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

在大鼠慢性可卡因处理20天后，用腹腔或侧脑室注射的方法，观察Gi蛋白在多巴胺D2受体拮抗剂SCH23390和主要的多巴胺D2受体拮抗剂氟哌啶醇诱发的触觉反应中的作用。在小鼠和静脉注射中。百日咳毒素(PTH)或霍乱毒素(CTX)，分别催化Gi蛋白和Gs蛋白的二磷酸腺苷(ADP)核糖化。在用可卡因、氟哌啶醇(0.1 mg/kg ip)长期处理的大鼠中，SCH23390(0.1 mg/kg ip)对小鼠的触觉反应有增强作用。在最后一次注射可卡因后20天给药，在第1天产生减弱的反应，并转变为超常反应。PTX治疗1d后，SCH23390致敏反应(Di受体超敏反应)减弱，而增强的氟哌啶醇致敏反应进一步增强。The…在PTX后20天，SCH23390和氟哌啶醇诱导的更多增强的触觉反应进一步增强(0.1iota g，i.c.v。在大鼠体内，1IOTA静脉注射。小鼠)和最后一次可卡因治疗。在Gs蛋白的ADP核糖化方面，CTX(0.1，1ota g，i.c.v)增强了SCH23390的增强作用，但不影响氟哌啶醇的增强作用。大鼠，静脉注射1010g/kg。在小鼠中)，其本身不受影响。这些结果表明，在慢性可卡因治疗的长期戒断期间，突触后D_1和D_2受体的亚敏感性(SCH23390加重)可能与CTX敏感的Gs和PTX敏感的Gi蛋白ADP核糖化或Gi蛋白ADP核糖化有关。非典型抗精神病药氯氮平或利培酮可剂量依赖性地增强慢性可卡因治疗20天后出现的SCH23390偏瘫，但氯氮平+可卡因可拮抗氯氮平和利培酮的作用。相比之下，慢性联合应用可卡因+利培酮20天后出现的SCH23390惊厥加重程度与单独使用慢性可卡因后相似。在强迫游泳实验中，慢性可卡因治疗后1~7天抑制小鼠的不动反应，但在20天后激活。氯氮平+可卡因的慢性治疗对抗了单独使用慢性可卡因20天后增强的不动反应。多巴胺拮抗剂引起的惊厥反应增强与慢性可卡因治疗20天后强迫游泳试验中的不动增强有关。较少

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