Kleven M, Prinssen E P, Koek W
Centre de Recherche Pierre Fabre, Castres, France.
Eur J Pharmacol. 1996 Oct 10;313(1-2):25-34. doi: 10.1016/0014-2999(96)00498-0.
Behavioral effects produced by the indirect-acting dopamine receptor agonist, methylphenidate (40 mg/kg i.p.) were examined in rats after administration of the 5-HT1A receptor agonists (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and flesinoxan, the mixed 5-HT1A receptor agonist/dopamine D2 receptor antagonists buspirone and 1-[-4-fluorobenzoylamino)ethyl]-ethyl]-4-(7-methoxynaphthyl) piperazine (S 14506), the neuroleptics haloperidol and clozapine, and the sigma receptor ligand/partial 5-HT1A receptor agonist alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol (BMY 14802). All of the compounds produced dose-related decreases in methylphenidate-induced stereotyped gnawing, and, as gnawing was inhibited, other methylphenidate-induced responses (i.e. sniffing, rearing and locomotion) appeared. Higher doses of haloperidol and buspirone, but none of the remaining compounds, inhibited these other responses, so that the behavior of the methyphenidate-treated animals became similar to that of normal controls. Pretreatment with the 5-HT1A receptor antagonist N-[2-4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl)- cyclohexanecarboxamide (WAY-100635; 0.63 mg/kg s.c.) blocked the ability of 8-OH-DPAT, S 14506 and flesinoxan to inhibit methylphenidate-induced gnawing, demonstrating the involvement of 5-HT1A receptors in their ability to inhibit methylphenidate-induced behaviors. In contrast, pretreatment with WAY-100635 did not alter the ability of haloperidol, clozapine, buspirone, or BMY 14802 to inhibit methylphenidate-induced gnawing, or in the case of haloperidol and buspirone, to normalize behavior. The results indicate that mixed compounds with 5-HT1A receptor agonist and dopamine receptor antagonist properties can be differentiated on the basis of the ability of WAY-100635 to reverse their effects on methylphenidate-induced behaviors.
在给大鼠腹腔注射间接作用的多巴胺受体激动剂哌甲酯（40毫克/千克）后，研究了5-HT1A受体激动剂（±）-8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）和氟司立生、5-HT1A受体激动剂/多巴胺D2受体拮抗剂丁螺环酮和1-[-4-（氟苯甲酰氨基）乙基]-乙基]-4-（7-甲氧基萘基）哌嗪（S 14506）、抗精神病药物氟哌啶醇和氯氮平以及西格玛受体配体/部分5-HT1A受体激动剂α-（4-氟苯基）-4-（5-氟-2-嘧啶基）-1-哌嗪丁醇（BMY 14802）所产生的行为效应。所有这些化合物都使哌甲酯诱导的刻板啃咬行为呈剂量相关减少，并且随着啃咬行为受到抑制，其他哌甲酯诱导的反应（即嗅探、竖毛和活动）出现。较高剂量的氟哌啶醇和丁螺环酮，但其余化合物均未，抑制了这些其他反应，因此接受哌甲酯治疗的动物的行为变得与正常对照相似。用5-HT1A受体拮抗剂N-[2-4-（2-甲氧基苯基）-1-哌嗪基]-乙基]-N-（2-吡啶基）-环己烷甲酰胺（WAY-100635；0.63毫克/千克皮下注射）预处理可阻断8-OH-DPAT、S 14506和氟司立生抑制哌甲酯诱导的啃咬行为的能力，表明5-HT1A受体参与了它们抑制哌甲酯诱导行为的能力。相反，用WAY-100635预处理并未改变氟哌啶醇、氯氮平、丁螺环酮或BMY 14802抑制哌甲酯诱导的啃咬行为的能力，就氟哌啶醇和丁螺环酮而言，也未改变使行为正常化的能力。结果表明，具有5-HT1A受体激动剂和多巴胺受体拮抗剂特性的混合化合物可根据WAY-100635逆转它们对哌甲酯诱导行为的影响的能力来区分。
