Forced swim stress activates rat hippocampal serotonergic neurotransmission involving a corticotropin-releasing hormone receptor-dependent mechanism

Summary Serotonin is important for adequate coping with stress. Aberrant serotonin function is implicated in the aetiology of major depression and anxiety disorders. Dysregulation of the hypothalamic–pituitary–adrenocortical axis, involving elevated corticotropin‐releasing hormone (CRH) activity, also plays a role in these stress‐related illnesses. Here we studied the effects of stress on hippocampal serotonin and the role of the CRH system using in vivo microdialysis. First, rats were subjected to a forced swim stress, resulting in a dramatic increase in hippocampal serotonin (1500% of baseline), which was associated with the occurrence of diving behaviour. The diving‐associated increase in serotonin depended on activation of CRH receptors, as it was antagonized by intracerebroventricular pretreatment with D‐Phe‐CRH12−41. Secondly, the effects of intracerebroventricular administration of CRH and urocortin (0.03–1.0 µg) were studied. Both CRH and urocortin caused a dose‐dependent rise in hippocampal serotonin (maximally 350% of baseline) and 5‐hydroxyindoleacetic acid levels, suggesting the involvement of CRH receptor type 1. Because the effects of urocortin were prolonged, CRH receptor type 2 could play a role in a later phase of the neurotransmitter response. Experiments using adrenalectomized rats showed that CRH‐induced serotonin changes were adrenally independent. These data suggest that the raphe‐hippocampal serotonin system is able to mount, CRH receptor‐dependent, responses to specific stressful situations that surpass the usually observed maximal increases of about 300% of baseline during stress and enhanced vigilance.