Development of an adenoviral vector for intracerebral delivery of the dopamine D-2 receptor

The age-related loss of striatal dopamine D-2 receptors (D2R) has been obse rved in numerous species, including rodents, monkeys, and man, and is partl y responsible for impaired motor function in aged mammals. We have develope d an adenoviral vector designed for intracerebral transfer of cDNA for D2R. Results of in vitro studies demonstrated that the vector produced abundant message for D2R and that the vector was membrane bound and capable of bind ing appropriate ligand. Results of in vivo studies provided clear evidence of D2R production when injected into the striatum of rats. The D2R produced were capable of binding appropriate ligand. In addition, evidence of funct ional receptors was produced by demonstrating apomorphine-induced rotationa l behavior in rats receiving a unilateral injection of the vector. Despite these successes, we have been unable to demonstrate improvement in the moto r behavior of aged rats receiving bilateral injections of the vector. A maj or problem with this vector as with similar adenoviral vectors is the loss of expression beginning 3-5 days after injection to undetectable levels at 21 days. Because of the lack of motor functional effects in aged rats and t he loss of expression of the vector, other strategies for development of th e vector are being pursued. Regarding functional effects, we have examined the feasibility of manipulating hippocampal acetylcholine (ACh) release thr ough D2R manipulation to improve memory performance. Using microdialysis, w e have demonstrated in vivo in rats that treatment with a D2R agonist incre ases hippocampal ACh release while treatment with a D2R antagonist attentua tes this effect as well as impairs performance in a complex maze task. In a ddition, a D2R null mutant mouse is being used to examine possible therapeu tic effects of the vector. These mice show specific motor deficits. Recent studies using positron emission tomography have also demonstrated the feasi bility of in vivo imaging of the vector. Thus, use of adenoviral vectors sp ecific for neurotransmitter receptors can provide a highly useful research tool for examining age-related alterations in behavioral function and a pos sible strategy for therapeutic intervention. (C) 2000 Published by Elsevier Science Ireland Ltd.