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 CaMKII␣-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mechanism in the opiate-naive state, but switches to a D2-mediated CaMKII␣-dependent mechanism in the dependent/withdrawn state.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and a dramatic reduction in both total and phosphorylated CaMKII␣ signaling, specifically in the opiate-dependent/ withdrawn state, demonstrating functional control of ERK1/2-dependent versus CaMKII␣-dependent memory mechanisms within the BLA, controlled by opiate-exposure state.

CaM Kinases: From Memories to Addiction

“…In contrast, in chronically treated and withdrawn rats, mPFC blockade of CaMKII has no effect on CPP-establishment. Intra-BLA pharmacological blockade of CaMKII, however, blocks morphine-and heroin CPP-establishment [102,105]. This effect is most evident in the late phase of CPP consolidation 12h post conditioning [106].…”

Microinjection of histone deacetylase inhibitor into the ventrolateral orbital cortex potentiates morphine induced behavioral sensitization

“…In addition, extracellular signal-regulated kinase (ERK) plays an important role in synaptic plasticity and long-lasting behavioral alterations induced by opiate abuse (Li et al, 2008;Lyons et al, 2013). ERK activation by phosphorylation (p-ERK) serves as an intracellular bridging mechanism that facilitates neuronal communication and plasticity (Zamora-Martinez and Edwards, 2014).…”

Dorsal hippocampal NMDA receptor blockade impairs extinction of naloxone‐precipitated conditioned place aversion in acute morphine‐treated rats by suppressing ERK and CREB phosphorylation in the basolateral amygdala

“…ERK is an important downstream target molecule regulated by NMDA receptors and plays an important role in synaptic plasticity (Thomas and Huganir, ). Its activation has been demonstrated in different brain regions with several learning paradigms (Eckel‐Mahan et al ., ; Fan et al ., ; Lyons et al ., ) and it is involved in activity‐dependent modulation of synaptic plasticity in various brain areas (Shiflett and Balleine, ; Zhai et al ., ).…”