Pharmacology Biochemistry& Behavior, Vol. 37, pp. 303-310. © Pergamon Press plc, 1990. Printed in the U.S.A. 0091-3057/90 $3.00 + .00 Preexposure to Foot-Shock Sensitizes the Locomotor Response to Subsequent Systemic Morphine and Intra-Nucleus Accumbens Amphetamine MARCO LEYTON AND JANE STEWART Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University 1455 de Maisonneuve Blvd., Montreal, Quebec, Canada, H3G 1M8 Received 15 March 1990 LEYTON, M. AND J. STEWART. Preexposure tofoot-shock sensitizes the locomotorresponseto subsequent systemicmorphineand intra-nucleus accumbensamphetamine. PHARMACOL BIOCHEM BEHAV 37(2) 303-310, 1990.--The effect of repeated exposure to foot-shock on locomotor activity was examined by testing rats in the shock boxes for one hour following shock exposure. Early in testing activity was elevated relative to the nonshocked control group, between 40-60 min following shock. Over days this period of elevated activity occurred sooner in time and lengthened in duration. When these animals were tested in the absence of shock, those preexposed to shock were more active following either saline or morphine (0.5 and 5.0 mg/kg 1P) injections. In a second experiment, elevated spontaneous and morphine-induced activity was also found when rats had been preexposed to shock in boxes distinct from the activity test boxes. In a final experiment, animals preexposed to shock were tested after bilateral infusions of either amphetamine (5 and 10 Ixg/Ixl/side)or morphine (5 p,g/p,l/side) into the nucleus accumbens (NAS). On the amphetamine tests, previously shocked animals were significantly more active than control animals. In contrast, intra-NAS infusions of morphine failed to differentiate between the two groups. These results suggest that repeated mild foot-shock sensitizes the mesolimbic dopamine system by mechanisms similar to those mediating the sensitized behavioral and dopaminergic responses seen following repeated opioid or stimulant administration. Sensitization Foot-shock Mesolimbic dopamine system Locomotor activity Morphine Amphetamine Nucleus accumbens THE mesolimbic dopamine (DA) system has been implicated in the positive incentive motivational properties of abused drugs, electrical brain stimulation, and naturally occurring rewards such as food and sex: each of these events has been demonstrated to engage this system. The simultaneous activation of this pathway by other means enhances an animal's approach toward, and by implication interest in, each of these events. Conversely, DA receptor antagonists or lesions of this system severely disrupt an animal's approach toward these normally rewarding events. Systemic administration of either the opioid, morphine, or the stimulant, amphetamine, causes an increase in extracellular DA in both cell body and terminal regions (7, 15, 20, 22). In the case of opioids, this is brought about by increased cell firing (11,31); amphetamine causes direct release and reuptake blockade (25). Behaviorally, these increases in DA activity elicit increased locomotor activity, although at high doses of morphine and amphetamine the hyperactivity may be preceded by hypoactivity or stereotypy respectively (4, 7, 18, 24). Repeated systemic injections or infusions into the cell body region of these agents leads to increases in both terminal DA release and turnover, and potentiated locomotor activity responses (42) referred to as sensi- tization. Over days the behavioral sensitization to repeated sys- temic opiate injections is characterized by a successively greater hyperactivity that appears sooner and sooner in time. Similarly, the behavioral response to an amphetamine challenge following repeated administrations is a potentiated locomotor activity or stereotypy response depending on the dose and number of previous administrations. Acute injections into the nucleus accumbens (NAS) of either amphetamine or opioids also elevate locomotor activity. In con- trast to systemic or intra-VTA pretreatments, however, repeated intra-NAS infusions do not precipitate later augmented responses to systemic or further intra-NAS applications (47,48). These findings support suggestions that sensitization results from alter- ations in the cell body region. Kalivas and his colleagues (8, 20, 21) have provided evidence indicating that in behaviorally sensi- tized animals there is reduced somatodendritic release of DA to drug challenge. Such an alteration would lead to decreased activation of somatodendritic autoreceptors and, in turn, reduced autoinhibition (42). There are, as well, changes in the terminal regions that accompany the development of sensitization. The striatal tissue from animals previously sensitized to amphetamine releases ele- vated levels of DA when later challenged with amphetamine in 303