The striatum is believed to be a crucial brain region associated with drug reward. Adaptive alteration of neurochemistry in this area might be one potential mechanism underlying drug dependence. It has been proposed that the dysfunction of Na+,K+-ATPase function is involved in morphine tolerance and dependence. The present study, therefore, was undertaken to study the adaptation of the striatal Na+,K+-ATPase activity in response to morphine treatment. The results demonstrated that in vivo short-term morphine treatment stimulated Na+,K+-ATPase activity in a dose-dependent manner. This action could be significantly inhibited by D2-like dopamine receptor antagonist S(-)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxybenzamine (eticlopride). Contrary to shortterm morphine treatment, long-term morphine treatment significantly suppressed Na+,K+-ATPase activity. This effect could be significantly inhibited by D(1)-like dopamine receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390). However, both short-term and long-term morphine treatment-induced changes in Na+,K+-ATPase activity could be reversed by opioid receptor antagonist naltrexone. It was further found that cAMP-dependent protein kinase (PKA) was crucially involved in regulating Na+,K+-ATPase activity by morphine. Different regulation of the phosphorylation levels of the alpha3 subunit of Na+,K+-ATPase by PKA was related to the distinct modulations of Na+,K+-ATPase by short-term and long-term morphine treatment. Short-term morphine treatment inhibited PKA activity and then decreased the phosphorylation of Na+,K+-ATPase, leading to increase in enzyme activity. These effects were sensitive to eticlopride or naltrexone. Conversely, long-term morphine treatment stimulated PKA activity and then increased the phosphorylation of Na+,K+-ATPase, leading to the reduction of enzyme activity. These effects were sensitive to SCH 23390 or naltrexone. These findings demonstrate that dopamine receptors are involved in regulation of Na+,K+-ATPase activity after activation of opioid receptors by morphine.