title: Down-regulated striatal gene expression for synaptic plasticity-associated proteins in addiction and relapse vulnerable animals.
abstract: Reducing the likelihood of relapse represents one of the greatest obstacles in the successful treatment of cocaine addiction. Dysregulation of the synaptic plasticity processes long-term potentiation (LTP) and long-term depression (LTD) is thought to be associated with protracted relapse risk. To improve our understanding of the molecular mechanisms contributing to relapse vulnerability we trained rats (n=52) to self-administer cocaine and phenotyped animals as relapse-vulnerable or relapse-resilient using procedures adapted from Deroche-Gamonet et al. (Science 2004, 305, 1014-1017). Gene expression analysis, targeted at synaptic plasticity-related genes, revealed significant transcript down-regulation in the ventral and dorsal striatum of relapse-vulnerable animals compared to relapse-resilient controls. This included reduced expression of genes encoding proteins implicated in the dendritic translation of synaptic plasticity-related transcripts, the dynamic regulation and trafficking of ionotropic glutamate receptors important for LTP and LTD, along with neuronal surface receptors that initiate downstream signalling pathways associated with synaptic plasticity. Together, our data are consistent with recent reports of an inability to evoke LTD in the striatum of addiction-vulnerable rats. To our knowledge, this is the first study to demonstrate down-regulated synaptic plasticity-associated gene expression not only in the ventral striatum, where the majority of addiction-related synaptic plasticity studies have been conducted, but also in the dorsal striatum of animals categorized as relapse-vulnerable. As these neural correlates were elucidated using an approach incorporating individual behavioural differences, they potentially provide more relevant insight into addiction and assist the development of novel pharmacotherapies to treat relapse.
authors.affiliation: Neurobiology of Addiction Laboratory, School of Biomedical Sciences and Pharmacy, Centre for Brain and Mental Health Research, University of Newcastle and the Hunter Medical Research Institute, Newcastle, NSW, Australia.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Brown
authors.forename: Jamie R
authors.initials: JR
authors.lastname: Flynn
authors.forename: Doug W
authors.initials: DW
authors.lastname: Smith
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Dayas
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001522:Behavior, Animal / Q000502:physiology*; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D003214:Conditioning, Classical / Q000187:drug effects; D003342:Corpus Striatum / Q000502:physiology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005108:Extinction, Psychological / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D058990:Molecular Targeted Therapy; D009042:Motivation; D009473:Neuronal Plasticity / Q000502:physiology*; D011506:Proteins / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D055502:Secondary Prevention; D012646:Self Administration; D019966:Substance-Related Disorders / Q000188:drug therapy / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics
chemical_list: D018765:Dopamine Uptake Inhibitors; D011506:Proteins; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D003042:Cocaine