Nicotine Normalizes Increased Prefrontal Cortical Dopamine D1 Receptor Binding and Decreased Working Memory Performance Produced by Repeated Pretreatment with MK-801: A PET Study in Conscious Monkeys

摘要

The effects of acute nicotine were determined on dopamine (DA) D1 (D1R) and D2 (D2R) receptor binding in the neocortex of conscious monkeys under control conditions as well as after chronic pretreatment with MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Extrastriatal neocortical D1R and D2R binding was evaluated with [11C]NNC112 and [11C]FLB457 with high-specific radioactivity using positron emission tomography (PET). Acute administration of nicotine bitartrate, given as an intravenous (i.v.) bolus plus infusion for 30min at doses of 32g/kg+0.8g/kg/min or 100g/kg+2.53g/kg/min as base, induced slight but significant dose-dependent increases of DA in the extracellular fluid of prefrontal cortex (PFC) as determined by microdialysis. However, acute nicotine did not affect either [11C]NNC112 or [11C]FLB457 binding to D1R or D2R, respectively, in any cortical region. Chronic MK-801 (0.03mg/kg, intramuscularly (i.m.), twice daily for 13 days) increased [11C]NNC112 binding to D1R in PFC. No significant changes were detected in [11C]FLB457 binding to PFC D2R. Although chronic MK-801 lowered baseline DA and glutamate levels in PFC, acute nicotine normalized reduced DA to control levels. Acute nicotine dose-dependently normalized the increased binding of [11C]NNC112 to D1R produced by chronic MK-801 but [11C]FLB457 binding to PFC D2R did not change. Working memory performance, impaired after chronic MK-801, was partially improved by acute nicotine. These results demonstrate that acute nicotine normalizes MK-801-induced PFC abnormality of D1R in PFC.