title: Nanotherapeutic approach for opiate addiction using DARPP-32 gene silencing in an animal model of opiate addiction.
abstract: Opiates act on the dopaminergic system of the brain and perturb 32 kDa dopamine and adenosine 3', 5'-monophosphate-regulated phosphoprotein (DARPP-32) function. The DARPP-32 mediated inhibition of protein phosphatase-1 (PP-1) and modulation of transcriptional factor CREB is critical to the changes in neuronal plasticity that result in behavioral responses during drug abuse. To investigate the role of DARPP-32 mediated signaling on withdrawal behavior in a rat model of opiate addiction, we used intracerebral administration of gold nanorods (GNR) complexed to DARPP-32 siRNA to silence DARPP-32 gene expression and measure its effects on the opiate withdrawal syndrome. We hypothesized that DARPP-32 siRNA will suppress the neurochemical changes underlying the withdrawal syndrome and therefore prevent conditioned place aversion by suppressing or removing the constellation of negative effects associated with withdrawal, during the conditioning procedure. Our results showed that opiate addicted animals treated with GNR-DARPP-32 siRNA nanoplex showed lack of condition place aversive behavior consequent to the downregulation of secondary effectors such as PP-1 and CREB which modify transcriptional gene regulation and consequently neuronal plasticity. Thus, nanotechnology based delivery systems could allow sustained knockdown of DARPP-32 gene expression which could be developed into a therapeutic intervention for treating drug addiction by altering reward and motivational systems and interfere with conditioned responses.
authors.affiliation: Department of Pathology and Anatomical Sciences, 206 Farber Hall, State University of New York at Buffalo, Buffalo, NY, 14214, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Ignatowski
authors.forename: R
authors.initials: R
authors.lastname: Aalinkeel
authors.forename: J L
authors.initials: JL
authors.lastname: Reynolds
authors.forename: B B
authors.initials: BB
authors.lastname: Nair
authors.forename: D E
authors.initials: DE
authors.lastname: Sykes
authors.forename: C P K
authors.initials: CP
authors.lastname: Gleason
authors.forename: W C
authors.initials: WC
authors.lastname: Law
authors.forename: M J
authors.initials: MJ
authors.lastname: Mammen
authors.forename: P N
authors.initials: PN
authors.lastname: Prasad
authors.forename: S A
authors.initials: SA
authors.lastname: Schwartz
authors.forename: Supriya D
authors.initials: SD
authors.lastname: Mahajan
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods*; D006046:Gold; D006801:Humans; D009021:Morphine Dependence / Q000523:psychology / Q000628:therapy; D050997:Nanomedicine / Q000379:methods*; D043942:Nanotubes; D009293:Opioid-Related Disorders / Q000523:psychology / Q000628:therapy*; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000627:therapeutic use; D051381:Rats; D020318:Rats, Long-Evans; D013375:Substance Withdrawal Syndrome / Q000523:psychology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497930:Ppp1r1b protein, rat; D034741:RNA, Small Interfering; D006046:Gold; D054645:Protein Phosphatase 1