1. ¹Central Research Laboratory, Hamamatsu Photonics KK, Hamakita, Shizuoka, Japan
2. ²School of Medicine, Saint Marianna University, Kawasaki, Kanagawa, Japan
3. ³Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA

Correspondence: Dr EF Domino, Department of Pharmacology, University of Michigan, Ann Arbor, MI 48108-0632, USA. Tel: +1 734 764 9115; Fax: +1 734 763 4450; E-mail: efdabcde@umich.edu

Received 3 December 2004; Revised 14 March 2005; Accepted 14 March 2005; Published online 27 April 2005.

Abstract

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 30 min at doses of 32 g/kg+0.8 g/kg/min or 100 g/kg+2.53 g/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 (0.03 mg/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.