In vivo regulation of central nervous system progesterone receptors: Cocaine induces steroid-dependent behavior through dopamine transporter modulation of D5 receptors in rats

To characterize the membrane pathway by which the cocaine-sensitive dopamine transporter (DAT) modulates progesterone receptor activation, steroid-dependent behavior lordosis was used in estrogen-primed ovariectomized Sprague-Dawley rats with stereotaxic implanted third ventricle cannulas. Lordosis in response to solicitous males was observed in females after intercerebral ventricular administration of DAT antagonists WIN35,428 (80 ng) and cocaine (0.016-1.6 mu g). Significantly, antisense oligonucleotides (AS) to DAT mRNA also induced reproductive behavior. In contrast, the D1-D2 receptor membrane-repopulation inhibitor N-ethoxycarbonyl-2 ethoxy-1,2-dihydroquinoline and the D1-like antagonist SCH23390 blocked cocaine-inducible behavior. Further, facilitation of behavior by AS to the DAT was suppressed by N-ethoxycarbonyl-2 ethoxy-1,2-dihydroquinoline. Behavior was not dependent on D2 receptors, since animals pretreated with the D2 antagonist sulpride displayed lordosis after cocaine challenge. Antisense oligonucleotides to D5 but not D1 dopamine receptor mRNA suppressed reproductive behavior associated with cocaine. Microinjections of cocaine to the ventromedial nucleus (VMN) but not arcuate nucleus or preoptic area potentiated lordosis, suggesting the functional presence of DAT in the VMN. Finally, cocaine facilitation of behavior was blocked by both antiprogestin RU486 and progesterone receptor AS microinjected into either the third ventricle or the VMN. Collectively, the data provide strong evidence for cocaine modulation of reproductive behavior through presynaptic cocaine-sensitive dopamine transporters and postsynaptic D5 dopamine receptor mediation of progesterone receptor-dependent behavior in rat central nervous system.