Premium
The D 1 receptor‐mediated effects of the ergoline derivative LEK‐8829 in rats with unilateral 6‐hydroxydopamine lesions
Author(s) -
Z̆ivin Marko,
S̆prah Lilijana,
Sket Dus̆an
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb16021.x
Subject(s) - sch 23390 , haloperidol , medial forebrain bundle , eticlopride , dopamine receptor d2 , striatum , medicine , endocrinology , antagonist , dopaminergic , chemistry , pharmacology , receptor , dopamine , biology
1 Previous experiments have suggested a potential atypical antipsychotic activity of the ergoline derivative LEK‐8829. In vitro experiments showed a high affinity to 5‐HT 1A , 5‐HT 2 and D 2 receptors (the ratio of p K i values 5‐HT 2 /D 2 = 1.11) and a moderate affinity to D 1 receptors. In vivo experiments showed antagonism of dopamine and 5‐hydroxytryptamine (5‐HT) receptor‐linked behaviours. 2 In the present study, the rats with unilateral dopaminergic deafferentation of the striatum, induced by the lesion of the median forebrain bundle with 6‐hydroxydopamine (6‐OHDA), were used to determine the effects of LEK‐8829 on turning behaviour and on striatal c‐fos mRNA levels. 3 The administration of LEK‐8829 induced a long lasting contralateral turning behaviour that was dose‐dependent. It was found that the specific D 1 receptor antagonist SCH‐23390 but not the D 2 receptor antagonist haloperidol or 5‐HT 1A antagonist pindolol, dose‐dependently inhibited the turning behaviour induced by LEK–8829. 4 In an attempt to clarify the D 1 :D 2 receptor interactions involved in the action of LEK‐8829 in the 6‐OHDA model, we used in situ hybridization histochemistry to compare the effect of SCH‐23390 pretreatment on striatal c‐fos mRNA expression induced either by LEK‐8829 or by the typical antipsychotic haloperidol. 5 LEK‐8829 induced a bilateral striatal c‐fos mRNA expression that was significantly higher in the denervated striatum as compared to the intact striatum and was completely blocked on both sides by pretreatment with SCH‐23390. In contrast, haloperidol‐induced striatal c‐fos mRNA expression was limited to the innervated striatum and was not blocked by SCH‐23390. 6 Our data demonstrate an intrinsic activity of LEK‐8829 on D 1 receptors that is potentiated in the dopamine‐depleted striatum. We conclude, therefore, that the putative atypical antipsychotic LEK‐8829 may prove useful as an experimental tool for the study of D 1 :D 2 receptor interactions and could have beneficial effects in the treatment of drug‐induced psychosis in patients with Parkinson's disease.