Psychopharmacology (1992) 107:221-228 Psychopharmacolog ~ Springer-Verlag 1992 Ontogeny of cocaine hyperactivity and conditioned place preference in mice Giovanni Laviola, Giacomo Dell'Omo, Enrico Alleva, and Giorgio Bignami Section of Behavioural Pathophysiology, Laboratorio di Fisiopatologia di Organo e di Sistema, Istituto Superiore di Sanitfi, Viale Regina Elena, 299, 1-00161 Roma, Italy Received July 30, 1991 / Final version October 30, 1991 Abstract. Conditioned place preference (CPP) pro- ceduresusing jointly visual and tactile cues (white compartment with a wide-mesh metal floor versus black compartment with a narrow-mesh floor) were employed to assess the ontogenetic pattern of cocaine reinforcing properties in outbred CD 1 mice. A classical 11-day-long schedule, in which the drug experience occurred in the initially less-preferred compartment ("biased" procedure, Spyraki 1988), served to study cocaine (0, 1, 5, or 25 mg/kg IP repeated four times at 48 h intervals) during the early postweaning stage (21-32 days). The result was a fully-fledged CPP at all cocaine doses. A subsequent experiment used a shortened (4-day) "un- biased" CPP schedule (animals assigned at random to drug experience in one or the other compartment); this enabled an assessment of the ontogenetic pattern of the drug action (single treatment, same dose range) in pups of both sexes at three different developmental ages (14-17, 21-24, or 28-31 days). At the 25 mg/kg dose, CPP developed in animals of all ages, while the 5 mg/kg dose was effective only in 21-24 day pups and the 1 mg/kg dose was ineffective. No significant sex differences were found, but the use of the unbiased procedure enabled a demonstration of an interaction between treatment, age, and type of CS. At the preweaning stage, CPP was due mainly to an increased preference for the black/narrow- mesh compartment, while at the early postweaning stage it consisted mainly of an increased preference for the white/wide-mesh compartment; at the late postweaning stage the cue and the treatment factor did not interact. At all ages tested cocaine induced a dose-dependent in- crease in locomotor activity which was much more mark- ed at both post-weaning stages than before weaning. Key words: Behavioural development - Ontogeny of locomotor activity - Conditioned place preference - Co- caine - Mouse Off))rint requests to: G. Bignami Literature data on the rewarding (positive reinforcing) properties of cocaine as assessed by Conditioned Place Preference (CPP) procedures, are mainly limited to adult male subjects (see reviews by Spyraki 1988; Cart et al 1989;Hoffman 1989;for recent data on interactions between treatment and test variables see Nomikos and Spyraki 1988;Lawley and Kantak 1990). In fact, an ontogenetic analysis of such properties must overcome some important methodological difficulties. For exam- ple, the more commonly used CPP procedure (van der Kooy 1987;Carr et al. 1989; Swerdlow et al. 1989) requires a training period [association of repeated drug administration (unconditioned stimulus, UCS) and ex- ternal stimuli (CS)] which lasts between 6 and 8 day while the entire schedule needs several additional days to be completed. This may cause a confounding between treatment and organismic variables during periods of fast developmental change, particularly in the case of a drug such as cocaine, whose effects can strongly depend on previous exposure (see e. g. the sensitization to the activ- ity enhancing effects over repeated treatments; Roy et al. 1978; Pan et al. 1991). On the other hand, Bardo an colleagues (1986) have shown in adult rats that a singl IP cocaine administration can suffice to produce CPP, which may help circumventing some of the difficulties just mentioned. In general, developmental work on altricial rodent CPP has been limited so far to the early postnatal phase; due to sensory and motor immaturity of the subjects, only olfactory, gustatory, and/or tactile CS have been used (Camp and Rudy 1988; Sullivan and Hall 1988; Lariviere et al. 1990; Spear 1990; Weller and Blass 1990 As concerns c0caine, the drug appears to be able to produce important effects, such as hyperactivity, from the early postnatal stage (Spear and Brick 1979). More- over, an early development of the positive reinforcing properties of the drug is suggested by the finding in rats of a CPP on postnatal day 18 after a drug experience in the presence of an odor cue at the age of 2 days (Smith and Holman t987). At this point, it seemed advisable to perform a more systematic study of cocaine CPP in