Löscher W, Hönack D
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, F.R.G.
J Pharmacol Exp Ther. 1991 Jun;257(3):1146-53.
The novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849) was found to produce a phencyclidine (PCP)-like behavioral syndrome (ataxia, locomotion, stereotypies) in amygdala-kindled rats, whereas the amphetamine-like behavioral alterations of the syndrome (locomotion, stereotypies) were only infrequently seen in nonkindled rats. In dose-response experiments in kindled and nonkindled rats, behavioral effects were scored using a ranked intensity scale, and the behaviors and behavioural scores determined after CGP 37849 were compared with those determined after i.p. administration of the noncompetitive NMDA receptor antagonist dizocilpine maleate (MK-801). In kindled rats, 20 mg/kg of CGP 37849 produced about the same scores for hyperlocomotion and head weaving as 0.1 mg/kg of MK-801. Kindled rats exhibited higher behavioral scores than nonkindled rats, especially in the case of CGP 37849. The behavioral effects produced by CGP 37849 in kindled rats were almost indistinguishable from the PCP-like behavioral effects induced by MK-801, indicating that CGP 37849 indeed produces a PCP-like pattern of behavior in kindled rats. Hyperlocomotion and head weaving induced by CGP 37849 in kindled rats could be attenuated or totally prevented by pretreatment with ipsapirone, a partial agonist/antagonist at postsynaptic 5-hydroxytryptamine (5-HT) receptors of the 5-HT1A subtype. Furthermore, these behavioural effects were attenuated or blocked by the dopamine antagonist haloperidol and the alpha-1 adrenoceptor antagonist, prazosin. The data demonstrate that kindling induces a hypersensitivity to PCP-like behavioral effects of competitive and noncompetitive NMDA receptor antagonists, which could relate to the recent finding of increased function of NMDA receptors following kindling.(ABSTRACT TRUNCATED AT 250 WORDS)
新型竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂DL-(E)-2-氨基-4-甲基-5-膦酰基-3-戊烯酸（CGP 37849）被发现可在杏仁核点燃大鼠中产生类似苯环利定（PCP）的行为综合征（共济失调、运动、刻板行为），而该综合征类似苯丙胺的行为改变（运动、刻板行为）在未点燃大鼠中很少见。在点燃和未点燃大鼠的剂量反应实验中，使用分级强度量表对行为效应进行评分，并将CGP 37849给药后确定的行为和行为评分与腹腔注射非竞争性NMDA受体拮抗剂马来酸氯氮平（MK-801）后确定的进行比较。在点燃大鼠中，20mg/kg的CGP 37849产生的运动亢进和头部摆动评分与0.1mg/kg的MK-801大致相同。点燃大鼠的行为评分高于未点燃大鼠，尤其是在CGP 37849的情况下。CGP 37849在点燃大鼠中产生的行为效应与MK-801诱导的类似PCP的行为效应几乎无法区分，表明CGP 37849确实在点燃大鼠中产生了类似PCP的行为模式。CGP 37849在点燃大鼠中诱导的运动亢进和头部摆动可通过5-HT1A亚型突触后5-羟色胺（5-HT）受体的部分激动剂/拮抗剂伊沙匹隆预处理来减弱或完全预防。此外，这些行为效应被多巴胺拮抗剂氟哌啶醇和α-1肾上腺素能受体拮抗剂哌唑嗪减弱或阻断。数据表明，点燃诱导对竞争性和非竞争性NMDA受体拮抗剂类似PCP行为效应的超敏反应，这可能与最近发现的点燃后NMDA受体功能增强有关。（摘要截短于250字）
