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 C a r m e l i n a G e m m a , P i e t r o G h e z z i a n d M a r i a G r a z i a D e 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 m R N A 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 hypothalamus-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 cytokine-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 serotoninergic 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 following the surgical procedure described previously (De Simoni et al., 1987). Electrodes (tip diameter: 8 /xm) were stereotaxically implanted in the anterior hypothalamus (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 Farmacologiche '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 induced a rapid increase in extracellular 5-HIAA, followed by a slower long-lasting enhancement, showing 200 175 150 125 100 I
75
,
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 C a r m e l i n a G e m m a , P i e t r o G h e z z i a n d M a r i a G r a z i a D e 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 m R N A 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 hypothalamus-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 cytokine-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 serotoninergic 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 following the surgical procedure described previously (De Simoni et al., 1987). Electrodes (tip diameter: 8 /xm) were stereotaxically implanted in the anterior hypothalamus (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 Farmacologiche '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 induced a rapid increase in extracellular 5-HIAA, followed by a slower long-lasting enhancement, showing 200 175 150 125 100 I
75
,
