Dopamine and cyclic AMP-regulated phosphoprotein-32 phosphorylation pattern in cocaine and morphine-sensitized rats

This study reports some of the modifications in dopaminergic signaling that accompany cocaine and morphine behavioral sensitization. Cocaine-sensitized rats showed increased phosphorylation of dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa (DARPP-32) at threonine-75 (Thr75) and decreased DARPP-32 phosphorylation at Thr34, in the caudate-putamen (CPu) and nucleus accumbens (NAc), 7 days after sensitization assessment. However, in morphine-sensitized rats, no apparent modifications in DARPP-32 phosphorylation pattern were observed. Morphine-sensitized rats have increased binding and coupling of μ-opioid receptors and increased dopaminergic transmission in striatal areas and, upon morphine challenge, exhibit dopamine D1 receptor-dependent stereotypies. Thus, the DARPP-32 phosphorylation pattern was studied in morphine-sensitized rats at different times after morphine challenge. Morphine challenge increased levels of phospho-Thr75 DARPP-32 and decreased levels of phospho-Thr-34 DARPP-32 in a time-dependent manner in the CPu and NAc. In order to assess whether these modifications were related to modified PKA activity, the phosphorylation levels of two other PKA substrates were examined, the GluR1 and NR1 subunits of AMPA and NMDA receptors, respectively. The phosphorylation levels of GluR1 and NR1 subunits decreased in parallel with those of phospho-Thr-34 DARPP-32, thus supporting the hypothesis that morphine challenge elicited a decrease in PKA activity in morphine-sensitized rats.