Behavioral expression of cocaine sensitization in rats is accompanied by a distinct pattern of modifications in the PKA/DARPP-32 signaling pathway

Department of Neuroscience, Pharmacology Unit, University of Siena, Siena, Italy.
Journal of Neurochemistry (Impact Factor: 4.28). 12/2007; 103(3):1168-83. DOI: 10.1111/j.1471-4159.2007.04818.x
Source: PubMed


Repeated cocaine administration induces behavioral sensitization and modifications in the phosphorylation pattern of dopamine and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32), characterized by a tonic increase in the Thr75 phosphorylated form, and a decrease in the Thr34 phosphorylated form. This study further investigated the correlations between cocaine sensitization and modifications in the DARPP-32 phosphorylation pattern, cAMP-dependent protein kinase (PKA) activity, and mGluR5 tone in the medial prefrontal cortex and nucleus accumbens. Behavioral sensitization and modifications in these neurochemical markers followed a similar temporal pattern. Moreover, in sensitized rats acute cocaine administration modified phosphorylation levels of Thr75- and Thr34-DARPP-32, GluR1, and NR1 subunits in the nucleus accumbens only at a dose double the efficacious dose in control rats. These results suggest that the high levels of phospho-Thr75 DARPP-32 maintain PKA in a prevalent inhibited state. Furthermore, in sensitized rats the acute administration of 6-methyl-2-(phenylethynyl)-pyridine, a mGluR5 antagonist, reinstated the phosphorylation levels of Thr75- and Thr34-DARPP-32, GluR1, and NR1 to control values, and a subsequent cocaine challenge did not elicit a sensitized response. These data suggest that a tonic increase in mGluR5 transmission in cocaine-sensitized rats sustains both the increase in phospho-Thr75 DARPP-32 levels and the expression of behavioral sensitization.

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Available from: Alessandro Tagliamonte, Mar 04, 2015
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    • "After the habituation period, the rats received saline or cocaine and were immediately returned to the locomotor activity cage. Based on the protocol of Scheggi et al. (22), the locomotor activity of rats was monitored for 30 min, and locomotion counts were registered every 10 min. "
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    • "Tissues were flash-frozen in liquid nitrogen and stored at −80 • C until assayed. Immunoblotting was performed as previously described (Scheggi et al., 2007; Danielli et al., "
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    • "Imi treatment would restore to control values the DARPP-32 phosphorylation pattern and Cdk5 levels in the NAcS and mPFC that are modified in CS rats (Scheggi et al. 2004, 2007). Moreover, the possible effect of Y-maze exposure on these variables was also examined (rats from expt 2B). "
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