Du W, Aloyo V J, Pazdelski P S, Harvey J A
Department of Pharmacology, MCP Hahnemann University, Philadelphia, PA 19129, USA.
Brain Res. 1999 Jul 31;836(1-2):194-8. doi: 10.1016/s0006-8993(99)01567-x.
Acute amphetamine (AMPH) challenge has been used to probe the neurochemical and behavioral integrity of dopaminergic neurons under various conditions including prenatal cocaine exposure. In this study, we employed in vivo microdialysis to examine the effects of prenatal cocaine exposure on AMPH-induced dopamine (DA) release in the caudate nucleus of the awake adult rabbit. Pregnant rabbits were given intravenous injections of either saline or cocaine (4 mg/kg) twice a day from gestational day 8 (G8) through G29. Microdialysis was performed in adult saline and cocaine progeny at approximately postnatal day 70 (P70). There were no significant differences between cocaine and saline progeny in their basal concentrations of DA or its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). AMPH (5 mg/kg, i.v.) significantly increased extracellular DA in the caudate of both groups. However, AMPH-induced DA release was 2 to 3-fold greater in cocaine progeny than in the saline controls. Although, DOPAC decreased in both groups following AMPH injection, there was no significant group effect. In addition, there were no significant changes in concentrations of HVA. AMPH is known to release DA by a mechanism of exchange diffusion via the presynaptic DA transporter (DAT). Therefore, we examined the binding of [(3)H]WIN 35,428 to membrane fractions prepared from fresh caudate tissue to determine whether prenatal exposure to cocaine had altered the density (B(max)) or affinity (K(d)) of the DAT. While the B(max) for [(3)H]WIN 35,428 binding increased 3-fold between P3 and P120, there were no significant differences between saline and cocaine progeny at any age examined. The K(d) for [(3)H]WIN 35,428 binding did not change with postnatal age and did not differ between cocaine and saline progeny. These findings suggest that prenatal exposure to cocaine produces a long-term increase in the size of the presynaptic, AMPH releasable, cytoplasmic pool of DA.
急性苯丙胺（AMPH）激发试验已被用于探究在包括产前可卡因暴露在内的各种条件下多巴胺能神经元的神经化学和行为完整性。在本研究中，我们采用体内微透析技术来检测产前可卡因暴露对成年清醒兔尾状核中AMPH诱导的多巴胺（DA）释放的影响。从妊娠第8天（G8）至第29天，每天给怀孕兔子静脉注射生理盐水或可卡因（4 mg/kg）两次。在出生后约70天（P70）对成年期的生理盐水组和可卡因组后代进行微透析。可卡因组后代和生理盐水组后代在DA及其代谢产物3,4-二羟基苯乙酸（DOPAC）和高香草酸（HVA）的基础浓度上没有显著差异。AMPH（5 mg/kg，静脉注射）显著增加了两组尾状核中的细胞外DA水平。然而，可卡因组后代中AMPH诱导的DA释放比生理盐水对照组高2至3倍。虽然注射AMPH后两组的DOPAC均降低，但没有显著的组间效应。此外，HVA的浓度没有显著变化。已知AMPH通过经由突触前DA转运体（DAT）的交换扩散机制释放DA。因此，我们检测了[(3)H]WIN 35,428与从新鲜尾状核组织制备的膜组分的结合情况，以确定产前可卡因暴露是否改变了DAT的密度（B(max)）或亲和力（K(d)）。虽然[(3)H]WIN 35,428结合的B(max)在出生后第3天至第120天之间增加了3倍，但在任何检测年龄，生理盐水组和可卡因组后代之间均无显著差异。[(3)H]WIN 35,428结合的K(d)不随出生后年龄变化，且在可卡因组后代和生理盐水组后代之间没有差异。这些发现表明，产前可卡因暴露会使突触前、AMPH可释放的DA细胞质池的大小长期增加。
