Neuroadaptations in the dentate gyrus following contextual cued reinstatement of methamphetamine seeking
Abstinence from unregulated methamphetamine self-administration increases hippocampal dependent, context-driven reinstatement of methamphetamine seeking. The current study tested the hypothesis that alterations in the functional properties of granule cell neurons (GCNs) in the dentate gyrus (DG) of the hippocampus in concert with altered expression of synaptic plasticity-related proteins and ultrastructural changes in the DG are associated with enhanced context-driven methamphetamine-seeking behavior. Whole-cell patch-clamp recordings were performed in acute brain slices from methamphetamine naïve (controls) and methamphetamine experienced animals (during acute withdrawal, during abstinence, after extinction and after reinstatement). Spontaneous excitatory postsynaptic currents (sEPSCs) and intrinsic excitability were recorded from GCNs. Reinstatement of methamphetamine seeking increased sEPSC frequency and produced larger amplitude responses in GCNs compared to controls and all other groups. Reinstatement of methamphetamine seeking reduced spiking capability in GCNs compared to controls, and all other groups, as indicated by reduced intrinsic spiking elicited by increasing current injections, membrane resistance and fast after hyperpolarization. In rats that reinstated methamphetamine seeking, these altered electrophysiological properties of GCNs were associated with enhanced expression of Fos, GluN2A subunits and PSD95 and reduced expression of GABAA subunits in the DG and enhanced expression of synaptic PSD in the molecular layer. The alterations in functional properties of GCNs and plasticity related proteins in the DG paralleled with no changes in structure of microglial cells in the DG. Taken together, our results demonstrate that enhanced reinstatement of methamphetamine seeking results in alterations in intrinsic spiking and spontaneous glutamatergic synaptic transmission in the GCNs and concomitant increases in neuronal activation of GCNs, and expression of GluNs and decreases in GABAA subunits that may contribute to the altered synaptic connectivity—neuronal circuitry—and activity in the hippocampus, and enhance propensity for relapse.
KeywordsGranule cell neurons Whole-cell patch-clamp recording Fos GluN Electron microscopy Microglia
This work was supported by grants from the National Science Foundation, USA (DGE-1144086 to M.H.G), National Institute on Drug Abuse, USA (DA034140 to C.D.M.), National Institute of Alcoholism and Alcohol Abuse, USA (AA020098, AA06420 to C.D.M.) and start-up funds from the Veterans Medical Research Foundation to C.D.M. We sincerely thank Dr. Bryan W. Luikart from the Geisel School of Medicine, Dartmouth College, for his scientific collaboration and extensive discussion on the electrophysiology data. We thank Ying Jones at the UCSD EM core for preparation of the brain samples and training on the EM. We thank Ryan Ostrom from the division of biological sciences independent study program at UCSD and Jasmine Guevara from the NIDA summer internship program for assistance with animal behavior.
Compliance with ethical standards
Conflict of interest
The authors declare no competing financial interests in relation to the work described.
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