Jackisch R, Huang H Y, Reimann W, Limberger N
Pharmakologisches Institut der Universität, Freiburg, Federal Republic of Germany.
J Pharmacol Exp Ther. 1993 Feb;264(2):889-98.
The effects of the antiparkinsonian drugs budipine and biperiden on spontaneous and electrically evoked release of dopamine (DA), acetylcholine (ACh), GABA or noradrenaline (NA) were studied in caudate nucleus or cortex slices, respectively, of the rabbit brain. Whereas both drugs (1-10 microM) strongly increased spontaneous [3H]outflow in caudate nucleus slices preincubated with [3H]DA, budipine inhibited but biperiden facilitated the evoked DA release. In the presence of the DA-reuptake inhibitor nomifensine, a significant part of the budipine-induced basal [3H] outflow consisted of unmetabolized DA. Synaptosomal high-affinity uptake of [3H]DA was only weakly affected by budipine and biperiden (IC50 values, 11 and 9 microM, respectively). Budipine enhanced also basal [3H]outflow from cortex slices prelabeled with [3H]NA, however this outflow consisted mainly of NA metabolites even in the presence of cocaine. The evoked release of [3H]ACh in rabbit caudate nucleus slices preincubated with [3H] choline was almost unaffected by budipine but enhanced by biperiden in the absence of further drugs. In the presence of nomifensine, however, budipine inhibited, but biperiden still enhanced, the evoked ACh release. Moreover, both drugs showed antimuscarinic properties in the presence of the ACh esterase inhibitor physostigmine, i.e., they facilitated the evoked ACh release, exhibiting pA2 values of about 6.9 (budipine) and 8.3 (biperiden). Addition of the D2 receptor antagonist domperidone diminished all inhibitory effects of budipine on the evoked ACh release. The evoked overflow of [3H] in caudate nucleus slices preincubated with [3H]GABA was reduced by both budipine and biperiden. It is concluded that both anticholinergic and indirect dopaminomimetic properties contribute to the antiparkinsonian effects of budipine, whereas biperiden exhibits mainly anticholinergic effects. Moreover, both drugs might disinhibit GABA controlled neurons in the central nervous system.
在兔脑的尾状核或皮层切片中，分别研究了抗帕金森病药物布地品和比哌立登对多巴胺（DA）、乙酰胆碱（ACh）、γ-氨基丁酸（GABA）或去甲肾上腺素（NA）的自发释放和电诱发释放的影响。两种药物（1 - 10微摩尔）均能强烈增加预先用[3H]DA预孵育的尾状核切片中的自发[3H]外流，而布地品抑制但比哌立登促进诱发的DA释放。在DA再摄取抑制剂诺米芬辛存在的情况下，布地品诱导的基础[3H]外流的很大一部分由未代谢的DA组成。[3H]DA的突触体高亲和力摄取仅受到布地品和比哌立登的微弱影响（IC50值分别为11和9微摩尔）。布地品还增强了预先用[3H]NA标记的皮层切片的基础[3H]外流，然而即使在可卡因存在的情况下，这种外流主要由NA代谢物组成。在预先用[3H]胆碱预孵育的兔尾状核切片中，诱发的[3H]ACh释放几乎不受布地品影响，但在没有其他药物的情况下，比哌立登可增强其释放。然而，在诺米芬辛存在的情况下，布地品抑制但比哌立登仍增强诱发的ACh释放。此外，在ACh酯酶抑制剂毒扁豆碱存在的情况下，两种药物均表现出抗胆碱能特性，即它们促进诱发的ACh释放，布地品和比哌立登的pA2值分别约为6.9和8.3。添加D2受体拮抗剂多潘立酮可消除布地品对诱发的ACh释放的所有抑制作用。布地品和比哌立登均降低了预先用[3H]GABA预孵育的尾状核切片中诱发的[3H]溢出。结论是，抗胆碱能和间接拟多巴胺特性均有助于布地品的抗帕金森病作用，而比哌立登主要表现出抗胆碱能作用。此外，两种药物可能会解除中枢神经系统中GABA控制的神经元的抑制作用。
