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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 Previous studies in rodents show that early exposure to methylphenidate alters later responsiveness to drugs of abuse. An interesting feature of these studies is that early methylphenidate treatment decreases the rewarding value of cocaine when measured by conditioned place preference (CPP), but the same treatment increases cocaine self-administration. Objective The goal of the present study was to examine the effects of early methylphenidate exposure on cocaine-induced responding using both reward paradigms. Methods Rats were treated with methylphenidate (0, 2, or 5 mg/kg) from postnatal day (PD) 11 to PD 20 and then cocaine-induced CPP or cocaine self-administration was measured in separate groups of rats in adulthood. The CPP procedure included eight days of acquisition training, eight days of extinction training, and a reinstatement test. Rats were conditioned with 0, 10 or 20 mg/kg cocaine. Reinstatement was assessed after a priming dose of cocaine (10 mg/kg). For the self-administration experiment, a jugular catheter was implanted and rats were trained to press a lever reinforced with cocaine (0.25 or 0.75 mg/kg/infusion) on a fixed ratio (FR) 1 schedule. Rats were gradually moved from an FR1 to an FR10 schedule and, after criterion was reached, rats were placed on a progressive ratio schedule for five days. Results Cocaine produced robust rewarding effects as determined by both the CPP and self-administration experiments; however, early methylphenidate exposure only enhanced the reinforcing effects of cocaine on the self-administration paradigm. Interestingly, this methylphenidate enhancement was only seen in male rats. Conclusions These data suggest that in males methylphenidate enhances the reinforcing value of cocaine, but not cocaine-associated cues.

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The behavioral evidence indicates that, during the preweanling period, terguride antagonizes D(2)-like post-synaptic receptors in a state of high dopaminergic tone; however, there is no evidence that terguride is capable of stimulating D(2)-like post-synaptic receptors during states of low dopaminergic tone.