Potentiated Response of ERK/MAPK Signaling is Associated with Prolonged Withdrawal from Cocaine Behavioral Sensitization

Among the neuroadaptations underlying the expression of cocaine-induced behaviors are modifications in glutamate-mediated signaling and synaptic plasticity via activation of mitogen-activated protein kinases (MAPKs) within the nucleus accumbens (NAc). We hypothesized that exposure to cocaine leads t...

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Bibliographic Details
Published in:	Journal of molecular neuroscience Vol. 71; no. 11; pp. 2229 - 2236
Main Authors:	Bingor, Alexey, Azriel, Matityahu, Amiad, Lavi, Yaka, Rami
Format:	Journal Article
Language:	English
Published:	New York Springer US 01-11-2021 Springer Nature B.V
Subjects:	Animals Behavior, Animal Biomedical and Life Sciences Biomedicine Cell Biology Cocaine Cocaine - adverse effects Drug withdrawal Excitatory Amino Acid Antagonists - pharmacology Extracellular signal-regulated kinase Glutamatergic transmission Glutamic acid receptors Glutamic acid receptors (ionotropic) Kinases Male MAP kinase MAP Kinase Signaling System Microinjection Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors Mitogen-Activated Protein Kinase 3 - metabolism N-Methyl-D-aspartic acid receptors Neurochemistry Neurology Neurosciences Nucleus accumbens Nucleus Accumbens - drug effects Nucleus Accumbens - metabolism Piperidines - pharmacology Protein kinase Protein Kinase Inhibitors - pharmacology Proteomics Rats Receptors Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors Receptors, N-Methyl-D-Aspartate - genetics Receptors, N-Methyl-D-Aspartate - metabolism Signaling Substance Withdrawal Syndrome - metabolism Substance Withdrawal Syndrome - physiopathology Synaptic plasticity NR2B NMDA Ifenprodil Cocaine Behavioral sensitization ERK
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Summary:	Among the neuroadaptations underlying the expression of cocaine-induced behaviors are modifications in glutamate-mediated signaling and synaptic plasticity via activation of mitogen-activated protein kinases (MAPKs) within the nucleus accumbens (NAc). We hypothesized that exposure to cocaine leads to alterations in MAPK signaling in NAc neurons, which facilitates changes in the glutamatergic system and thus behavioral changes. We have previously shown that following withdrawal from cocaine-induced behavioral sensitization (BS), an increase in glutamate receptor expression and elevated MAPK signaling was evident. Here, we set out to determine the time course and behavioral consequences of inhibition of extracellular signal-regulated kinase (ERK) or NMDA receptors following withdrawal from BS. We found that inhibiting ERK by microinjection of U0126 into the NAc at 1 or 6 days following withdrawal from BS did not affect the expression of BS when challenged with cocaine at 14 days. However, inhibition of ERK 1 day before the cocaine challenge abolished the expression of BS. We also inhibited NR2B-containing NMDA receptors in the NAc by microinjection of ifenprodil into the NAc following withdrawal from BS, which had no effect on the expression of BS. However, microinjection of ifenprodil to the NAc 1 day before challenge attenuated the expression of BS similar to ERK inhibition. These results suggest that following a prolonged period of withdrawal, NR2B-containing NMDA receptors and ERK activity play a critical role in the expression of cocaine behavioral sensitization.
ISSN:	0895-8696 1559-1166
DOI:	10.1007/s12031-021-01799-6