Differential effects of olanzapine, haloperidol and risperidone on calcitonin gene-related peptide in the rat brain Francesco Angelucci a,b, * , Susanne H.M. Gruber a , Carlo Caltagirone b , Aleksander A. Mathe ´ a, * a Karolinska Institutet, Clinical Neuroscience, Psychiatry M56, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden b IRCCS Santa Lucia Foundation, Department of Clinical and Behavioural Neurology, Rome, Department of Neuroscience, Tor Vergata University, Rome, Italy Received 22 April 2008; accepted 17 June 2008 Available online 26 July 2008 Abstract Calcitonin gene-related peptide (CGRP) is a 37 amino acid peptide which acts on central nervous system (CNS) neurons and is involved in activities related to dopamine. These effects of CGRP suggest that the peptide may have a role in pathophysiology and treatment of schizophrenia where dopaminergic system hypoactivity in the frontal cortex and hyperactivity in the subcortical struc- tures have been demonstrated. In this study we measured by radioimmunoassay (RIA) the brain levels of CGRP-like immunoreac- tivity (CGRP-LI) in rats treated with either classical (haloperidol) or atypical (risperidone and olanzapine) antipsychotic drugs. Both haloperidol and risperidone decreased CGRP-LI in the striatum. Risperidone also decreased CGRP-LI in the occipital cortex. On the other hand, olanzapine increased CGRP-LI in the striatum, the frontal cortex and hypothalamus. The differential effects on CGRP could reflect a different profile of side effects and further suggest that CGRP is involved in CNS functions related to psychi- atric disorders. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: CGRP; Olanzapine; Haloperidol; Risperidone; Rat brain 1. Introduction Calcitonin gene-related peptide (CGRP) is a 37 amino acid peptide, product of the calcitonin gene which encodes also for calcitonin and its carboxyl-terminal flanking peptide katacalcin (Steenbergh et al., 1986). CGRP is widely distributed in the brain (Mathe ´ et al., 1990a,b; Van Rossum et al., 1997) and acts on neurons located in the amygdala, ventral tegmental area (VTA), hippocampus, and hypothalamus (Deutch and Roth, 1987; Drumheller et al., 1992). CGRP is involved in sev- eral central activities, like olfaction, audition, learning, feeding and motor activity (Van Rossum et al., 1997). In addition, CGRP seems to be involved in a number of disorders of the central nervous system (CNS), such as migraine (Edvinsson and Petersen, 2007), depression (Wo ¨rtwein et al., 2006) and dementia (Mathe ´ et al., 2006). Experimental evidence suggests involvement of CGRP in dopaminergic neurotransmission. When given intracerebroventricularly (icv) CGRP affects dopamine (DA)-related behaviors (Clementi et al., 1992) and delays the extinction of an active avoidance response in a dose-dependent manner (Kovacs and Telegdy, 1995). CGRP also potentiates haloperidol-induced 0143-4179/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.npep.2008.06.002 * Corresponding authors. Tel.: +46 70 4840743; fax: +46 8 300972 (A.A. Mathe ´). E-mail addresses: F.angelucci@hsantalucia.it (F. Angelucci), Aleksander.Mathe@ki.se (A.A. Mathe ´). www.elsevier.com/locate/npep Available online at www.sciencedirect.com Neuropeptides 42 (2008) 535–541 Neuropeptides