INTERACTION BETWEEN NEUROPEPTIDE FF AND OPIOIDS IN THE VENTRAL TEGMENTAL AREA IN THE BEHAVIORAL RESPONSE TO NOVELTY M. CADOR, a * N. MARCO, b L. STINUS a and G. SIMONNET b a Laboratoire Neuropsychobiologie des De ¨sadaptations, UMR CNRS 5541, Universite ¨ Bordeaux 2, 146, rue Le ¨o Saignat, B.P. 31, 33076 Bordeaux Cedex, France b INSERM U 259, rue Camille Saint-Sae «ns, 33077 Bordeaux, France AbstractöConsiderable evidence has focused on the interaction between endogenous opioid peptides and the dopami- nergic mesocorticolimbic system in behavioral responses to stress. Recently, it has been proposed that the CNS synthe- sizes and secretes neuropeptides that act as part of a homeostatic system to attenuate the e¡ects of morphine or endogenous opioid peptides. Among these antiopioids, neuropeptide FF (NPFF) is particularly interesting since both NPFF immunoreactive-like terminals and NPFF binding sites are located in the vicinity of the dopaminergic cell bodies within the ventral tegmental area (VTA) suggesting an interaction at this level. The purpose of the present study was to evaluate the respective implication of opioid and antiopioid peptides at the level of the VTA in the locomotor response to novelty in rats. The results indicate that s.c. naloxone pretreatment, an opiate receptor antagonist, reduced locomotor activity in rats placed in a novel environment without having any e¡ect in a familiar environment. This e¡ect takes place in the VTA since intra-VTA administration of naloxone methobromide diminished similarly and dose-dependently the motor response to novelty. This e¡ect is mainly dependent on opioid peptides released at VTA level since local injections of thiorphan, an inhibitor of enkephalin degradation, strongly increased locomotor response to novelty and this e¡ect is completely prevented by the co-administration of naloxone methobromide. When injected in the VTA, NPFF is acting as an antiopioid compound, i.e. it reduces the locomotor activity triggered by exposure to novelty to the level recorded in a familiar environment. Moreover, NPFF decreased dose-dependently the potentiation of novelty-induced locomotor response produced by VTA injection of thiorphan. Taken together, these results suggest that NPFF neurons may participate at the level of the VTA to a homeostatic regulating process counteracting opioid e¡ects induced by a mild stress such as novelty. ß 2002 IBRO. Published by Elsevier Science Ltd. All rights reserved. Key words: opioid, antiopioids, behavior, opponent process, mild stress. Compelling evidence has demonstrated interaction between opioid peptides and the dopaminergic mesocor- ticolimbic system in behavioral responses to stressors (Stinus et al., 1980; Kelley et al., 1980; Cador et al., 1988; Dauge ¨ et al., 1992; Spanagel et al., 1992 and for review see Kalivas, 1993). However, stressors generally used, such as foot-shocks, cold water, restraint or tail- pinch are fearful non-natural stimuli compared to etho- logical situations (Amit and Galina, 1986). Exposure of animals to a novel environment is also a stressful event associated with an increased circulating corticosterone level (Seggie and Brown, 1975; Datta and King, 1980; Muir and P¢ster, 1986, 1987), and increased motor activ- ity (Berlyne et al., 1966) and appears as a more natural- istic stimulus. Pharmacological studies indicate that this psychomotor response to novelty involves activation of the mesocorticolimbic dopaminergic system. Thus, spe- ci¢c mesocorticolimbic dopaminergic depletion prevents locomotor hyperactivity produced by novelty exposure (Fink and Smith, 1979) and low doses of dopamine receptor antagonists decrease motor activity elicited by novelty without altering basal motor activity in habitu- ated animals (Bardo et al., 1990; Kumar, 1981; Ossowska et al., 1990). The way through which novelty exposure is leading to increased dopaminergic activity and increased motor activity is not well characterized. Opioid peptides are good candidates since it has been previously reported that s.c. administration of the opioid receptor antagonist naloxone depresses locomotor activity in a novel envi- ronment (Katz and Gelbart, 1978; Rodgers and Deacon, 1979). Endogenous opioid peptides, such as enkephalin and beta-endorphin are physiological (endogenous) mod- ulators of the dopaminergic system at the level of their perikarya located in the ventral tegmental area (VTA) (Glimcher et al., 1984; Kalivas and Richardson-Carlson, 1986; Kalivas and Abhold, 1987; Dauge ¨ et al., 1992; Klitenick et al., 1992; for a review see Kalivas, 1993). Injections of opiates or opioid peptides into the VTA induce behavioral activation which is reversed by either 309 *Corresponding author. Tel.: +33-557 57 15 46; fax: +33-556 90 02 78. E-mail address : martine.cador@lnpb.u-bordeaux2.fr (M. Cador). Abbreviations : ANOVA, analysis of variance ; NalMb, naloxone methobromide; NPFF, neuropeptide FF; VTA, ventral tegmen- tal area. NSC 5422 26-2-02 www.neuroscience-ibro.com Neuroscience Vol. 110, No. 2, pp. 309^318, 2002 ß 2002 IBRO. Published by Elsevier Science Ltd All rights reserved. Printed in Great Britain PII:S0306-4522(01)00587-5 0306-4522 / 02 $22.00+0.00