多巴胺D3/D2受体激动剂的非条件行为效应特征

Characterization of unconditioned behavioral effects of dopamine D3/D2 receptor agonists.

作者信息

Geter-Douglass B, Katz J L, Alling K, Acri J B, Witkin J M

机构信息

Preclinical Pharmacology Laboratory, NIDA Addiction Research Center, National Institutes of Health, Baltimore, Maryland 21224, USA.

出版信息

J Pharmacol Exp Ther. 1997 Oct;283(1):7-15.

DOI:
PMID:9336302
Abstract

A series of experiments examined the ability of dopamine D3/D2 receptor agonists [(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]b enzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride (PD 128,907), (+/-)-7-hydroxy-dipropylaminotetralin hydrobromide (7-OH-DPAT), quinpirole and bromocriptine] to produce a variety of dopaminergically mediated behaviors. The effects of these drugs with selectivity for D3/D2 receptors over D1 receptors were compared with those produced by the selective D1 agonists [(+/-)-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF 38393), (+/-)-6-Chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-be nzazepine hydrobromide (SKF 82958)], a nonselective dopaminergic agonist (apomorphine), and an indirect dopamine agonist (cocaine). The D3/D2 agonists decreased locomotor activity, had no effect on gnawing and only inconsistently induced climbing in mice. Further, these agonists dose-dependently produced scratching in squirrel monkeys. In contrast, the D1 agonists, SKF 82958 and SKF 38393, did not produce scratching in squirrel monkeys. Whereas the full D1 agonist, SKF 82958, produced increases in locomotor activity and in climbing and gnawing, the partial D1 agonist, SKF 38393, did not increase the frequencies of these behaviors. The nonselective dopamine agonist, apomorphine, produced decreases in locomotor activity and increases in climbing and gnawing in mice. Apomorphine dose-dependently produced scratching in squirrel monkeys. The indirect dopamine agonist, cocaine, produced increases in locomotor activity and climbing, but had no effect on climbing or gnawing in mice and did not produce scratching in squirrel monkeys. These findings suggest that D3/D2 agonists can be distinguished on various behavioral measures from the nonselective agonist, apomorphine (gnawing), D1 agonists (scratching) and the indirect agonist, cocaine (locomotor activity and scratching). Behaviors once attributed to stimulation of D2 (locomotor activity and scratching) or D1/D2 (climbing and gnawing) receptors may also involve dopamine D3 receptors.

摘要

一系列实验研究了多巴胺D3/D2受体激动剂[(+)-(4aR,10bR)-3,4,4a,10b-四氢-4-丙基-2H,5H-[1]苯并吡喃并-[4,3-b]-1,4-恶嗪-9-醇盐酸盐(PD 128,907)、(+/-)-7-羟基-二丙基氨基四氢萘氢溴酸盐(7-OH-DPAT)、喹吡罗和溴隐亭]产生多种多巴胺能介导行为的能力。将这些对D3/D2受体比对D1受体具有选择性的药物的作用,与选择性D1激动剂[(+/-)-苯基-2,3,4,5-四氢-(1H)-3-苯并氮杂卓-7,8-二醇盐酸盐(SKF 38393)、(+/-)-6-氯-去甲肾上腺素-7,8-二羟基-3-烯丙基-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓氢溴酸盐(SKF 82958)]、非选择性多巴胺能激动剂(阿扑吗啡)和间接多巴胺激动剂(可卡因)所产生的作用进行了比较。D3/D2激动剂降低了小鼠的自发活动,对啃咬无影响,仅在小鼠中偶尔诱发攀爬。此外,这些激动剂在松鼠猴中剂量依赖性地产生抓挠行为。相比之下,D1激动剂SKF 82958和SKF 38393在松鼠猴中未产生抓挠行为。虽然完全D1激动剂SKF 82958使自发活动、攀爬和啃咬增加,但部分D1激动剂SKF 38393并未增加这些行为的频率。非选择性多巴胺激动剂阿扑吗啡使小鼠的自发活动减少,攀爬和啃咬增加。阿扑吗啡在松鼠猴中剂量依赖性地产生抓挠行为。间接多巴胺激动剂可卡因使自发活动和攀爬增加,但对小鼠的啃咬或攀爬无影响,且在松鼠猴中未产生抓挠行为。这些发现表明,D3/D2激动剂在各种行为指标上可与非选择性激动剂阿扑吗啡(啃咬)、D1激动剂(抓挠)和间接激动剂可卡因(自发活动和抓挠)区分开来。曾经归因于D2受体刺激(自发活动和抓挠)或D1/D2受体刺激(攀爬和啃咬)的行为,可能也涉及多巴胺D3受体。

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