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 the rat brain is the beta-1 subunit of the Na+/K(+)-ATPase pump. We examined 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 approximately 30% decrease in Na+/K(+)-ATPase activity. Western blot analyses demonstrated an approximately 25% decrease in levels of the beta-1 isoform, without changes in pump total alpha subunit levels. Treatment with dopamine type 1 or type 2 receptor agonists for the same period did not affect Na+/K(+)-ATPase activity. The serotonin-selective reuptake inhibitor paroxetine caused an approximately 45% decrease in rubidium uptake after 4 days, whereas pump function was not altered after treatment with either the dopamine-selective reuptake blocker nomifensine or the norepinephrine-selective reuptake blocker desipramine. Chronic treatment with both cocaine and LY 278,584, a serotonin type 3 receptor antagonist, did not replicate the cocaine-associated decrease in pump function. Long-term cocaine exposure regulates expression and function of the Na+/K(+)-ATPase pump in neuronal-like cells; this regulation is mediated in part via the serotonin type 3 receptor. Similar Na+/K(+)-ATPase pump regulation in vivo may selectively alter neuronal function in the mammalian brain.
Mackler
S A
SA
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia VAMC, USA.
Kleyman
T R
TR
Cha
X Y
XY
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects; D012701:Serotonin / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects* / Q000502:physiology
D003042:Cocaine; D018491:Dopamine Agonists; D018342:Receptors, Adrenergic, beta-1; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D000254:Sodium-Potassium-Exchanging ATPase