Editors' ChoiceNeuroscience

Obstructing the Craving

Sci. Signal.  28 May 2013:
Vol. 6, Issue 277, pp. ec121
DOI: 10.1126/scisignal.2004370

One mechanism through which cocaine stimulates long-term changes in the central nervous system is by increasing dopamine- and serotonin-mediated transcription in postsynaptic neurons. Cocaine is highly addictive, and prolonged use induces neurotoxicity and neuronal cell death. Xu et al. found that cocaine induced the nitrosylation of GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and that the neuroprotective drug CGP3466B inhibited this cocaine-induced nitrosylation and reduced the transcriptional reprogramming and neurotoxic effects of cocaine in mice. Increased abundance of nitrosylated GAPDH correlated with decreased histone methylation and increased binding of the transcription factor CREB to the c-fos promoter, resulting in increased abundance of c-fos and Arc (activity-regulated cytoskeleton-associated protein), markers of neuronal activation. In contrast, either single or multiple doses at higher concentrations induced the acetylation and binding of p53 to the PUMA promoter and increased the abundance of the proapoptotic proteins PUMA and Bax. The cocaine-induced increases in transcriptional activity and protein abundance after either dosing regimen were decreased or abolished in mice deficient for neuronal nitric oxide synthase (nNOS). Similarly, these cocaine-induced effects on CREB-mediated transcription or p53-mediated transcription after either dosing regimen were absent in striatum of mice injected with a GAPDH mutant that cannot be nitrosylated. Mice treated with CGP3466B prevented the nitrosylation and nuclear translocation of GAPDH induced by either low or high doses of cocaine, and it reduced apoptosis in striatum exposed to high doses of cocaine. CGP3466B also prevented the histone demethylation and binding of CREB to the c-fos promoter, and acetylation and binding of p53 to the PUMA promoter, induced by low or high doses of cocaine, respectively. Treatment with CGP3466B reduced the locomotor stimulation of cocaine-treated mice without affecting basal locomotor activity. Furthermore, drug-seeking behavior of cocaine-addicted mice was reduced when the mice were treated with CGP3466B. The findings suggest that treating addicts with CGP3466B may be a therapeutic tool to block cocaine’s effects on the brain.

R. Xu, A.V. Serritella, T. Sen, J. M. Farook, T. W. Sedlak, J. Baraban, S. H. Snyder, N. Sen, Behavioral effects of cocaine mediated by nitric oxide-GAPDH transcriptional signaling. Neuron 78, 623–630 (2013). [Online Journal]