REGULATION OF THE NA+ K+-ATPASE PUMP IN-VITRO AFTER LONG-TERM EXPOSURE TO COCAINE - ROLE OF SEROTONIN/

Long-term exposure to cocaine can cause persistent behavioral changes and alterations in neuronal function. One cocaine-regulated mRNA in th e rat brain is the beta-1 subunit of the Na+/K+-ATPase pump. We examin ed both Na+/K+-ATPase function and expression after cocaine treatment of pheochromocytoma cells. One-hour exposure to cocaine did not alter Na+/K+-ATPase activity, as measured by the ouabain-sensitive component of rubidium uptake. Four days of cocaine resulted in an similar to 30 % decrease in Na+/K+-ATPase activity. Western blot analyses demonstrat ed an similar to 25% decrease in levels of the beta-1 isoform, without changes in pump total alpha subunit levels. Treatment with dopamine t ype 1 or type 2 receptor agonists for the same period did not affect N a+/K+-ATPase activity. The serotonin-selective reuptake inhibitor paro xetine caused an similar to 45% decrease in rubidium uptake after 4 da ys, whereas pump function was not altered after treatment with either the dopamine-selective reuptake blocker nomifensine or the norepinephr ine-selective reuptake blocker desipramine. Chronic treatment with bot h cocaine and LY 278,584, a serotonin type 3 receptor antagonist, did not replicate the cocaine-associated decrease in pump function. Long-t erm cocaine exposure regulates expression and function of the Na+/K+-A TPase pump in neuronal-like cells; this regulation is mediated in part via the serotonin type 3 receptor. Similar Na+/K+-ATPase pump regulat ion in vivo may selectively alter neuronal function in the mammalian b rain.