title: Opiate exposure and withdrawal induces a molecular memory switch in the basolateral amygdala between ERK1/2 and CaMKIIα-dependent signaling substrates.
abstract: Opiate reward memories are powerful triggers for compulsive opiate-seeking behaviors. The basolateral amygdala (BLA) is an important structure for the processing of opiate-related associative memories and is functionally linked to the mesolimbic dopamine (DA) pathway. Transmission through intra-BLA DA D1-like and D2-like receptors independently modulates the formation of opiate reward memories as a function of opiate-exposure state. Thus, in the opiate-naive state, intra-BLA D1 transmission is required for opiate-related memory formation. Once opiate dependence and withdrawal has developed, a functional switch to a DA D2-mediated memory mechanism takes place. However, the downstream molecular signaling events that control this functional switch between intra-BLA DA D1 versus D2 receptor transmission are not currently understood. Using an unbiased place conditioning procedure in rats combined with molecular analyses, we report that opiate reward memory acquisition requires intra-BLA ERK1/2 signaling only in the previously opiate-naive state. However, following chronic opiate exposure and withdrawal, intra-BLA reward memory processing switches to a CaMKIIα-dependent memory substrate. Furthermore, the ability of intra-BLA DA D1 or D2 receptor transmission to modulate the motivational salience of opiates similarly operates through a D1-mediated ERK-dependent mechanism in the opiate-naive state, but switches to a D2-mediated CaMKIIα-dependent mechanism in the dependent/withdrawn state. Protein analysis of BLA tissue revealed a downregulation of ERK1/2 phosphorylation and a dramatic reduction in both total and phosphorylated CaMKIIα signaling, specifically in the opiate-dependent/withdrawn state, demonstrating functional control of ERK1/2-dependent versus CaMKIIα-dependent memory mechanisms within the BLA, controlled by opiate-exposure state.
authors.affiliation: Department of Anatomy & Cell Biology, Department of Psychiatry, Department of Psychology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada.
authors.forename: Danika
authors.initials: D
authors.lastname: Lyons
authors.forename: Xavier
authors.initials: X
authors.lastname: de Jaeger
authors.forename: Laura G
authors.initials: LG
authors.lastname: Rosen
authors.forename: Tasha
authors.initials: T
authors.lastname: Ahmad
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Lauzon
authors.forename: Jordan
authors.initials: J
authors.lastname: Zunder
authors.forename: Lique M
authors.initials: LM
authors.lastname: Coolen
authors.forename: Walter
authors.initials: W
authors.lastname: Rushlow
authors.forename: Steven R
authors.initials: SR
authors.lastname: Laviolette
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009020:Morphine / Q000009:adverse effects*; D009294:Narcotics / Q000009:adverse effects*; D009293:Opioid-Related Disorders / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology
chemical_list: D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D009294:Narcotics; D009020:Morphine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517675:Camk2a protein, rat; D048052:Mitogen-Activated Protein Kinase 3
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