TY - JOUR
T1 - Erk-directed phosphorylation of mglu5 gates methamphetamine reward and reinforcement in mouse
AU - Fultz, Elissa K.
AU - Quadir, Sema G.
AU - Martin, Douglas
AU - Flaherty, Daniel M.
AU - Worley, Paul F.
AU - Kippin, Tod E.
AU - Szumlinski, Karen K.
N1 - Funding Information:
Funding: This work was funded by NIH grants AA016650 (KKS) and DA10309 (PFW) and funds from the Undergraduate Research and Creative Activities program of UCSB (EKF, SGQ, DM, and DMF).
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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 im-plicated 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 phosphory-lated 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 re-ceptor, we discovered that ERK-dependent mGlu5 phosphorylation normally suppresses MA-in-duced conditioned place-preference (MA-CPP), but is necessary for this drug’s reinforcing proper-ties. 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.
AB - 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 im-plicated 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 phosphory-lated 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 re-ceptor, we discovered that ERK-dependent mGlu5 phosphorylation normally suppresses MA-in-duced conditioned place-preference (MA-CPP), but is necessary for this drug’s reinforcing proper-ties. 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.
KW - Addiction
KW - Metabotropic glutamate receptor 5
KW - Methamphetamine
KW - Place-conditioning
KW - Reinforcement
KW - Self-administra-tion
KW - Vulnerability
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U2 - 10.3390/ijms22031473
DO - 10.3390/ijms22031473
M3 - Article
C2 - 33540617
AN - SCOPUS:85100089375
SN - 1661-6596
VL - 22
SP - 1
EP - 21
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 3
M1 - 1473
ER -