Research report Influence of acute or repeated restraint stress on morphine-induced locomotion: involvement of dopamine, opioid and glutamate receptors Capriles Nancy del Rosario 1 , Alejandra Maria Pacchioni 2 , Liliana Marina Cancela * Departamento de Farmacologı ´a, Facultad de Ciencias Quı ´micas, Universidad Nacional de Co ´rdoba, Ciudad Universitaria, 5000 Co ´rdoba, Argentina Received 14 May 2001; received in revised form 2 January 2002; accepted 28 January 2002 Abstract The development of restraint stress-induced sensitization to the locomotor stimulating effect of morphine (2 mg/kg i.p.) was investigated. In experiment 1, both a single restraint session (2 h) and a repeated restraint stress (2 h per day for 7 days), similarly enhanced the effects of morphine on motor activity. In experiment 2, we observed that this sensitization was prevented by administration of both D 1 and D 2 dopaminergic antagonist [SCH-23390 (0.5 mg/kg i.p.) and (9 /)-sulpiride (60 mg/kg i.p.)] 10 min prior to the stress session. In experiment 3, we showed that an opioid antagonist pretreatment [naltrexone (1 mg/kg i.p.) 10 min prior to stress session, suppressed the stress-induced sensitization after morphine administration. In experiment 4, pretreatment with a non-competitive antagonist of the N -methyl-D-aspartate (NMDA) type of glutamate receptors [( /)-MK-801 (0.1 mg/kg i.p.)], 30 min prior to the acute restraint session, prevented the development of sensitization to morphine. All these results suggest that: (1) sensitization to morphine on stimulating locomotor effect does not depend on the length of exposure to stress (acute vs. repeated); (2) stimulation of both D 1 and D 2 dopaminergic receptors is necessary for the development of restraint stress-induced sensitization to morphine; (3) an opioid system is also involved in this sensitization process; and (4) the stimulation of glutamatergic NMDA receptors is involved in this acute restraint-induced effect. # 2002 Elsevier Science B.V. All rights reserved. Keywords: Restraint stress; Sensitization; Morphine; Locomotor activity; Sulpiride; SCH23390; Naltrexone-MK-801 1. Introduction It is well known that repeated exposure to stressful events sensitizes motor and addictive effects of drugs of abuse in rats. Several studies have shown that stress may modify the susceptibility to the reinforcing properties induced by psychostimulants and opiates. For instance, repeated exposure to tail-pinch [51], immobilization [57,58], competition in the colony [45], prenatal stress [18], social deprivation [2] and social stress [47], enhance the propensity to develop psychostimulant self-admin- istration. Repeated stress not only increases the pro- pensity to drug-taking, but also augments the psy- chomotor effects of psychostimulants and opiates [3,20,21,24,28,29,37,43,48,50,54,58,59]. Opiate and psychostimulant drugs share several characteristics regarding their behavioral effects in animals. Peripheral or central administration of these substances can result in hypermotility [39,42,49], are self-administered by animals [19,30,67] and are capable of inducing behavioral sensitization [64,65]. Behavioral sensitization is defined as a potentiated behavioral response to a drug following prior chronic treatment with the drug or stress [37,54,55]. This process may affect the interaction between stress and drugs depending on the properties of the stressors applied, predictable versus unpredictable [27], escapable versus inescapable [46], the number of stress sessions as well as the type of stress applied [20,28,29,43] and the type of behavior being monitored [3,15,24,46]. * Corresponding author. Tel./fax: 54-351-4334-437 E-mail address: lcancela@fcq.unc.edu.ar (L.M. Cancela). 1 Fellowship from CONICET. Present address: Center for Studies in Behavioral Neurobiology, Concordia University, Room H1013, 1455 de Maisonneuve Boulevard West, Montreal, Quebec, Canada H3G 1M8. 2 Fellowship from F.O.M.E.C. Behavioural Brain Research 134 (2002) 229 /238 www.elsevier.com/locate/bbr 0166-4328/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved. PII:S0166-4328(02)00038-4