| Title | Benzodiazepine Withdrawal-Induced Glutamatergic Plasticity Involves Upregulation of GluR1-Containing AMPA Receptors in Hippocampal CA1 Neurons. | | Author(s) | Song J, Shen G, Greenfield Jr LJ, Tietz EI | | Institution | University of Toledo College of Medicine. | | Source | J Pharmacol Exp Ther 2007 May 17. | | Abstract | Modification of glutamatergic synaptic function, a mechanism central to neuronal plasticity, may also mediate long-term drug effects, including dependence and addiction. Benzodiazepine withdrawal results in increased glutamatergic strength, but whether AMPARs are functionally and structurally remodeled during benzodiazepine withdrawal is uncertain. Whole-cell recordings of rat hippocampal CA1 neurons, either acutely-dissociated or in hippocampal slices, revealed that AMPAR function was enhanced up to 50% during flurazepam (FZP) withdrawal, without changes in whole-cell channel kinetic properties. Agonist-elicited AMPA currents showed a negative shift in rectification in the presence of spermine, suggesting augmented membrane incorporation of GluR2-lacking AMPARs. As GluR1-containing AMPARs are critical for activity-dependent alterations in excitatory strength, we sought to determine whether changes in GluR1 subunit distribution in CA1 neurons occurred during benzodiazepine withdrawal. Confocal image analysis revealed that FZP withdrawal promoted GluR1 subunit incorporation into somatic and proximal dendritic membranes of CA1 neurons, without GluR2 subunit alterations. Findings of immunoblot studies were consistent with immunofluorescent studies indicating increased GluR1, but not GluR2, subunit protein levels in cytosolic, crude membrane and PSD-enriched fractions from CA1 minislices. As with LTP, the FZP-withdrawal-induced GluR1 incorporation into CA1 neuron membranes may require the GluR1-trafficking protein, SAP97, which was also elevated in membrane-associated fractions. Together, our findings provide evidence that during FZP withdrawal, increased membrane incorporation of GluR1-containing AMPARs and associated upregulation of AMPAR functions in hippocampal CA1 pyramidal neurons share fundamental similarities with the mechanisms underlying LTP. This implies that glutamatergic neuronal remodeling observed in LTP also subserves physiological adaptations to drug withdrawal. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 17510319 |
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