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Abstract
Glutamate, the most abundant excitatory neurotransmitter in the central nervous system, serves an integral role in homeostatic processes and in various forms of neuroplasticity, including learning and memory, injury-induced pain and drug tolerance, dependence and reward. Extracellular levels of glutamate are tightly regulated by sodium-dependent glutamate transporters responsible for its uptake into cells. Following association of glutamate with its ionotropic (NMDA, AMPA, kainate) or metabotropic receptors, downstream signaling pathways are triggered leading to the mobilization of second messengers and activation of transcription factors, neuropeptides, receptors and ion channels. Several recent studies utilizing pharmacological antagonists have implicated AMPA/kainate receptors in the neuroadaptive responses to drugs such as morphine and cocaine. However, due to the incomplete selectivity of these inhibitors, the function of kainate receptors, particularly those comprised of GluR5 subunits, has remained elusive. The recent availability of constitutive GluR5 knockout mice on a congenic C57BL/6 background affords the ability to examine the specific contribution of GluR5 to various biological responses without the confounds associated with the use of antagonists.
This dissertation reports that GluR5 knockout mice do not differ from wildtype littermates with respect to thermal or mechanical nociceptive thresholds, morphine disposition in CNS, morphine dependence or withdrawal-induced pain hypersensitivity. In contrast, deletion of G1uR5 prevents the development of tolerance following sustained morphine administration. Parallel biochemical characterization of wildtype and G1uR5 knockout mice revealed that the expression of several mediators in the spinal cord dorsal horn either were unchanged or were altered in the same direction by morphine in both groups, indicating that these factors are not involved selectively in tolerance. However, we identified 4 candidates exhibiting differential regulation by morphine in wildtype versus GluR5 knockout mice, suggesting their potential contribution to the development of tolerance at the spinal level in wildtype but not in GluR5 knockout mice. Surprisingly, G1uR5 mutant mice also display enhanced cocaine sensitivity and preference. These findings advance our current understanding of the mechanisms underlying morphine tolerance and cocaine sensitivity, and thus have important clinical implications for the development of new strategies in the management of morphine analgesic tolerance and psychostimulant addiction.
