ROLE OF 5-HT IN STRESS, ANXIETY, AND DEPRESSION

There are conflicting results on the function of 5-HT in anxiety and d epression. To reconcile this evidence, Deakin and Graeff have suggeste d that the ascending 5-HT pathway that originates in the dorsal raphe nucleus (DRN) and innervates the amygdala and frontal cortex facilitat es conditioned fear, while the DRN-periventricular pathway innervating the periventricular and periaqueductal gray matter inhibits inborn fi ght/flight reactions to impending danger, pain, or asphyxia. To study the role of the DRN 5-HT system in anxiety, we microinjected 8-OH-DPAT into the DRN to inhibit 5 HT release. This treatment impaired inhibit ory avoidance (conditioned fear) without affecting one-way escape (unc onditioned fear) in the elevated T-maze, a new animal model of anxiety . We also applied three drug treatments that increase 5-HT release fro m DRN terminals: 1) intra-DRN microinjection of the benzodiazepine inv erse agonist FG 4172, 2) intra-DRN microinjection of the excitatory am ino acid kainic acid, and 3) intraperitoneal injection of the 5-HT rel easer and uptake blocker D-fenfluramine. All treatments enhanced inhib itory avoidance in the T-maze. D-Fenfluramine and intra-DRN kainate al so decreased one-way escape. In healthy volunteers, D-fenfluramine and the 5-HT agonist mCPP (mainly 5-HT2C) increased, while the antagonist s ritanserin (5-HT2A/(2C)) and SR 46349B (5-HT2A) decreased skin condu ctance responses to an aversively conditioned stimulus (tone). In addi tion, D-fenfluramine decreased, whereas ritanserin increased subjectiv e anxiety induced by simulated public speaking, thought to represent u nconditioned anxiety. Overall, these results are compatible with the a bove hypothesis. Deakin and Graeff have suggested that the pathway con necting the median raphe nucleus (MRN) to the dorsal hippocampus promo tes resistance to chronic, unavoidable stress. In the present study, w e found that 24 h after electrolytic lesion of the rat MRN glandular g astric ulcers occurred, and the immune response to the mitogen concana valin A was depressed. Seven days after the same lesion, the ulcerogen ic effect of restraint was enhanced. Microinjection of 8-OH-DPAT, the nonselective agonist 5-MeO-DMT, or the 5-HT uptake inhibitor zimelidin e into the dorsal hippocampus immediately after 2 h of restraint rever sed the deficits of open arm exploration in the elevated plus-maze, me asured 24 h after restraint. The effect of the two last drugs was anta gonized by WAY-100135, a selective 5-HT1A receptor antagonist. These r esults are compatible with the hypothesis that the MRN-dorsal hippocam pus 5-HT system attenuates stress by facilitation of hippocampal 5-HT1 A-mediated neurotransmission. Clinical implications of these results a re discussed, especially with regard to panic disorder and depression.