Ward B O, Stephens D N
Laboratory of Experimental Psychology, University of Sussex, Falmer, Brighton, UK.
Psychopharmacology (Berl). 1998 Feb;135(4):342-52. doi: 10.1007/s002130050521.
Three experiments examined the effect of either withdrawal from diazepam, or repeated treatment with the convulsant, pentylenetetrazol (PTZ), on behaviour and seizure threshold. The behaviours measured were on the elevated plus maze and in the four-plate test; seizure threshold was measured as dose of PTZ infused via the tail vein to the first clonic twitch. In experiment 1, we examined the effect of either single or repeated withdrawal from diazepam using a procedure in which the drug was administered SC in a slow release depot. Three cycles of withdrawal from diazepam were compared to a single withdrawal experience. A single withdrawal from diazepam following chronic treatment gave rise, 72 h following the last dosing, to behavioural changes, suggestive of anxiety, in both tests, but did not result in a reduced convulsant threshold. In contrast, repeated withdrawal resulted in a reduction in sensitivity in several measures of anxiety, but sensitised the mice to the convulsive effects of the PTZ. The unexpected failure to find an increased sensitivity to a convulsive agent following a single withdrawal from SC diazepam was examined in experiment 2. The seizure threshold following a single withdrawal of mice which had received diazepam chronically IP in aqueous vehicle was significantly reduced relative to vehicle-treated controls, whereas that of animals receiving the same dose SC in oil, was not. It is argued that the difference may arise from the animals treated repeatedly with IP diazepam unintentionally experiencing repeated withdrawal, since the half-life of the drug by this route is short. In experiment 3, repeated sub-convulsant PTZ treatment reduced the convulsant threshold (the dose of PTZ required to give rise to the first clonic twitch), but had no significant effect on the behavioural measures of anxiety compared to a single dose of PTZ or vehicle controls. The results suggest that repeated withdrawal from chronic treatments with diazepam sensitises mice to convulsant stimuli in a manner resembling the effects of repeated administration of sub-convulsant doses of PTZ, but that neither repeated PTZ nor repeated diazepam withdrawal results in increased sensitivity to anxiogenic stimuli; rather, repeated withdrawal from diazepam may reduce the susceptibility of mice to behavioural measures of anxiety.
三项实验研究了地西泮戒断或用惊厥剂戊四氮（PTZ）反复治疗对行为和惊厥阈值的影响。所测量的行为包括高架十字迷宫实验和四板实验中的行为；惊厥阈值通过经尾静脉注射PTZ至首次阵挛抽搐的剂量来衡量。在实验1中，我们采用药物以缓释剂型皮下注射的程序，研究了单次或反复地西泮戒断的影响。将三个周期的地西泮戒断与单次戒断经历进行了比较。慢性治疗后单次地西泮戒断，在末次给药72小时后，在两项实验中均引起了提示焦虑的行为变化，但并未导致惊厥阈值降低。相比之下，反复戒断导致在几种焦虑测量指标上敏感性降低，但使小鼠对PTZ的惊厥作用敏感化。在实验2中，研究了单次皮下注射地西泮戒断后未发现对惊厥剂敏感性增加这一意外结果。相对于溶剂处理的对照组，长期腹腔注射地西泮水溶液后单次戒断的小鼠惊厥阈值显著降低，而接受相同剂量油剂皮下注射的动物则未出现这种情况。有人认为，这种差异可能源于反复腹腔注射地西泮的动物无意中经历了反复戒断，因为该途径给药药物的半衰期较短。在实验3中，反复给予亚惊厥剂量的PTZ治疗降低了惊厥阈值（引发首次阵挛抽搐所需的PTZ剂量），但与单次剂量的PTZ或溶剂对照组相比，对焦虑的行为测量指标没有显著影响。结果表明，慢性地西泮治疗后反复戒断使小鼠对惊厥刺激敏感化，其方式类似于反复给予亚惊厥剂量的PTZ的效果，但反复给予PTZ或反复地西泮戒断均未导致对致焦虑刺激的敏感性增加；相反，反复地西泮戒断可能会降低小鼠对焦虑行为测量指标的易感性。
