Evenden John
Department of Neuroscience, CNS Discovery, AstraZeneca R&D Wilmington, 1800 Concord Pike, Wilmington, DE 19850, USA.
Psychopharmacology (Berl). 2002 Oct;163(3-4):381-90. doi: 10.1007/s00213-002-1184-1. Epub 2002 Aug 29.
Psychosis and psychotomimetic drugs result in a disorganisation of the structure of thought and behaviour. Normalising these is one of the objects of antipsychotic therapy, and methods for predicting such a therapeutic effect would be of value.
The effects of a number of psychotomimetic agents were examined on the way in which rats distributed responding over two response levers using two different procedures, to assay their effects on behavioural organisation. Previously, amphetamine has been found to increase response switching using these schedules.
In the first, the random reinforcement procedure, one of the two levers was selected at random as "correct", and responses on this lever were reinforced with food under a random ratio schedule. No signal was given to distinguish the levers. Responding could also result in the food tray being illuminated, but no food pellet was delivered ("no-food" event). Responses on the second lever ("incorrect") had no programmed consequences. After each food delivery or "no-food" event the levers designated as "correct" and "incorrect" were reassigned at random, and the rat had to open the food tray to restart the schedule. In the second procedure, the rats were required to make 21 responses before a switch between the two levers resulted in food delivery [Fixed Ratio (FR) 21-switch]. The responses making up the FR could be distributed freely between the two levers.
Phencyclidine (PCP), scopolamine, caffeine and ethanol increased switching under the random reinforcement procedure, but (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) and atropine did not. PCP, caffeine, lysergic acid diethylamide (LSD) and atropine increased switching under the FR21-switch procedure, but ethanol did not. The increases in switching produced by PCP, LSD and the anticholinergics were accompanied by marked reductions in response rate, whereas those produced by amphetamine and caffeine were not. The effects of amphetamine, and PCP were strongly dependent on the baseline probability of switching, those of atropine and caffeine moderately so, and those of LSD and ethanol only weakly so.
Of the agents tested, psychomotor stimulants appear to produce the most selective increases in switching. The procedures described here may be useful for assaying the disorganisation of behaviour produced by other psychotomimetics and may have value in the detection of novel antipsychotic drugs.
精神病和拟精神病药物会导致思维和行为结构的紊乱。使其正常化是抗精神病治疗的目标之一，预测这种治疗效果的方法将具有重要价值。
使用两种不同程序，研究多种拟精神病药物对大鼠在两个反应杆上分配反应方式的影响，以测定它们对行为组织的作用。此前已发现苯丙胺使用这些程序会增加反应切换。
第一种是随机强化程序，两个杠杆中的一个被随机选为“正确”杠杆，在此杠杆上的反应按随机比率时间表用食物进行强化。没有信号用于区分杠杆。反应也可能导致食物盘亮起，但没有食物颗粒被递送（“无食物”事件）。在第二个杠杆（“错误”）上的反应没有设定的结果。每次食物递送或“无食物”事件后，被指定为“正确”和“错误”的杠杆会随机重新分配，大鼠必须打开食物盘才能重新开始程序。在第二种程序中，大鼠在两个杠杆之间切换导致食物递送之前需要做出21次反应[固定比率（FR）21切换]。构成FR的反应可以在两个杠杆之间自由分配。
苯环利定（PCP）、东莨菪碱、咖啡因和乙醇在随机强化程序下增加了切换，但盐酸（±）-2,5-二甲氧基-4-碘苯丙胺（DOI）和阿托品没有。PCP、咖啡因、麦角酸二乙酰胺（LSD）和阿托品在FR21切换程序下增加了切换，但乙醇没有。PCP、LSD和抗胆碱能药物引起的切换增加伴随着反应率的显著降低，而苯丙胺和咖啡因引起的则没有。苯丙胺和PCP的作用强烈依赖于切换的基线概率，阿托品和咖啡因的作用中等依赖，而LSD和乙醇的作用仅微弱依赖。
在所测试的药物中，精神运动兴奋剂似乎产生了最具选择性的切换增加。这里描述的程序可能有助于测定其他拟精神病药物产生的行为紊乱，并且在检测新型抗精神病药物方面可能具有价值。
