Interactions among stress, serotonin 1A (5-HT_1A) receptors, and the hypothalamic–pituitary–adrenocortical (HPA) system have been proposed to influence the development of depression in humans. The investigation of depression-relevant behaviors and physiological responses to environmental stressors in animal models of depression may provide valuable insight regarding these mechanisms. The purpose of these experiments was to investigate the interactions among central 5-HT_1A receptors, endocrine function, and behavior in an animal model of depression, chronic mild stress (CMS). The current study examined behavioral responses to a pleasurable stimulus (sucrose), estrous cycle length (in female rats), and plasma hormone levels following systemic administration of a selective 5-HT_1A receptor agonist [(+)8-hydroxy-N,N-dipropyl-2-aminotetralin hydrobromide (8-OH-DPAT); 40 μg/kg, s.c.; administered 15 min prior to sacrifice], in male and female rats exposed to 4 weeks of CMS. Four weeks of CMS produced a reduction in the intake of 1% sucrose (anhedonia), as well as attenuated adrenocorticotropic hormone (ACTH) responses to 8-OH-DPAT in both male and female rats (22 and 18% lower than the control groups, respectively). Corticosterone and oxytocin responses to 8-OH-DPAT were not altered by exposure to CMS. In female rats, CMS induced a lengthening of the estrous cycle by ∼40%. CMS produces minor HPA disruptions along with behavioral disruptions. Alterations in 5-HT_1A receptor function in specific populations of neurons in the central nervous system may be associated with the CMS model. The current findings contribute to our understanding of the relations that stress and neuroendocrine function have to depressive disorders.

An imbalance between serotonin-2A (5-HT_2A) and 5-HT_1A receptors may underlie several mood disorders. The present studies determined whether 5-HT_2A receptors interact with 5-HT_1A receptors in the rat hypothalamic paraventricular nucleus (PVN). The sensitivity of the hypothalamic 5-HT_1A receptors was measured as oxytocin and adrenocorticotropic hormone (ACTH) responses to the 5-HT_1A receptor agonist (+)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide [(+)8-OH-DPAT] (40 μg/kg s.c.). The 5-HT_2A/2C receptor agonist (-)DOI [(-)-1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane HCl] (1 mg/kg s.c.) injected 2 h prior to (+)8-OH-DPAT significantly reduced the oxytocin and ACTH responses to (+)8-OH-DPAT, producing a heterologous desensitization of the 5-HT_1A receptors. Microinjection of the 5-HT_2A receptor antagonist MDL100,907 [(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol; 0, 10, or 20 nmol, 15 min prior to (-)DOI] into the PVN dose-dependently prevented the desensitization of 5-HT_1A receptors induced by the 5-HT_2A receptor agonist (-)DOI. Double-label immunocytochemistry revealed a high degree of colocalization of 5-HT_1A and 5-HT_2A receptors in the oxytocin and corticotropin-releasing factor neurons of the PVN. Thus, activation of 5-HT_2A receptors in the PVN may directly induce a heterologous desensitization of 5-HT_1A receptors within individual neuroendocrine cells. These findings may provide insight into the long-term adaptation of 5-HT_1A receptor signaling after changes in function of 5-HT_2A receptors; for example, during pharmacotherapy of mood disorders.