Shoji S, Simms D, Yamada K, Gallagher J P
Department of Pharmacology and Toxicology, University of Texas Medical Branch at Galveston, USA.
J Pharmacol Exp Ther. 1998 Jul;286(1):509-18.
Previous reports of membrane hyperpolarizations, associated with acute application of cocaine, have been recorded from brain slice preparations containing aminergic nuclei and have always been attributed to cocaine's ability to elevate levels of local biogenic amines followed by activation of their receptors. The majority of these studies were conducted with brain slices obtained from rats that had not received prior chronic in vivo treatment with cocaine. We observed that cocaine alone, at 3 microM, could induce a membrane hyperpolarization (COC-HYP) in 100% of rat dorsolateral septal nucleus (DLSN) neurons from brain slices of rats treated chronically with cocaine for either 14 or 28 days in vivo. The DLSN is a nucleus absent of biogenic amine cell bodies, but does contain biogenic amine terminals with GABAergic cell bodies and terminals. Cocaine applied to brain slices from rats not previously administered cocaine or administered cocaine for up to seven days in vivo yielded a maximum incidence of COC-HYPs at only 50%. COC-HYPs recorded from DLSN neurons were not blocked by previous treatment with amine receptor antagonists or by a TTX and zero calcium medium. Based on these results, the ability of DLSN neurons to respond to a cocaine challenge with a COC-HYP did not involve inhibition of amine reuptake/uptake or action potential release of neuroactive substances. Rather, the COC-HYP, with an apparent reversal potential of -80 mV, was reduced by the GABA receptor antagonists-bicuculline and CGP-55845A. Lowering extracellular Na+ or Cl-, lowering of temperature, or previous superfusion with the GABA uptake blocker NO-711 could block the COC-HYP. In summary, our data suggest that COC-HYPs, after application of a cocaine challenge to brain slices from rats treated chronically (14-28 days, but not acutely, 7 days) with cocaine are due to cocaine-induced changes in GABA release and/or transporter function. The latter changes in transporter function may involve the reversal of the GABA transporter with release of GABA and subsequent activation of postsynaptic GABAA and GABAB receptors.
先前关于与急性应用可卡因相关的膜超极化的报道，是在含有胺能核的脑片制备中记录到的，并且一直归因于可卡因提高局部生物胺水平并随后激活其受体的能力。这些研究大多是用从未接受过可卡因慢性体内治疗的大鼠的脑片进行的。我们观察到，在体内用可卡因慢性治疗14天或28天的大鼠脑片中，单独使用3 microM的可卡因可在100%的大鼠背外侧隔核（DLSN）神经元中诱导膜超极化（COC-HYP）。DLSN是一个没有生物胺细胞体的核，但确实含有具有GABA能细胞体和终末的生物胺终末。应用于未预先给予可卡因或在体内给予可卡因长达7天的大鼠脑片的可卡因，仅在50%时产生COC-HYPs的最大发生率。从DLSN神经元记录到的COC-HYPs不受先前用胺受体拮抗剂治疗或用TTX和零钙培养基治疗的阻断。基于这些结果，DLSN神经元对可卡因刺激产生COC-HYP的能力不涉及胺再摄取/摄取的抑制或神经活性物质的动作电位释放。相反，COC-HYP的表观反转电位为-80 mV，被GABA受体拮抗剂荷包牡丹碱和CGP-55845A降低。降低细胞外Na+或Cl-、降低温度或先前用GABA摄取阻断剂NO-711灌注可阻断COC-HYP。总之，我们的数据表明，在用可卡因慢性（14 - 28天，但不是急性，7天）治疗的大鼠脑片中应用可卡因刺激后，COC-HYPs是由于可卡因诱导的GABA释放和/或转运体功能变化所致。转运体功能的后者变化可能涉及GABA转运体的反转，伴有GABA释放以及随后突触后GABAA和GABAB受体的激活。
