Marek G J, Li A A, Seiden L S
University of Chicago, Department of Pharmacological and Physiological Sciences, Illinois.
J Pharmacol Exp Ther. 1989 Jul;250(1):60-71.
Previous work in this laboratory has suggested that antagonist action of 5-hydroxytryptamine2 (5-HT2) receptors and agonist action of 5-HT1 receptors results in antidepressant-like effects (increased reinforcement rate and decreased response rate) in rats performing under the differential-reinforcement-of-low-rate 72-sec schedule (DRL 72-s) of reinforcement. Serotonergic mediation of antidepressant drug effects on DRL 72-s behavior was assessed with a series of 5-HT agonists, and blockade of the effects of the antidepressant drugs clorgyline and fluoxetine (which presumably indirectly stimulate 5-HT1 receptors) was attempted in separate experiments with the 5-HT1 and 5-HT2 antagonist methysergide and the 5-HT neurotoxin 5,7-dihydroxytryptamine. Direct 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)tetralin and 5-methoxy-N,N-dimethyltryptamine and the 5-HT precursor 5-hydroxytryptophan all increased the reinforcement rate. The 5-HT1B and 5-HT1C agonists m-chlorophenylpiperazine and 1-(m-trifluoromethylphenyl)piperazine did not increase the reinforcement rate. The 5-HT2 agonist and 5-HT3 antagonist quipazine also did not increase the reinforcement rate. The monoamine oxidase inhibitor clorgyline and the 5-HT uptake inhibitor fluoxetine increased the reinforcement rate and decreased the response rate as seen with other antidepressant drugs on the DRL 72-s schedule. Methysergide antagonized the reinforcement rate increasing effects of both clorgyline and fluoxetine. Depletion of brain 5-HT with i.v.t. 5,7-dihydroxytryptamine blocked the antidepressant-like effects of clorgyline. These results suggest that central 5-HT1A receptors are involved in mediating the antidepressant-like effects of some drugs on DRL 72-s behavior. These results provide evidence that stimulation of 5-HT1A receptors and antagonism of 5-HT2 receptors lead to an antidepressant-like effect on the DRL 72-s schedule and implies that these two receptors may be important in mediating clinical drug effects in depression.
本实验室之前的研究表明，5-羟色胺2（5-HT2）受体的拮抗作用以及5-HT1受体的激动作用会使大鼠在低速率72秒强化程序（DRL 72-s）下的行为产生抗抑郁样效应（强化率增加和反应率降低）。使用一系列5-HT激动剂评估了抗抑郁药物对DRL 72-s行为的5-羟色胺能介导作用，并在单独的实验中尝试用5-HT1和5-HT2拮抗剂美西麦角以及5-羟色胺神经毒素5,7-二羟基色胺来阻断抗抑郁药物氯吉兰和氟西汀的作用（这两种药物可能间接刺激5-HT1受体）。直接的5-HT1A激动剂8-羟基-2-（二正丙基氨基）四氢萘和5-甲氧基-N,N-二甲基色胺以及5-羟色胺前体5-羟色氨酸均提高了强化率。5-HT1B和5-HT1C激动剂间氯苯哌嗪和1-（间三氟甲基苯基）哌嗪并未提高强化率。5-HT2激动剂和5-HT3拮抗剂喹哌嗪也未提高强化率。单胺氧化酶抑制剂氯吉兰和5-羟色胺摄取抑制剂氟西汀提高了强化率并降低了反应率，正如其他抗抑郁药物在DRL 72-s程序下的表现。美西麦角拮抗了氯吉兰和氟西汀提高强化率的作用。静脉注射5,7-二羟基色胺使脑内5-羟色胺耗竭，阻断了氯吉兰的抗抑郁样效应。这些结果表明，中枢5-HT1A受体参与介导某些药物对DRL 72-s行为的抗抑郁样效应。这些结果提供了证据，表明刺激5-HT1A受体和拮抗5-HT2受体可导致DRL 72-s程序下产生抗抑郁样效应，并暗示这两种受体可能在介导抑郁症的临床药物效应中起重要作用。
