 µg/dl) observed in severeto-moderate stress (Raghupathi and McGonigle 1997), produced functional subsensitivity of 5-HT 1A receptors in the CA1 region of the hippocampus. Corticosterone treatment did not affect significantly the passive membrane properties, such as resting membrane potential, membrane resistance and cell rectification, recorded before 8-OH-DPAT administration, thus ruling out the possibility that effects on these membrane properties contribute importantly to the observed results.…”

“…This dose yielded blood levels comparable to those obtained by Karten et al (1999) in their electrophysiological study showing decreased responsiveness of 5-HT 1A receptors. Similar levels are also induced by different stressors that modulate of 5-HT 1A receptor expression in the hippocampus (Raghupathi and McGonigle 1997). Since electrophysiological studies have evaluated the effect of corticosterone on 5-HT 1A receptor responsiveness elicited by the endogenous agonist 5-HT (Karten et al 1999), we decided to confirm and extend those results and to examine the effect of repeated treatment with corticosterone on the reactivity of CA1 neurons to (±)-8-hydroxy-2-di-N-propylamino)tetralin hydrobromide (8-OH-DPAT), a selective agonist at 5-HT 1A receptors.…”

Serotonin and Stress

“…Acute stress either increases or decreases hippocampal and/or cortical 5-HT 1A receptor binding in a stressorand subregion-dependent manner (Raghupathi and McGonigle 1997), providing support for specificity. This result is noteworthy given the belief that stressors need to be administered repeatedly to observe a (glucocorticoid-dependent) decrease in 5-HT 1A receptor binding, especially in the hippocampus (Flügge 1995, but see Mendelson andMcEwen 1991).…”

Corticosteroids Alter the 5-HT1A Receptor-Mediated Response in CA1 Hippocampal Pyramidal Cells

“…Both a decrease (Chalmers et al 1993) as well as no change in 5-HT 1A receptor number in the CA1 subfield have been reported following treatment with high doses of corticosterone (Kuroda et al 1994;Mendelson and McEwen 1992). Chronic stress increases, decreases or has no effect on 5-HT 1A receptor levels, depending on the nature of the stress paradigm (Fernandes et al 1997;Kuroda et al 1994;Mendelson and McEwen 1992;Raghupathi and McGonigle 1997).…”

“…GR occupancy increases from 10% at the circadian trough to 80% at the circadian peak or following a stressful stimulus (Akana et al 1988;Reul et al 1987a). Stress produces plasma corticosterone levels in the range of 20-75 g/dl depending on the type of stressor (Bhatnagar et al 1997;Dallman et al 1994;Galea et al 1997;Groenink et al 1996;Kirby and Lucki 1998;Liberzon et al 1997;Mendelson and McEwen 1992;Raghupathi and McGonigle 1997). In pathophysiological states, such as chronic stress or depression, basal plasma cortisol levels are elevated (Dinan 1996).…”