title: Opiate Exposure State Controls a D2-CaMKIIα-Dependent Memory Switch in the Amygdala-Prefrontal Cortical Circuit.
abstract: The mammalian basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) comprise a functionally interconnected circuit that is critical for processing opiate-related associative memories. In the opiate-naïve state, reward memory formation in the BLA involves a functional link between dopamine (DA) D1 receptor (D1R) and extracellular signal-related kinase 1/2 (ERK1/2) signaling substrates, but switches to a DA D2 (D2R)/Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα)-dependent memory substrate following chronic opiate exposure and spontaneous withdrawal. Using conditioned place preference (CPP) in rats paired with molecular analyses, we examined the role of intra-mPFC CaMKII, ERK and DAergic activity during the formation of opiate associative memories, and how opiate exposure state may regulate the functions of these molecular memory pathways. We report that the role of CaMKIIα signaling is functionally reversed within the BLA-mPFC pathway depending on opiate exposure state. Thus, in the opiate-naïve state, intra-mPFC but not intra-BLA blockade of CaMKII signaling prevents formation of opiate reward memory. However, following chronic opiate exposure and spontaneous withdrawal, the role of CaMKII signaling in the BLA-mPFC is functionally reversed. This behavioral memory switch corresponds to a selective increase in the expression of D2R and CaMKIIα, but not other calcium/calmodulin-related molecules, nor D1R expression levels within the mPFC.
authors.affiliation: Addiction Research Group, University of Western Ontario, London, ON, Canada.|Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
authors.forename: Laura G
authors.identifier: http://orcid.org/0000-0002-9168-2531
authors.initials: LG
authors.lastname: Rosen
authors.affiliation: Addiction Research Group, University of Western Ontario, London, ON, Canada.|Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
authors.forename: Jordan
authors.initials: J
authors.lastname: Zunder
authors.affiliation: Addiction Research Group, University of Western Ontario, London, ON, Canada.|Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
authors.forename: Justine
authors.identifier: http://orcid.org/0000-0001-7185-4829
authors.initials: J
authors.lastname: Renard
authors.affiliation: Addiction Research Group, University of Western Ontario, London, ON, Canada.|Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Fu
authors.affiliation: Addiction Research Group, University of Western Ontario, London, ON, Canada.|Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.|Department of Psychiatry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
authors.forename: Walter
authors.initials: W
authors.lastname: Rushlow
authors.affiliation: Addiction Research Group, University of Western Ontario, London, ON, Canada.|Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.|Department of Psychiatry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.|Department of Psychology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Laviolette
mesh_terms: D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D003932:Heroin / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology; D013375:Substance Withdrawal Syndrome / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; C000607792:DRD2 protein, rat; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D003932:Heroin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517675:Camk2a protein, rat