Abstract
Rationale
Repeated injections of cocaine alter extracellular nitric oxide (NO) efflux via interactions between dopamine and glutamate receptor-coupled signaling cascades.
Objectives
Putative cellular mechanisms underlying changes in NO efflux following repeated cocaine administration were investigated.
Methods
Real-time detection of NO efflux using a NO biosensor was mainly performed in the rat dorsal striatum in vivo.
Results
Repeated exposure to cocaine (20 mg/kg), once a day for seven consecutive days, increased NO levels. Repeated injections of cocaine also increased the phosphorylation of neuronal nitric oxide synthase (nNOS), and inhibition of nNOS decreased the repeated cocaine-evoked increases in NO levels. Inhibition of protein kinase A, but not protein phosphatases, synergistically increased NO levels elevated by repeated cocaine injections. Blockade of dopamine D1 (D1) receptors or stimulation of dopamine D2 (D2) receptors decreased the repeated cocaine-evoked increases in NO levels. Similarly, blockade of N-methyl-d-aspartate (NMDA) receptors and group I metabotropic glutamate receptors (mGluRs) or stimulation of group III mGluRs also decreased the repeated cocaine-evoked increases in NO levels.
Conclusion
Stimulation of D1 receptors or group I mGluRs following repeated cocaine administration upregulates NO efflux via an NMDA receptor-evoked Ca2+ influx, while stimulation of D2 receptors or group III mGluRs downregulates NO efflux. Dephosphorylation of phosphorylated nNOS by protein phosphatases is necessary for upregulating NO efflux in the dorsal striatum after repeated cocaine administration.
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Acknowledgements
The authors thank Dr. Jacqueline F. McGinty for reading and discussing the manuscript. This work was supported by the Korea Research Foundation (grant no. 2008-521-H00005 to E.S.C.), Korea.
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Lee, D.K., Koh, W.C.A., Shim, YB. et al. Repeated cocaine administration increases nitric oxide efflux in the rat dorsal striatum. Psychopharmacology 208, 245–256 (2010). https://doi.org/10.1007/s00213-009-1724-z
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DOI: https://doi.org/10.1007/s00213-009-1724-z