Behavioral inhibition during long-term withdrawal peridos from chronic cocaine treatment

通过腹腔或脑室内注射（小鼠腹腔注射，大鼠脑室注射）分别催化二磷酸腺苷（ADP）核糖基化的百日咳毒素（PTh）或霍乱毒素（CTX），研究gi -蛋白对慢性可卡因治疗后20天大鼠多巴胺二受体拮抗剂SCH23390和主要多巴胺D2受体拮抗剂氟哌啶醇诱导的催化反应的作用。在长期接受可卡因预处理的大鼠中，氟哌啶醇（0.1 mg/kg i.p.）发挥了增强的催化反应，但SCH23390 （0.1 mg/kg i.p.）在第1天产生了减弱的反应，并在最后一次可卡因注射后20天转化为超常反应。慢性可卡因治疗后1天，减弱的SCH23390催化反应（Di受体超敏感）在PTX治疗后1天被逆转，而增强的氟哌啶醇催化反应进一步增强。经PTX（大鼠0.1 IOTA g, i.c.v.，小鼠1 IOTA i.c.v.）和末次可卡因治疗后20天，SCH23390和氟哌啶醇诱导的催化反应进一步增强。对于gs -蛋白的ADP-核糖基化，CTX（大鼠0.1,IOTA g, i.c.v.，小鼠10 IOTA g/kg i.c.v.）对SCH23390猝睡的增强作用有增强作用，但对氟哌啶醇猝睡的增强作用不受影响，其本身不受影响。这些结果表明，在长期可卡因戒断期间，突触后D_1和d2受体的亚敏感性（SCH23390猝死性增加）可能涉及ctx敏感的Gs-和ptx敏感的Gi-蛋白adp -核糖基化，或Gi蛋白adp -核糖基化。慢性可卡因治疗20天后，单次给药氯氮平或非典型抗精神病药利培酮以剂量依赖的方式增强了SCH23390的猝厥，但在慢性氯氮平+可卡因预处理的动物中被拮抗。相比之下，长期联合使用可卡因+利培酮治疗前20天的SCH23390猝厥症状的增强程度与单独使用慢性可卡因治疗后相似。慢性可卡因单独给药后1 ~ 7 d的强迫游泳试验中，固定不动反应被慢性可卡因抑制，20 d后被激活。氯氮平+可卡因慢性治疗可拮抗单独使用慢性可卡因后20天出现的增强的不动反应。在慢性可卡因治疗后20天的强迫游泳试验中，多巴胺拮抗剂诱导的催化反应增加与活动能力增强之间存在关系。少

The role of Gi-proteins on cataleptic responses induced by SCH23390, a dopamine Di receptor antagonist, and haloperidol, a mainly dopamine D2 receptor antagonist, 20 days after chronic cocaine treatment in rats was examined by intraperitoneal or intracerebroventriculor injection (i.p. in mice and i.c.v. in rats) of pertussis toxin (PTh) or cholera toxin (CTX), which catalyzes adenosine diphosphate (ADP)-ribosylation of Gi-proteins and Gs-proteins, respectively. In rats pretreated chronically with cocaine, haloperidol (0.1 mg/kg i.p.) exerted an enhanced cataleptic response, but SCH23390 (0.1 mg/kg i.p.) produced an attenuated response at 1 day, which converted to a supernormal response, when it was administered 20 days after the last cocaine injection. The attenuated SCH23390 cataleptic response (Di receptor supersensitivity induced one day after chronic cocaine treatment), was reversed one day after PTX treatment, whereas the enhanced haloperidol catalepsy was further potentiated. The … More enhanced cataleptic responses induced by SCH23390 and haloperidol were further potentiated 20 days after PTX (0.1 IOTA g, i.c.v. in rats, and 1 IOTA i.v. in mice) and last cocaine treatment. Regarding ADP- ribosylation of Gs-protein, the enhancing effect of SCH23390 catalepsy was potentiated, but that of haloperidol catalepsy was not affected, by CTX (0.1 , IOTA g, i.c.v. in rats, and 10 IOTA g/kg i.v. in mice), which by itself was not affected. These' results suggest that the subsensitivity of postsynaptic D_1 and D_2 receptors (increased SCH23390 catalepsy) seen during long-term withdrawal periods from chronic cocaine treatment, may involve both CTX-sensitive Gs- and PTX-sensitive Gi-protein ADP-ribosylations, or Gi protein ADP-ribosylation. The enhanced SCH23390 catalepsy seen 20 days after chronic cocaine treatment was potentiated by a single administration of clozapine or risperidone, atypical neuroleptic, in dose dependent manner, but was antagonized in animals pretreated chronically with clozapine + cocaine. In contrast, the degree of enhanced SCH23390 catalepsy seen 20 days after pretreatment chronically with a combination of cocaine + risperidone was similar to that seen after chronic cocaine alone. Chronic cocaine treatment inhibited the immobility response in the forced swimming test' 1-7 days after the chronic cocaine alone, but activated 20 days later. Chronic treatment with clozapine + cocaine antagonized the enhanced immobility response seen 20 days after chronic cocaine alone. There is a relationship between the increased cataleptic responses induced by dopamine antagonists and the enhanced immobility in the forced swimming test 20 days after chronic cocaine treatment. Less