Abstract
Cocaine enhances dopamine-mediated neurotransmission by blocking dopamine re-uptake at axon terminals. Most dopamine-containing nerve terminals innervate medium spiny neurons in the striatum of the brain. Cocaine addiction is thought to stem, in part, from neural adaptations that act to maintain equilibrium by countering the effects of repeated drug administration1,2. Chronic exposure to cocaine upregulates several transcription factors that alter gene expression and which could mediate such compensatory neural and behavioural changes1,2,3,4. One such transcription factor is ΔFosB, a protein that persists in striatum long after the end of cocaine exposure3,5. Here we identify cyclin-dependent kinase 5 (Cdk5) as a downstream target gene of ΔFosB by use of DNA array analysis of striatal material from inducible transgenic mice. Overexpression of ΔFosB, or chronic cocaine administration, raised levels of Cdk5 messenger RNA, protein, and activity in the striatum. Moreover, injection of Cdk5 inhibitors into the striatum potentiated behavioural effects of repeated cocaine administration. Our results suggest that changes in Cdk5 levels mediated by ΔFosB, and resulting alterations in signalling involving D1 dopamine receptors, contribute to adaptive changes in the brain related to cocaine addiction.
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References
Berke, J. D. & Hyman, S. E. Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25, 515–532 (2000).
Nestler, E. J. Molecular mechanisms of opiate and cocaine addiction. Curr. Opin. Neurobiol. 7, 713–719 (1997).
Hope, B. T. et al. Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron 13, 1235–1244 (1994).
Kelz, M. B. et al. Expression of the transcriptional factor ΔFosB in the brain controls sensitivity to cocaine. Nature 401, 272–276 (1999).
Hiroi, N. et al. FosB mutant mice: Loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine's psychomotor and rewarding effects. Proc. Natl Acad. Sci. USA 94, 10397–10402 (1997).
Chen, J. et al. Transgenic animals with inducible, targeted gene expression in the brain. Mol. Pharmacol. 54, 495–503 (1998).
Bibb, J. A. et al. Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 402, 669–671 (1999).
Snyder, G. L. et al. Phosphorylation of DARPP-32 and protein phosphatase inhibitor-1 in rat choroid plexus: Regulation by factors other than dopamine. J. Neurosci. 12, 3071–3083 (1992).
Dulubova, I. et al. ARPP-16/ARPP-19: a highly conserved family of cAMP-regulated phosphoproteins. J. Neurochem. (in the press).
Caporaso, G. et al. Dopamine and drugs of abuse modulate phosphorylation of ARPP-21, a cyclic AMP-regulated phosphoprotein enriched in the neostriatum. Neuropharmacology 39, 1637–1644 (2000).
Roche, K. W., O'Brien, R. J., Mammen, A. L., Bernhardt, J. & Huganir, R. L. Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit. Neuron 16, 1179–1188 (1996).
White, F. J., Hu, X. -T., Zhang, X. -F. & Wolf, M. E. Repeated administration of cocaine or amphetamine alters neuronal responses to glutamate in the mesoaccumbens dopamine system. J. Pharmacol. Exp. Ther. 273, 445–454 (1995).
Zhang, X. -F., Hu, X. -T. & White, F. J. Whole-cell plasticity in cocaine withdrawal: Reduced sodium currents in nucleus accumbens neurons. J. Neurosci. 18, 488–498 (1998).
Dreher, J. K. & Jackson, D. M. Role of D1 and D2 dopamine receptors in mediating locomotor activity elicited from the nucleus accumbens of rats. Brain Res. 487, 267–277 (1989).
Self, D. W., Barnhart, W. J., Lehman, D. A. & Nestler, E. J. Opposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists. Science 271, 1586–1589 (1996).
Xu, M. et al. Elimination of cocaine-induced hyperactivity and dopamine-mediated neurophysiological effects in dopamine D1 receptor mutant mice. Cell 79, 945–955 (1994).
Nishi, A. et al. Amplification of dopaminergic signalling by a novel positive feedback loop. Proc. Natl Acad. Sci. USA 97, 12840–12845 (2000).
Hiroi, N. et al. Neuronal and behavioural abnormalities in striatal function in DARPP-32-mutant mice. Eur. J. Neurosci. 11, 1114–1118 (1999).
Chae, T. et al. Mice lacking p35, a neuronal specific activator of cdk5, displays cortical lamination defects, seizures, and adult lethality. Neuron 18, 29–42 (1997).
Ohshima, T. et al. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc. Natl Acad. Sci. USA 93, 11173–11178 (1996).
Patrick, G. N. et al. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615–622 (1999).
Zheng, M., Leung, C. L. & Liem, R. K. Region-specific expression of cyclin-dependent kinase 5 (cdk5) and its activators, p35 and p39, in the developing and adult rat central nervous system. J. Neurobiol. 35, 141–159 (1998).
Le Moine, C. & Bloch, B. D1 and D2 dopamine receptor gene expression in the rat striatum: sensitive cRNA probes demonstrate prominent segregation of D1 and D2 mRNAs in distinct neuronal populations of the dorsal and ventral striatum. J. Comp. Neurol. 355, 418–426 (1995).
Lee, H. -K., Kameyama, K., Huganir, R. L. & Bear, M. F. NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. Neuron 21, 1151–1162 (1998).
Ouimet, C. C. Immunocytochemical localization of protein phosphatases and their inhibitors. Neuroprotocols 6, 84–90 (1995).
Horger, B. A. et al. Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor. J. Neurosci. 19, 4110–4122 (1999).
Taylor, J. R. & Horger, B. A. Enhanced responding for conditioned reward produced by intra-accumbens amphetamine is potentiated after cocaine sensitization. Psychopharmacology 142, 31–40 (1999).
Punch, L., Self, D., Nestler, E. J. & Taylor, J. R. Opposite modulation of opiate withdrawal behaviors on microinfusion of a protein kinase A inhibitor versus activator into the locus coeruleus or periaquiductal gray. J. Neurosci. 17, 8520–8527 (1997).
Surmeier, D. J., Bargas, J., Hemmings, H. C. Jr, Nairn, A. C. & Greengard, P. Modulation of calcium currents by a D1 dopaminergic protein kinase/phosphatase cascade in rat neostriatal neurons. Neuron 14, 385–397 (1995).
Hamill, O. P., Marty, A., Neher, E., Sakmann, B. & Sigworth, F. J. Improved patch-clamp techniques for high resolution current recording from cells and cell-free membrane patches. Pflüegers Arch. 391, 85–100 (1981).
Acknowledgements
We thank R. Liem for Cdk5 and p35 cDNA probes; L. Meijer for roscovitine and olomoucine; and R. L. Huganir for phospho-Ser845 GluR1 antibody. We also thank V. Phantharagnsy, V. Stewart and E. Griggs for technical assistance. This work was supported by a NARSAD young investigator award (to J.A.B.), a postdoctoral fellowship from Stiftelsen för Internationalisering av högre utbildning och forskning (to P.S.), and grants from the USPHS (J.R.T., E.J.N., G.L.S., A.C.N. and P.G.).
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Bibb, J., Chen, J., Taylor, J. et al. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 410, 376–380 (2001). https://doi.org/10.1038/35066591
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DOI: https://doi.org/10.1038/35066591
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