Protein Kinase A Alterations Following Chronic Flurazepam Treatment: Implications for Inhibitory and Excitatory Synaptic Plasticity in Rat Hippocampal CA1
Chronic FZP treatment induces anticonvulsant tolerance and the expression of a withdrawal syndrome upon drug discontinuation. These behavioral changes are accompanied by selective in vitro alterations in synaptic neurotransmission of the hippocampal CA1 region that, like in vivo manifestations of tolerance and withdrawal, can be pharmacologically reversed with a single exposure to specific receptor antagonists. A candidate mechanism for the coordinate changes in inhibitory and excitatory neurotransmission occurring 2d after cessation of 1-week FZP treatment, is a reduction in membrane-associated PKA activity and PKA-RIIBeta protein, effects that are spatially and temporally consistent with inhibitory and excitatory synaptic alterations (Lilly et al., 2003). Indeed, the functional deficits apparent in GABAA receptors apparent at this time point, which include GABA/benzodiazepine allosteric uncoupling, a decreased in mIPSC amplitude, and a decrease in alpha 1 subunit protein expression, can be accomplished by local reductions in PKA activity. However, AKAP150, the major PKA-RIIBeta scaffolding protein and determinant of membrane-associated PKA activity, is located proximate to excitatory, not inhibitory synapses in rat hippocampal CA1 (Lilly et al., 2005). At these synapses, there is an increase in the expression of GluR1-containing AMPA receptors 2d after cessation of FZP treatment, a finding that implies an alteration in local trafficking of these receptors, for which AKAP150-tethered PKA has been implicated (Lilly et al., 2006). A decrease in AKAP150-tethered PKA activity would favor the 234 dephosphorylation of the AMPA receptor GluR1 subunit on Ser845, and the subsequent internalization of the receptor complex. This interpretation is consistent with the normalization of GluR1-pSer845 at this time point and the subsequent normalization of AMPA receptor synaptic currents. Collectively these studies provide support for the hypothesis that alterations in membrane-associated PKA activity contribute to the acquisition and persistence of GABAA receptor dysfunction, and the impending recovery of normal AMPA receptor function 2d after cessation of chronic FZP treatment.
School:University of Toledo Health Science Campus
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:benzodiapepines gabaa receptors hippocampus drug tolerance dependence plasticity
Date of Publication:01/01/2006