ERK-Directed Phosphorylation of mGlu5 Gates Methamphetamine Reward and Reinforcement in Mouse

Abstract

Methamphetamine (MA) is a highly addictive psychomotor stimulant drug. In recent years, MA use has increased exponentially on a global scale, with the number of MA-involved deaths reaching epidemic proportions. There is no approved pharmacotherapy for treating MA use disorder, and we know relatively little regarding the neurobiological determinants of vulnerability to this disease. Extracellular signal-regulated kinase (ERK) is an important signaling molecule implicated in the long-lasting neuroadaptations purported to underlie the development of substance use disorders, but the role for this kinase in the propensity to develop addiction, particularly MA use disorder, is uncharacterized. In a previous MA-induced place-conditioning study of C57BL/6J mice, we characterized mice as MA-preferring, -neutral, or -avoiding and collected tissue from the medial prefrontal cortex (mPFC). Using immunoblotting, we determined that elevated phosphorylated ERK expression within the medial prefrontal cortex (mPFC) is a biochemical correlate of the affective valence of MA in a population of C57BL/6J mice. We confirmed the functional relevance for mPFC ERK activation for MA-induced place-preference via site-directed infusion of the MEK inhibitor U0126. By contrast, ERK inhibition did not have any effect upon MA-induced locomotion or its sensitization upon repeated MA treatment. Through studies of transgenic mice with alanine point mutations on T1123/S1126 of mGlu5 that disrupt ERK-dependent phosphorylation of the receptor, we discovered that ERK-dependent mGlu5 phosphorylation normally suppresses MA-induced conditioned place-preference (MA-CPP), but is necessary for this drug’s reinforcing properties. If relevant to humans, the present results implicate individual differences in the capacity of MA-associated cues/contexts to hyper-activate ERK signaling within mPFC in MA Use Disorder vulnerability and pose mGlu5 as one ERK-directed target contributing to the propensity to seek out and take MA.

Investigating the Role of Corticostriatal Glutamate Signaling in Methamphetamine Reward and Reinforcement

“…14 days of training (e.g.,Brown et al, 2020;Fultz et al, 2017Fultz et al, , 2021Ruan et al, 2020;Sern et al, 2020;Shab et al, 2021;Szumlinski et al, 2017). Consistent with this prior work, the mice in all sub-experiments of Experiment 1 exhibited what we interpret as being novelty-induced responding on day 1 of training; it is non-selective as indicated by similar pattern of responding in both the active and inactive holes and a hole-discrimination of 45-60% (Figure10) and thus, does not likely reflect a high level of MA-reinforcement per se.…”

Analysis of the functional role and mRNA expression of GABABR in the nucleus accumbens of cocaine-addicted rats

“…Addictive drugs activate α-amino-3-hydroxy-5-methyl-4isoxazole propionic acid (AMPA) receptors, which further activate the downstream PKA and ERK pathways. 35 ERK can activate CREB by activating MSK, 36 and in addition, phosphorylated PKA can activate CREB, which binds to the CRE structural domain on DNA and in turn activates genes involved in learning and memory processes. 37 Reports suggest that phosphorylated PKA is involved in long-range synaptic plasticity and long-term memory formation.…”

Group I Metabotropic Glutamate Receptors and Interacting Partners: An Update

“…The ERK-dependent mGlu5 phosphorylation also suppresses the rewarding effect of methamphetamine as transgenic global disruption of mGlu5 T1123/S1126 phosphorylation augmented the methamphetamine-induced conditioned place preference [25]. Of note, T1123/S1126 phosphorylation is not involved in the methamphetamine-induced acute locomotion or locomotor sensitization but is necessary for the reinforcing property of methamphetamine as tested under operant-conditioning procedures [25] and for cocaine sensitization [24]. In addition, repeated nicotine injections increased the interaction of active ERK with mGlu5 in the rat nucleus accumbens (NAc) [26].…”