European Journal of Pharmacology, 209 ( 1991 ) 139-140 139 © 1991 Elsevier Science Publishers B.V. All rights reserved 0014-2999/91/$03.50 EJP 0327R Rapid communication Activation of the hypothalamic serotoninergic system by central interleuldn-1 Carmelina Gemma, Pietro Ghezzi and Maria Grazia De Simoni Isfituto di Ricerche Farmacologiche 'Mario Negri ', Via Er#rea 62, 1-20157 Milan, Italy Received 3 November 1991, accepted 12 November 1991 A large body of evidence indicates that cytokines and in particular interleukin-1 (IL-1) are constitutive substances of the brain (Dinarello, 1991; Schettini, 1990). IL-1 immunoreactivity and IL-1 receptors have been detected in the brain of humans, mice and rats, suggesting that IL-1 can act as a neurotransmitter within the brain. The presence of IL-1 mRNA and its increase following appropriate challenges indicates that the brain is normally able to synthesize IL-1. In the brain IL-1 is known to induce various effects such as fever, anorexia, sleep and activation of the hypothala- mus-pituitary-adrenal axis. We have recently shown (De Simoni et al., 1990) that intracerebroventricular (i.c.v.) injection of IL-1 induces high circulating levels of IL-6, indicating that central IL-1 might induce cy- tokine-mediated actions in the periphery. Since the neurochemistry of the central actions of IL-1 is largely unknown, we studied the effects of IL-1 on the sero- toninergic system in the anterior hypothalamus, an area receiving a dense serotoninergic innervation from the raphe nuclei and containing high levels of IL-1 immunoreactivity. Changes in the extracellular levels of the serotonin (5-HT) metabolite, 5-hydroxyindolacetic acid (5-HIAA), were recorded by in vivo voltammetry, using chronically implanted carbon fiber electrodes. Albino male rats (CD-COBS, Charles River, Italy, 250-300 g) were prepared for chronic recordings fol- lowing the surgical procedure described previously (De Simoni et al., 1987). Electrodes (tip diameter: 8 /xm) were stereotaxically implanted in the anterior hypotha- lamus (medial preotic area: A =-0.3 mm, L = 0.5 mm, V = 8.2 mm from the brain surface; teeth bar: -2.4 mm). Experiments were done with conscious, freely moving rats, starting one week after surgery. All drugs were administered icy in 6 /xl of sterile, pyrogen-free saline through one polyethylene cannula permanently implanted in the lateral ventricle. Correspondence to: M.G. De Simoni, Istituto di Ricerche Farmaco- logiche 'Mario Negrr, Via Eritrea 62, 1-20157 Milan, Italy. Tel. 39.2.390 141, fax 39.2.354 6277. One microgram of human recombinant IL-1/3 in- duced a rapid increase in extracellular 5-HIAA, fol- lowed by a slower long-lasting enhancement, showing ,< Lfb 200 175 150 125 100 I 75 50 -30 200 • i . R . i . i . i . i . i . 1 . i . J . i 0 30 60 90 120 150 180 210 240 270 300 175 150 125 100 I 1, 5 0 ~ . ~ . ~ . ~ . ~ . J . A . I • , . J • -30 0 30 60 90 120 150 180 210 240 270 300 MIN Fig. 1. (A) Effect of i.c.v. IL-1 (1 /xg/6 p.l, n = 8, full dots) and heat-inactivated IL-1 (1 /zg/6 ~1, n = 12, open dots) on extracellular 5-HIAA in the anterior hypothalamus of freely moving rats. (B) Effect of i.c.v. IL-lra (40 ~g/6 pA, n = 5, open dots) and IL-lra + IL-I (40 /zg/6 /xl, n = 5, open dots, 5 min before IL-1) on extracellular 5-HIAA in the anterior hypothalamus of freely moving rats. Data are expressed as percentage of the mean control value calculated by averaging six peak heights during the 30 min before injection (100%). Vertical bars represent the standard error. Arrow indicates the time of injection. * P < 0.05; * * P < 0.01, Student's t-test•