Fontana D.J., Schefke D.M., Commissaris R.L.
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions.
Behav Pharmacol. 1989;1(3):201-208.
The present study examined the effects of acute and chronic treatment with the alpha-2-adrenoceptor agonist clonidine on behavior in the Conditioned Suppression of Drinking (CSD) conflict paradigm, an animal model for the study of anti-anxiety treatments. In daily 10-min sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.25mA). Electrification was signalled by a tone. Within 3-4 weeks of 4 day/week CSD sessions, control (i.e. non-drug) CSD behavior had stabilized (approximately 40 shock/session and 11ml water/session). Acute treatment with clonidine across a range of doses (1.25-40µg/kg; 10-min pretreatment) did not exert an anti-conflict effect, with doses greater than 5µg/kg significantly depressing unpunished responding (i.e. water intake). Similarly, administration of a single dose of clonidine (40µg/kg) across a range of pretreatment times (10 to 120min) failed to increase punished responding. In contrast, chronic post-test treatment with clonidine (40µg/kg, twice daily for 18 weeks) resulted in a dramatic and time-dependent increase in punished responding, with a latency to onset of approximately 3-4 weeks. The response to an acute challenge with chlordiazepoxide (10mg/kg) or the benzodiazepine antagonist Ro 15-1788 (4.0mg/kg) did not differ in chronic clonidine-versus saline-treated subjects, indicating that benzodiazepine receptor sensitivity had not been affected by this chronic clonidine treatment. An acute challenge with a low dose of clonidine (10µg/kg) decreased punished and unpunished responding in chronic clonidine- or saline-treated subjects. Finally, an acute challenge with the alpha-2-antagonist yohimbine (1.25mg/kg) failed to block the increase in punished responding associated with chronic clonidine treatment, indicating that the anti-conflict effect of this chronic post-test clonidine treatment was not the result of alpha-2-adrenoceptor activation at the time of CSD testing (i.e. not due to drug accumulation). Discontinuation of chronic clonidine treatment resulted in a decline to near saline-treated levels of punished responding over the course of 3 weeks of conflict testing. The relationship of these findings to the anti-anxiety effects of clonidine in humans are discussed.
本研究考察了α-2肾上腺素能受体激动剂可乐定急性和慢性给药对条件性饮水抑制（CSD）冲突范式中行为的影响，CSD冲突范式是一种用于研究抗焦虑治疗的动物模型。在每天10分钟的实验时段中，剥夺水分的大鼠被训练从一根偶尔会通电（0.25mA）的管子饮水。通电由一个音调发出信号。在每周4天、持续3 - 4周的CSD实验时段内，对照（即未用药）的CSD行为已稳定（约每次实验40次电击和每次实验11毫升水）。可乐定在一系列剂量（1.25 - 40μg/kg；10分钟预处理）下的急性给药未产生抗冲突作用，剂量大于5μg/kg时显著抑制未受惩罚的反应（即饮水量）。同样，单次给予可乐定（40μg/kg）在一系列预处理时间（10至120分钟）内未能增加受惩罚的反应。相比之下，可乐定慢性实验后给药（40μg/kg，每日两次，持续18周）导致受惩罚反应显著且随时间增加，起效潜伏期约为3 - 4周。在慢性可乐定与生理盐水处理的受试者中，对氯氮卓（10mg/kg）或苯二氮䓬拮抗剂Ro 15 - 1788（4.0mg/kg）急性激发的反应无差异，表明这种慢性可乐定处理未影响苯二氮䓬受体敏感性。低剂量可乐定（10μg/kg）急性激发降低了慢性可乐定或生理盐水处理受试者的受惩罚和未受惩罚反应。最后，α-2拮抗剂育亨宾（1.25mg/kg）急性激发未能阻断与慢性可乐定处理相关的受惩罚反应增加，表明这种慢性实验后可乐定处理的抗冲突作用不是CSD测试时α-2肾上腺素能受体激活的结果（即不是由于药物蓄积）。在3周的冲突测试过程中，停止慢性可乐定处理导致受惩罚反应下降至接近生理盐水处理的水平。讨论了这些发现与可乐定对人类抗焦虑作用的关系。
