Relapse to drug use in abstinent human opioid addicts is the major obstacle impeding success of opioid addiction treatment. Relapse can be triggered by exposure to environmental cues associated with drug use; as such, disruption of the learned associations between the opioid and environmental cues may be an effective approach for reducing relapse and extending abstinence. Synaptic plasticity in the hippocampus, a key neural substrate of learning and memory, is an integral component of the development of context-dependent associations. Relatively stable changes in gene expression at the postsynaptic density (PSD), which receives and transduces synaptic information, are associated with synaptic plasticity. Thus changes in the protein expression profile within the hippocampal PSD may be integral in mediating synaptic plasticity that underlies the expression and extinction of a conditioned response to an opioid-paired environment. In the present proposal, we will test the hypothesis that the expression and extinction of a conditioned behavioral response to a previously morphine-paired environment are associated with differential protein expression profiles in the hippocampal PSD.
In Specific Aim 1, we will establish a paradigm for the study of extinction of morphine conditioned place preference (CPP) via repeated exposure of the rats to the previously morphine-paired CPP chambers in the absence of morphine.
In Specific Aim 2, we will characterize the protein expression profiles in hippocampal PSD that track with the expression and extinction of morphine CPP. Relative levels of protein expression will be analyzed through isotope-coded affinity tag (ICAT) followed by tandem mass spectrometry (LC-MS/MS).
In Specific Aim 3, we will validate the levels of expression of hippocampal PSD-associated proteins identified as being differentially expressed in animals that express morphine CPP compared to those in which morphine CPP has been extinguished; biochemical and immunohistochemical techniques will be employed. Proteins altered following extinction will be the basis for further analyses of the mechanisms of extinction of drug-associated conditioned responses, and will provide novel targets for pharmacotherapeutic intervention in the quest to rapidly and effectively disrupt learned drug-environment conditioned associations to reduce the risk of relapse and promote abstinence in opioid addicts. Opioid addiction is a chronic, relapsing behavioral disorder and exposure to environmental """"""""cues"""""""" associated with opioid consumption triggers relapse in opioid addicts. The present proposal will examine the protein changes linked to disruption of the behavioral response to morphine-associated environmental cues in order to identify new targets for developing therapeutic medications to reduce the risk of relapse in opioid addicts. ? ? ?
| Billa, Sophie K; Liu, Jie; Bjorklund, Nicole L et al. (2010) Increased insertion of glutamate receptor 2-lacking alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors at hippocampal synapses upon repeated morphine administration. Mol Pharmacol 77:874-83 |
| Billa, Sophie K; Sinha, Namita; Rudrabhatla, Sri Rajyalakshmi et al. (2009) Extinction of morphine-dependent conditioned behavior is associated with increased phosphorylation of the GluR1 subunit of AMPA receptors at hippocampal synapses. Eur J Neurosci 29:55-64 |
