A second-generation vaccine protects against the psychoactive effects of cocaine

The effects of immunization with the second-generation cocaine immunoconjugate GND-keyhole limpet hemocyanin (KLH) or with the anti-cocaine mAb GNC92H2 were assessed in a model of acute cocaine-induced locomotor activity. After i.p. administration of cocaine⋅HCl (15 mg/kg), rats were tested in photocell cages, and stereotypy was rated to determine preimmunization drug response (baseline). Experimental animals were subjected to an immunization protocol with GND-KLH or treated with the mAb GNC92H2. Rats were then challenged with systemic cocaine, and their locomotor responses were again measured. Active immunization with GND-KLH produced a 76% decrease in the ambulatory measure (crossovers) in the experimental group and a 12% increase in the control group compared with baseline values. Also, stereotypic behavior was significantly suppressed in the vaccinated animals. Decreases in both measures were seen in the experimental group on two subsequent challenges. The maximum effect was observed at the time of the second challenge with a dramatic 80% decrease in crossovers. Treatment with GNC92H2 resulted in a 69% decrease in crossovers compared with baseline. This effect persisted across two additional challenges over 11 days with decreases of 46–47%. In contrast, the control group showed increases of up to 28%. Significant differences between groups were observed in the stereotypic measure in all three challenges. The results indicate that these immunopharmacotherapeutic agents have significant cocaine-blockade potential and therefore may offer an effective strategy for the treatment of cocaine abuse.

本研究在可卡因急性诱导的运动活动模型中，评估了第二代可卡因免疫偶联物GND-钥孔戚血蓝蛋白（KLH）与抗可卡因单克隆抗体（mAb）GNC92H2的干预效应。向大鼠腹腔注射（i.p.）可卡因盐酸盐（15 mg/kg）后，将其置于光电池笼中开展行为学测试，并通过评分量化刻板行为，以确定免疫前的药物反应基线水平。实验动物接受GND-KLH免疫接种方案，或接受mAb GNC92H2处理。随后通过全身给药给予大鼠可卡因刺激，并再次检测其运动活动反应。与基线水平相比，GND-KLH主动免疫组的跨格数（自主活动量化指标）下降76%，而对照组则上升12%。此外，免疫接种大鼠的刻板行为也得到显著抑制。在后续两次可卡因给药刺激中，实验组两项指标均出现下降；其中第二次刺激时干预效果最为显著，跨格数大幅下降80%。GNC92H2处理组的跨格数较基线下降69%，该效应在11天内的两次追加刺激中持续存在，跨格数下降幅度为46%~47%。与之相反，对照组的跨格数最高上升28%。在三次给药刺激的刻板行为量化指标中，各组间均存在显著差异。本研究结果表明，上述两种免疫药物治疗制剂均具备显著的可卡因阻断潜力，有望为可卡因滥用的临床治疗提供有效策略。