Witkin J M, Barrett J E
Life Sci. 1985 Oct 28;37(17):1587-95. doi: 10.1016/0024-3205(85)90477-1.
The selective benzodiazepine receptor antagonist, Ro 15-1788, produced behavioral effects in pigeons at doses at least 100 times lower than those previously reported to possess intrinsic pharmacological activity in mammals. In contrast to its effects in mammalian species, in pigeons, Ro 15-1788 does not exhibit partial agonist activity. Key-peck responses of pigeons were studied under a multiple fixed-interval 3-min, fixed-interval 3-min schedule in which the first response after 3-min produced food in the presence of red or white keylights. In addition, every 30th response during the red keylight produced a brief electric shock (punishment). Under control conditions, punished responding was suppressed to 30% of unpunished response levels. Ro 15-1788 (0.01 mg/kg, i.m.) increased unpunished response rates by 33% without affecting rates of punished responding. Doses of 0.1 to 1.0 mg/kg Ro 15-1788 produced dose-related decreases in both punished and unpunished responding. As is characteristic of other benzodiazepines, midazolam (0.1 and 0.3 mg/kg, i.m.) markedly increased punished responding but had little effect on rates of unpunished responding. Ro 15-1788 antagonized the increases in punished responding and also reversed the rate-decreasing effects of higher doses of midazolam. However, the effectiveness of Ro 15-1788 as a benzodiazepine antagonist was limited by its intrinsic activity: rate-decreasing doses of Ro 15-1788 were unable to completely reverse behavioral effects of midazolam. Midazolam was an effective antagonist of the behavioral effects of Ro 15-1788 (up to 0.1 mg/kg) but midazolam did not influence the rate-decreasing effects of 1.0 mg/kg Ro 15-1788 across a 100-fold dose range. In the pigeon, the behavioral effects of relatively low doses of Ro 15-1788 (0.01-0.1 mg/kg) appear to be related to benzodiazepine receptor mechanisms, whereas other systems appear to be involved in the effects of higher doses.
选择性苯二氮䓬受体拮抗剂Ro 15 - 1788在鸽子身上产生行为效应的剂量，比先前报道的在哺乳动物中具有内在药理活性的剂量至少低100倍。与它在哺乳动物物种中的效应相反，在鸽子中，Ro 15 - 1788不表现出部分激动剂活性。在多重固定间隔3分钟、固定间隔3分钟的实验程序下研究鸽子的按键反应，在此程序中，3分钟后的首次反应在红色或白色按键灯亮起时会获得食物。此外，在红色按键灯亮起期间，每第30次反应会产生一次短暂电击（惩罚）。在对照条件下，受惩罚的反应被抑制到未受惩罚反应水平的30%。Ro 15 - 1788（0.01毫克/千克，肌肉注射）使未受惩罚的反应率提高了33%，而不影响受惩罚反应的速率。0.1至1.0毫克/千克剂量的Ro 15 - 1788使受惩罚和未受惩罚的反应都出现剂量相关的减少。正如其他苯二氮䓬类药物的特性一样，咪达唑仑（0.1和0.3毫克/千克，肌肉注射）显著增加受惩罚的反应，但对未受惩罚反应的速率影响很小。Ro 15 - 1788拮抗了受惩罚反应的增加，并且也逆转了较高剂量咪达唑仑的速率降低效应。然而，Ro 15 - 1788作为苯二氮䓬拮抗剂的有效性受到其内在活性的限制：降低速率剂量的Ro 15 - 1788无法完全逆转咪达唑仑的行为效应。咪达唑仑是Ro 15 - 1788行为效应的有效拮抗剂（高达0.1毫克/千克），但在100倍剂量范围内，咪达唑仑不影响1.0毫克/千克Ro 15 - 1788的速率降低效应。在鸽子中，相对低剂量的Ro 15 - 1788（0.01 - 0.1毫克/千克）的行为效应似乎与苯二氮䓬受体机制有关，而其他系统似乎参与了较高剂量的效应。
