Circuitry Underlying Regulation of the Serotonergic System by Swim Stress

Abstract

The dorsal raphe nucleus (DR)-serotonin (5-HT) system has been implicated in depression and is dramatically affected by swim stress, an animal model with predictive value for antidepressants. Accumulating evidence implicates the stress-related neuropeptide corticotropin-releasing factor (CRF) in the effect of swim stress on this system. This study investigated neural circuits within the DR that are activated by swim stress as revealed by neuronal expression of the immediate early gene, c-fos. Swim stress increased c-fos expression in the dorsolateral subregion of the DR. The majority of c-fos-expressing neurons were doubly labeled for GABA (85 Ϯ 5%), whereas relatively few were immunolabeled for 5-HT (4 Ϯ 1%), glutamate (0.5 Ϯ 0.3%) or calbindin (1.5 Ϯ 0.3%). Dual immunohistochemical labeling revealed that c-fos-expressing neurons in the dorsolateral DR were enveloped by dense clusters of CRF-immunoreactive fibers and also contained immunolabeling for CRF receptor, suggesting that c-fos-expressing neurons in the DR were specifically targeted by CRF. Consistent with this, the CRF receptor 1 antagonist, antalarmin, prevented swim-stress-elicited c-fos expression in the dorsolateral DR. Together with previous findings that both swim stress and CRF decrease 5-HT release in certain forebrain regions, these results suggest that swim stress engages CRF inputs to GABA neurons in the dorsolateral DR that function to inhibit 5-HT neurons and 5-HT release in the forebrain. This circuitry may underlie some of the acute behavioral responses to swim stress as well as the neuronal plasticity involved in long-term behavioral changes produced by this stress.

Restraint stress increases serotonin release in the central nucleus of the amygdala via activation of corticotropin-releasing factor receptors

“…The finding that central CRF receptor mechanisms mediate stress-induced CeA 5-HT release supports a growing body of literature demonstrating central CRF receptor-mediated regulation of stress responses, anxiety, anorexia and 5-HT release in a variety of the limbic brain regions [for example, 4,16,23,26,28,39,40,42]. However, this is the first report of CRF-mediation of stressinduced 5-HT release in the amygdala.…”

“…Corticotropin-releasing factor, acting as a neurotransmitter, is involved in initiating stress responses, partially by modulating serotonergic systems arising from the dRN [3,27]. The CeA is one of the major sources of CRF innervation to the dRN [24], and CRF type 1 and type 2 (CRF 1/2 ) receptors are present in the dRN [14,42]. The release of CRF from the CeA has been detected during stress [30] and CRF administered to the dRN concurrently increases freezing behavior and 5-HT release within the CeA [23].…”

Modulation of Neuronal Excitability by Serotonin-NMDA Interactions in Prefrontal Cortex

“…The stress procedures we used entailed forcing the rat to swim in deep water for 30 min (Price et al, 2002;Roche et al, 2003). As shown in Figure 6A, 8-OH-DPAT (with NMDA present) reduced AP firing to a similar extent in control vs. stressed animals (control: -32.3 ± 2.2%, n = 27; stressed: -30.5 ± 5.0%, n = 5, Figure 6C).…”

Early postnatal stress affects 5-HT1A receptor function in the medial prefrontal cortex in adult rats

“…Also, there is much evidence to correlate dysfunctions in central monoamine neurotransmission, particularly that related to 5-HT, with a variety of psychiatric disorders, including major depression (Mann et al, 1995;Drevets et al, 2000). In 5 animal studies, it is well known that 5-HT in the limbic system is involved in the regulation of emotional stress (Yoshioka et al, 1995;Roche et al, 2003).…”