Dopamine D1 receptor-dependent modifications in the dopamine and cAMP-regulated phosphoprotein of Mr 32 kDa phosphorylation pattern in striatal areas of morphine-sensitized rats

This study focused on morphine sensitization as a model of latent, functionally inducible increase in dopamine D1 receptor mediated transmission, which may be unmasked by an external stimulus. In fact, morphine-sensitized rats present stereotypies upon morphine challenge and resilience to unavoidable stress-induced behavioral deficits, and both these behavioral phenomena are dopamine D1 receptor-dependent. The tonic increase in D1 dopaminergic transmission is counter-adaptive to the enhanced μ-opioid receptor-dependent signaling in striatal areas. The dopamine and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32) phosphorylation pattern is not modified in the striatal areas of sensitized rats. Acute morphine administration induced an early increase and delayed decrease in phospho-Thr34 DARPP-32 levels accompanied by a delayed increase in phospho-Thr75 DARPP-32 levels in the nucleus accumbens and caudate-putamen of sensitized rats, while it had no effects in control animals. In sensitized rats the administration of a selective dopamine D1 receptor antagonist (SCH 23390) just before morphine challenge prevented the occurrence of stereotypies and the entire sequence of neurochemical modifications. The administration of a selective mGluR5 antagonist (MPEP) one hour after morphine challenge prevented the delayed phosphorylation changes. MPEP administered before the challenge did not antagonize the behavioral nor the neurochemical effects of acutely injected morphine. Moreover, influence of unavoidable stress on the DARPP-32 phosphorylation pattern in the caudate-putamen of sensitized rats was studied. The stress-induced modifications, and their sensitivity to receptor antagonists, were similar to the delayed modifications observed after morphine administration. The modifications in DARPP-32 phosphorylation pattern and their sensitivity to receptor antagonists observed in sensitized rats after morphine challenge or unavoidable stress exposure appeared to be intriguingly similar to those previously observed in rats after a palatable meal. In conclusion, these results suggest that in particular conditions an increase in dopamine output in striatal areas is followed by a general neurochemical pattern, in which an initial increase in dopamine D1 receptor-sustained PKA activation triggers a sequence of events that leads to an mGluR5-mediated increase in phospho-Thr75 DARPP-32 levels and the consequent decrease in PKA activity.