Pergamoo Pharmacology Biochemistry and Behavior, Vol. 51, No. I, pp. 49-55, 1995 Copyright o 1995 Ekevier Science Ltd Printed in the USA. All rights reserved oo91-3057195 $9.50 + .oo OQ91-3057(94)00342-4 Dose-Discrimination Performance of Mice for Self-Administration of Morphine Into the Lateral Hypothalamus PIERRE CAZALA’ AND VINCENT DAVID Laboratoire de Neurosciences Comportementales et Cognitives, CNRS URA 339, Universitk de Bordeaux I, Avenue des Facult&s, 33405 Talence Cedex, France Received 12 July 1993 CAZALA, P. AND V. DAVID. Dose-dkritnination performance of mice for self-administration of morphine into the lateral hypothalamus. PHABMACOL BIOCHEM BEHAV 51(l) 49-55, 1995. -Two experiments were performed in BALB/ c mice implanted bilaterally with guide cannulae. In the first experiment, the tips of the guide cannulae were positioned 1.5 mm above the lateral hypothalamus (LH). On each experimental day, injection cannulae were inserted into each side of the LH. The experiment, carried out in a Y-maze. was composed of two phases. During the initial acquisition period, which lasted 4 days, animals were allowed to self-inject, successively, on alternate days, one dose of morphine into one side of the LH and a different dose in the other side. From the fifth day, the subjects were given the possibility of choosing between these two doses by entering into a given arm of the Y-maze. When the two doses available were 5 ng and 50 ng or 15 ng and 50 ng, the subjects rapidly discrhuinated them and preferentially triggered the injection of the higher dose (50 ng). When the two doses available were 30 ng and 50 ng, the mice triggered indifferently the two doses during the first three sessions. A discrimination between these two doses began to become apparent from the fourth session, with the subjects preferring to trigger the dose of 50 ng. In a second experiment, the tips of the guide cannulae were positioned either 1.5 mm or 2.6 mm above the LH, the bilateral injection cannulae consequently being inserted either into the LH or into the overlying ventral thalamus (TH). Experimental conditions were the same as that of Experiment 1. During a preliminary phase (4 days), animals were allowed to self-inject morphine successively into the LH or the TH, on alternate days. From the fifth day, subjects were given the possibility of choosing between the two sites. For one group, a single low dose of morphine (5 ng) was applied in both structures. In an other group, the doses used were, respectively, 5 ng for the LH and 50 ng for the TH. A marked preference for injection into the LH was observed in the two groups. These results show that mice are capable of discriminating, at the intracerebral level, the motivational or rewarding components of two different doses of morphine even when the dose levels are relatively close (30 ng vs. 50 ng). Moreover, these effects of morphine seem to remain localized to the proximity of the injection sites, suggesting strongly that opiate receptors present in the LH mediate the self-administration response for the drug in this brain region. Intracranial self-administration Dose discrimination Morphine Lateral hypothalamus Mice PREVIOUS studies from our laboratory showed that BALB/c mice self-administer morphine into various brain sites. Placed in a Y-maze, where they were required to discriminate between a neutral arm and a reinforced arm, the animals entered more frequently into the reinforced arm to self-inject morphine into the lateral hypothalamus (LH) and the mesencephalic central gray (43). However, the characteristics of the self-administra- tion response induced by morphine varied as a function of the particular brain sites even when these were closely apposed such as LH and medial hypothalamus (6). Moreover, self- administration performance was highly influenced by the dose of morphine injected. Thus, whereas a clear self-administra- tion response was induced by injection of either 5 ng or 50 ng of morphine into LH, paradoxically the discrimination perfor- mance of mice was somewhat better with the lower dose (4,6). This result suggests that the motivational and/or emotional effects of the drug are not identical at these two doses. These data raise the following question: is an animal able to discrimi- nate between two different doses of morphine using the intra- cranial self-administration procedure? To attempt an answer ’ To whom requests for reprints should be addressed. 49