Pharmacokinetics and central nervous system effects of the novel dopamine D3 receptor antagonist GSK598809 and intravenous alcohol infusion at pseudo-steady state.

GSK598809 is a novel selective dopamine D(3) receptor antagonist, currently in development for the treatment of substance abuse and addiction. In a blinded, randomized, placebo-controlled study, effects of single oral doses of 175 mg GSK598809 were evaluated in healthy volunteers. Pharmacokinetics, central nervous system (CNS) effects and potential for interactions with alcohol were evaluated, using an alcohol infusion paradigm and analysis of eye movements, adaptive tracking, visual analogue scales, body sway, serum prolactin and verbal visual learning test. Adverse effects of GSK598809 included headache, dizziness and somnolence. Plasma concentration of GSK598809 was maximal 2-3 hours postdose and decreased with a half-life of roughly 20 hours. CNS effects were limited to prolactin elevation and decreased adaptive tracking. Co-administration of GSK598809 and alcohol did not affect alcohol pharmacokinetics, but caused a 9% decrease of C (max) and a 15% increase of AUC of GSK598809. CNS effects of co-administration were mainly additive, except a small supra-additive increase in saccadic reaction time and decrease in delayed word recall. In conclusion, GSK598809 causes elevation of serum prolactin and a small decrease in adaptive tracking performance. After co-administration with alcohol, effects of GSK598809 are mainly additive and the combination is well tolerated in healthy volunteers.

Adenoviral vector-mediated expression of neurotrophin-3 increases neuronal survival in suprachiasmatic nucleus grafts.

To improve transplantation results of fetal suprachiasmatic nucleus (SCN) in SCN-lesioned (SCNX) rats, grafts were ex vivo transduced with an adenoviral vector encoding for neurotrophin-3 (AdNT-3) before implantation. Mock- and AdLacZ-transduced grafts were used as controls. First, transplants were evaluated microscopically and by image analysis for the presence of vasopressinergic (VPergic) and vasoactive intestinal polypeptidergic (VIPergic) SCN neurons at 10 weeks or later postgrafting. Ex vivo AdNT-3-transduced transplants displayed increased volume areas of VPergic and VIPergic SCN cells in comparison with those in mock- and AdLacZ-transduced transplants, but significantly improved graft-to-host VPergic and VIPergic SCN fiber growth was not reached (though AdNT-3-transduced transplants tended to grow more VPergic fibers into the brain of VP-deficient SCNX Brattleboro rat recipients, which were chosen as recipients to circumvent the presence of non-SCN VP fiber staining). Second, a small group of arrhythmic Wistar rats received AdNT-3- or control-treated SCN grafts while continuously on-line for the monitoring of overt circadian activities in the pre- and postgrafting periods. The results indicated that ex vivo transduced SCN grafts can still restore arrhythmia, but that the NT-3-mediated anatomical improvements of the grafting results were not sufficient to enhance efficacy of reinstatement of circadian rhythm in SCN-lesioned rats. However, in this group VIP staining volume area, not VP staining volume area, correlated significantly with reinstatement of circadian rhythm.