Knuepfer M M, Gan Q
Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, St. Louis, Missouri 63104, USA.
J Pharmacol Exp Ther. 1997 Nov;283(2):592-603.
Several agents may treat cocaine addiction and toxicity including bromocriptine, desipramine, GBR 12909 [1-(2-(bis(4-fluorphenyl)-methoxy)-ethyl)-4-(3-phenyl-propyl) piperazine], diazepam, buprenorphine and dizocilpine. In this study, we sought to determine whether these specific therapeutic agents alter cardiovascular responses to cocaine in conscious rats. Arterial pressure responses to cocaine (5 mg/kg, i.v.) were similar in all rats whereas cardiac output responses varied widely. In 26 of 33 rats (named vascular responders), cocaine induced a decrease in cardiac output of 8% or more. The remaining rats with little change or an increase in cardiac output were classified as mixed responders. Pretreatment with bromocriptine (0.1 mg/kg) or desipramine (1 mg/kg) increased cardiac output in mixed responders and increased systemic vascular resistance in vascular responders similar to the differential effects noted with cocaine. GBR 12909 (0.5-10 mg/kg) elicited a decrease in cardiac output at higher doses. Diazepam (0.1 and 0.5 mg/kg) had small, short-lasting effects on cardiovascular parameters. Buprenorphine (0.3 mg/kg) or the NMDA (N-methyl-D-aspartic acid) receptor antagonist, dizocilpine (0.05 mg/kg), increased arterial pressure, heart rate and cardiac output in vascular responders. Bromocriptine and desipramine prevented the difference in cardiac output responses in vascular and mixed responders by reducing the cocaine-induced decrease in cardiac output in vascular responders. Pretreatment with GBR 12909 (1 mg/kg) had little effect on cardiovascular responses to cocaine except to depress the increase in cardiac output noted in mixed responders. Buprenorphine selectively enhanced the increase in systemic vascular resistance whereas dizocilpine enhanced the pressor response. These data suggest that several treatment regimens for cocaine addiction alter the cardiovascular responses to cocaine and that dopamine D2 receptor activation may be necessary for the decrease in cardiac output noted in vascular responders.
几种药物可用于治疗可卡因成瘾及毒性，包括溴隐亭、地昔帕明、GBR 12909 [1-(2-(双(4-氟苯基)-甲氧基)-乙基)-4-(3-苯基丙基)哌嗪]、地西泮、丁丙诺啡和地佐环平。在本研究中，我们试图确定这些特定治疗药物是否会改变清醒大鼠对可卡因的心血管反应。所有大鼠对静脉注射可卡因（5 mg/kg）的动脉压反应相似，而心输出量反应差异很大。在33只大鼠中的26只（称为血管反应者），可卡因使心输出量降低8%或更多。其余心输出量变化很小或增加的大鼠被归类为混合反应者。用溴隐亭（0.1 mg/kg）或地昔帕明（1 mg/kg）预处理可增加混合反应者的心输出量，并增加血管反应者的全身血管阻力，类似于可卡因引起的不同效应。GBR 12909（0.5 - 10 mg/kg）在较高剂量时可使心输出量降低。地西泮（0.1和0.5 mg/kg）对心血管参数有小而短暂的影响。丁丙诺啡（0.3 mg/kg）或NMDA（N-甲基-D-天冬氨酸）受体拮抗剂地佐环平（0.05 mg/kg）可增加血管反应者的动脉压、心率和心输出量。溴隐亭和地昔帕明通过减少血管反应者中可卡因引起的心输出量降低，消除了血管反应者和混合反应者在心输出量反应上的差异。用GBR 12909（1 mg/kg）预处理对可卡因的心血管反应影响很小，只是抑制了混合反应者中的心输出量增加。丁丙诺啡选择性增强全身血管阻力的增加，而地佐环平增强升压反应。这些数据表明，几种治疗可卡因成瘾的方案会改变对可卡因的心血管反应，并且多巴胺D2受体激活可能是血管反应者中心输出量降低所必需的。
