Rotational behavior produced by adenovirusmediated gene transfer of dopamine D2 receptor into rat striatum

Abstract

We investigated the expression and functionality of a previously developed adenoviral vector carrying the rat cDNA for the dopamine D2 receptor (D2R), AdCMV.DopD2R. Comparative analysis of the autoradiographic images from the striatum injected with AdCMV.DopD2R and the contralateral striatum injected with a control vector, AdCMV.Null, in male rats indicated that D2R binding was increased by 40-60% on days 3 and 5 after injection, but then declined to baseline levels by day 21. When injected with apomorphine on days 3 and 7 after vector injection, experimental groups that had received unilateral striatal injections of AdCMV.DopD2R exhibited a distinct and significant laterality in rotational behavior. These results provide the first demonstration of an adenovirally mediated, intracerebral delivery of a functional neurotransmitter receptor.

cAMP Responsive Element-Binding Protein Phosphorylation Is Necessary for Perirhinal Long-Term Potentiation and Recognition Memory

“…The functionality of the adenoviral A-CREB-expressing vector was established in a previous study: a CREB-expressing vector but not the A-CREB vector protected cells from excitotoxic and ischemic stress (Glover et al, 2004). Although adenoviral transduction has been used previously in behavioral studies, such as those investigating restoration of motor function in animal models of dopamine depletion (Umegaki et al, 1997;McMenamin et al, 2004), to our knowledge, this is the first time it has been used to demonstrate an interference with recognition memory.…”

Dopamine D2R DNA transfer in dopamine D2 receptor-deficient mice: Effects on ethanol drinking

“…DNA transfer via adenoviral vector has been an effective strategy to introduce particular genes into tissue and has provided a high specificity targeting and delivery (Crystal, 1992;Suhr and Gage, 1993). The effectiveness of the present vector for intracerebral transfer of D2R as well as the expression of functional D2R effects has been previously well established (Ikari et al, 1995(Ikari et al, , 1999Ingram et al, 1998;Ogawa et al, 2000;Thanos et al, 2001;Umegaki et al, 1997). Rats infected with this adenoviral vector produced significant increases in D2R expression with significant decreases in alcohol preference and intake (Thanos et al, 2001(Thanos et al, , 2004.…”

“…Previous reports describe details of the vector construction (Ikari et al, 1995;Umegaki et al, 1997). Briefly, the recombinant Ad vectors were derived from Ad type 5 in which the majority of the E1 and a portion of the E3 regions had been deleted, and an expression cassette containing the rat D2R cDNA along with the cytomegalovirus (CMV) immediate early promotor and enhancer was inserted at the site of the E1 deletion.…”

Gene therapy in Parkinson?s disease

“…Retrograde transport of the AdV follows virus uptake into neurons. Expression levels with first-generation constructs in vivo generally decline after a few weeks; this is related to the host immune response against residual viral proteins or the transgene itself or to the down-regulation of transcripts (Akli et al 1993;Davidson et al 1993;Tripathy et al 1996;Umegaki et al 1997). In some studies, a residual 20%-50% expression has been found after 7 weeks, resulting more from down-regulation than from cell loss (Choi- Lundberg et al 1997Lundberg et al , 1998.…”

“…Transient rotational behaviour has been induced after unilateral striatal transduction with AdV-dopamine D2 receptor; this might be relevant for parkinsonian syndromes with concurrent striatal degeneration (Ikari et al 1995;Umegaki et al 1997). …”