In the present study, we examined whether exposing rats to a high-dose regimen of manganese chloride (Mn) during the postnatal period would depress presynaptic dopamine functioning and alter nonassociative and associative behaviors. To this end, rats were given oral supplements of Mn (750 μg/day) on postnatal days (PD) 1-21. On PD 90, dopamine transporter (DAT) immunoreactivity and [ 3 H]dopamine uptake were assayed in the striatum and nucleus accumbens, while in vivo microdialysis was used to measure dopamine efflux in the same brain regions. The effects of postnatal Mn exposure on nigrostriatal functioning were evaluated by assessing rotorod performance and amphetamine-induced stereotypy in adulthood. In terms of associative processes, both cocaineinduced conditioned place preference (CPP) and sucrose-reinforced operant responding were examined. Results showed that postnatal Mn exposure caused persistent declines in DAT protein expression and [ 3 H]dopamine uptake in the striatum and nucleus accumbens, as well as long-term reductions in striatal dopamine efflux. Rotorod performance did not differ according to exposure condition, however Mn-exposed rats did exhibit substantially more amphetamine-induced stereotypy than vehicle controls. Mn exposure did not alter performance on any aspect of the CPP task (preference, extinction, or reinstatement testing), nor did Mn affect progressive ratio responding (a measure of motivation). Interestingly, acquisition of a fixed ratio task was impaired in Mn-exposed rats, suggesting a deficit in procedural learning. In sum, these results indicate that postnatal Mn exposure causes persistent declines in various indices of presynaptic dopaminergic functioning. Mninduced alterations in striatal functioning may have long-term impact on associative and nonassociative behavior.

Rationale-Preweanling rats, unlike adults, exhibit context-independent behavioral sensitization after a single pretreatment injection of cocaine.Objective-The purpose of this study was to examine environmental factors modulating one-and three-trial sensitization in preweanling rats.Methods-For preweanling rats, drug pretreatments occurred on PD 17-PD 19 (Experiment 1) or PD 19 (Experiment 2). One set of rats was injected with cocaine (30 mg/kg) and placed in anesthesia ("small"), operant conditioning ("large"), or activity chambers for 30 min. Rats were returned to the home cage and injected with saline. Additional groups of rats were injected with saline and placed in small, large, or activity chambers for 30 min and then injected with cocaine after being returned to the home cage. Control groups were injected with saline at both time points. In separate experiments, rats were pretreated with cocaine or saline and restricted to the home cage. On PD 20, all rats were injected with cocaine (20 mg/kg) and placed in activity chambers where locomotor activity was assessed for 60 min. For comparison purposes, sensitization was also assessed in adult rats.Results-Adult male and female rats exhibited only context-dependent sensitization, whereas preweanling rats showed context-independent sensitization in a variety of conditions (e.g., when pretreated with cocaine in various novel chambers or the home cage).Conclusions-These results suggest that nonassociative mechanisms underlying behavioral sensitization are functionally mature in preweanling rats, but associative processes modulating the strength of the sensitized response do not function in an adult-like manner during the preweanling period.

Persistence of the sensitized response cannot be used to dissociate the one-trial context-dependent and context-independent sensitization of young rats. Fos data indicate that the CP and PFC may be involved in the mediation of short-term behavioral sensitization on PD 22.

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Abstractκ-Opioid receptor stimulation attenuates psychostimulant-induced increases in extracellular dopamine in the caudate-putamen (CPu) and nucleus accumbens of adult rats, while reducing cocaine-induced locomotor activity and stereotyped behaviors. Because κ-opioid receptor agonists (e.g., U50,488 or U69,593) often affect the behavior of preweanling rats in a paradoxical manner, the purpose of the present study was to determine whether κ-opioid receptor stimulation differentially affects dopaminergic functioning in the CPu depending on age. In vivo microdialysis was used to determine whether U50,488 (5 mg/kg) attenuates cocaine-induced dopamine overflow in the dorsal CPu on postnatal day (PD) 17 and PD 85. In the microinjection experiment, cocaineinduced stereotyped behaviors were assessed in adult and preweanling rats after bilateral infusions of vehicle or U50,488 (1.6 or 6.4 µg per side) into the CPu. Results showed that U50,488 attenuated the cocaine-induced increases in CPu dopamine overflow on PD 85, while the same dose of U50,488 did not alter dopamine dialysate levels on PD 17. Cocaine also increased stereotyped behaviors (repetitive motor movements, behavioral intensity scores, and discrete behaviors) at both ages, but adult rats appeared to exhibit more intense stereotypic responses than the younger animals. Consistent with the microdialysis findings, bilateral infusions of U50,488 into the dorsal CPu decreased the cocaine-induced stereotypies of adult rats, while leaving the behaviors of preweanling rats unaffected. These results suggest that the neural mechanisms underlying κ-opioid/dopamine interactions in the CPu are not fully mature during the preweanling period. This lack of functional maturity may explain why κ-opioid receptor agonists frequently induce different behavioral effects in young and adult rats.