Effect of environmental enrichment on methylphenidate-induced locomotion and dopamine transporter dynamics

▶ Environmental enrichment regulates PKC-mediated down-regulation of DAT. ▶ Methylphenidate dose-dependently decreases DAT function and expression. ▶ Rearing environments differentially alter locomotor effects of methylphenidate. Rats raised in an enriched condition (EC) are less sensitive to the locomotor effects of stimulant drugs than rats raised in an impoverished condition (IC). Methylphenidate (MPD), a primary pharmacotherapy for attention-deficit/hyperactivity disorder, has abuse potential. This study determined whether environmental enrichment differentially altered the effects of MPD on locomotor activity and dopamine (DA) transporter (DAT) function. Acute and repeated MPD (3 or 10mg/kg, s.c.) increased locomotion in EC, IC and social condition (SC) rats; however, EC rats showed a blunted response to repeated MPD (3mg/kg). The maximal velocity (Vmax) of [3H]DA uptake in the presence of the combination of phorbol 12-myristate 13-acetate, a protein kinase C (PKC) activator and okadaic acid, a protein phosphatase inhibitor was decreased in EC and IC rats by 68% and 40%, respectively, indicating that DAT in prefrontal cortex (PFC) is more sensitive to PKC-mediated down-regulation in EC rats. Acute MPD (10mg/kg) administration decreased the Vmax of [3H]DA uptake in PFC and striatum in EC rats, but not in IC rats. Furthermore, [3H]WIN 35,428 binding density was decreased in PFC of EC and IC rats, and in striatum of EC rats given repeated MPD (10mg/kg). These results demonstrate that environmental enrichment modulates DAT dynamics in PFC. However, since the change in DAT function was observed only following the high dose of MPH (10mg/kg), the attenuated locomotor response to repeated MPD (3mg/kg) in EC rats is not likely due to a specific DAT alteration in the brain regions examined.