Abstracts

Rationale: Mutations of different subunits of the neuronal nicotinic acetylcholine receptor (nAChR) occur in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). These mutations increase receptor sensitivity to ACh and cholinergic-mediated neurotransmitter release. PET studies show that individuals with ADNFLE have regional nACh receptor upregulation. We used PET and the D1 receptor ligand [11C]-SCH23390 to assess the effect of the mutation on dopamine release following cholinergic activationMethods: Thirteen subjects with the α4 subunit gene, CHRNA4-Ser248Phe mutation (4 male, mean age 35.4 ± 10 years) and twenty-six healthy volunteers (9 male, mean age 35 ± 13 years) matched for gender, age, and smoking status were studied. Binding of [11C]-SCH23390 was measured at baseline and following physostigmine infusion. Parametric images were generated using a simplified reference region model. Co-registered high resolution T1-weighted MRI scans were used to generate regions of interest (ROIs).Results: In controls, the whole brain BP for SCH23390 increased by 7% following physostigmine infusion (baseline BP 0.30 ± 0.03, activation BP 0.32 ± 0.04, P<0.05). Increases in [11C]-SCH23390 binding with physostigmine were greatest in the mesial prefrontal cortex (MPFC 7%). Subjects with the mutation displayed marked increases in the whole brain BP (10%), striatum (13%) and insula (9%). Regional and global K1 ratio values did not change significantly (1-4% in both groups). Patients with the mutation demonstrated reduced baseline [11C]-SCH23390 binding in the striatum (0.97 ± 0.1) compared to controls (1.1 ± 0.1; P<0.05).Conclusions: The CHRNA4-Ser248Phe mutation is associated with down-regulation of the D1 receptor. The changes in receptor binding seen following physostigmine may relate to increased cholinergic-mediated dopamine release in vivo. Dysfunction of cholinergic-dopaminergic interactions in mesostriatal circuits may contribute to heightened nocturnal paroxysmal motor activity.