Development of behavioral tolerance and reverse tolerance during withdrawal periods after chronic psychostimulant treatment

用多巴胺间接激动剂可卡因和甲基苯丙胺长期处理小鼠，在戒断早期引起D_1受体的超敏感性（SCH 23390僵住症减少）和D_2受体的亚敏感性（氟哌啶醇僵住症增加）。可卡因暴露后，对SCH 23390的僵直反应减弱，这可能是多巴胺D_1受体超敏感性的发展，与可卡因致敏性的发展相对应。可卡因暴露后氟哌啶醇性僵住症的增加可能代表多巴胺D_2受体的亚敏感状态，这与可卡因耐受的发展相对应。提示D_1受体可能主要参与精神兴奋药的致敏作用，在人中表现为精神兴奋药所致的精神病和精神分裂症样症状。慢性可卡因预处理可引起D_1受体亚敏感性（SCH-23390浓度增加，D_1受体亚敏感性增加），而D_1受体亚敏感性（SCH-23390浓度增加，D_1受体亚敏感性增加）。 ...更多信息 （一）长期停药后。可卡因预处理时间越长，剂量越大，对多巴胺D_1受体拮抗剂的初始反应的改变越小，而对后续反应的改变越大。SCH 23390或氟哌啶醇合用可防止在停药早期引起的D_1受体超敏和D_2受体亚敏。而长期停药期多巴胺D_1受体的亚敏感效应则因合用SCH-23390或氟哌啶醇而加重，提示多巴胺D_1或D_2受体拮抗剂在停药期不能作为有效的抗精神病药物。此外，单独用百日咳毒素预处理可抑制慢性可卡因对SCH 23390小鼠僵直症的抑制作用，而增强其对氟哌啶醇僵直症的增强作用。百日咳毒素可催化G_i蛋白的ADP-核糖基化。这些结果提示，在戒断早期，D_2受体亚敏感性与Gi蛋白ADP核糖基化之间可能存在相互关系，而D_1受体超敏感性与Gi蛋白ADP核糖基化无关。少

Chronic treatment with the indirect dopamine agonists cocaine and methamphetamine, caused supersinsitivity of D_1 receptors (decrease of SCH23390 catalepsy) and subsensitivity of D_2 receptors (increase of haloperidol catalepsy) during the early withdrawal period in mice. This decrease in cataleptic response to SCH23390 after exposure to cocaine could be interpreted as development of supersensitivity of dopamine D_1 receptors, which corresponds to the development of sensitization to cocaine. The increase in haloperidol catalepsy after exposure to cocaine may represent a state of subsensitivity of dopamine D_2 receptors, which corresponds with the development of tolerance to cocaine. This would indicate that the D_1 receptor may be mainly involved in psychostimulant-induced sensitization, which in man is manifested as psychostimulant-induced psychosis and schizophrenia-like symptoms. The chronic cocaine pretreatment caused sub-sensitivity of D_1 receptors (an increase in SCH-23390 catal … More epsy) after a longer period of withdrawal. It was apparent that the longer the period and the higher the dose of pretreatment with cocaine, the less were the alterations in initial responses and the greater were the alterations in subsequent responses to the dopamine D_1 receptor antagonists. Coadministration of either SCH23390 or haloperidol prevented the development of D_1 receptor supersinsitivity and D_2 receptor subsensitivity induced during early with- drawal periods. However, the subsensitive effect of dopamine D_1 receptors during long-term withdrawal period was rather aggravated by coadministration of SCH-23390 or haloperidol, suggesting that dopamine D_1 or D_2 receptor antagonist is not effective as an antipsychotic drug in the withdrawal periods. Furthermore, the decreasing effect of chronic cocaine on SCH23390 catalepsy was inhibited by a single pretreatment with pertussis toxin which catalyze ADP-ribosylation of G_i-proteins, whereas the increasing effect of that on haloperidol catalepsy was enhanced. These results suggest that there may be an interrelationship between D_2 receptor subsensitivity, but not D_1 receptor supersensitivity and, during early withdrawal periods and Gi-protein ADP-ribosylation. Less