THE D-1 RECEPTOR-MEDIATED EFFECTS OF THE ERGOLINE DERIVATIVE LEK-8829IN RATS WITH UNILATERAL 6-HYDROXYDOPAMINE LESIONS

1 Previous experiments have suggested a potential atypical antipsychot ic activity of the ergoline derivative LEK-8829. In vitro experiments showed a high affinity to 5-HT1A, 5-HT2 and D-2 receptors (the ratio o f pK(i) values 5-HT2/D-2 = 1.11) and a moderate affinity to D-1 recept ors. In vivo experiments showed antagonism of dopamine and 5-hydroxytr yptamine (5-HT) receptor-linked behaviours. 2 In the present study, th e rats with unilateral dopaminergic deafferentation of the striatum, i nduced by the lesion of the median forebrain bundle with 6-hydroxydopa mine (6-OHDA), were used to determine the effects of LEK-8829 on turni ng behaviour and on striatal c-fos mRNA levels. 3 The administration o f LEK-8829 induced a long lasting contralateral turning behaviour that was dose-dependent. It was found that the specific D-1 receptor antag onist SCH-23390 but not the D-2 receptor antagonist haloperidol or 5-H T1A antagonist pindolol, dose-dependently inhibited the turning behavi our induced by LEK-8829. 4 In an attempt to clarify the D-1:D-2 recept or 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 eith er by LEK-8829 or by the typical antipsychotic haloperidol. 5 LEK-8829 induced a bilateral striatal c-fos mRNA. expression that was signific antly higher in the denervated striatum as compared to the intact stri atum and was completely blocked on both sides by pretreatment with SCH -23390. In contrast, haloperidol-induced striatal c-fos mRNA expressio n was limited to the innervated striatum and was not blocked by SCH-23 390. 6 Our data demonstrate an intrinsic activity of LEK-8829 on D-1 r eceptors that is potentiated in the dopamine-depleted striatum. We con clude, therefore, that the putative atypical antipsychotic LEK-8829 ma y prove useful as an experimental tool for the study of D-1:D-2 recept or interactions and could have beneficial effects in the treatment of drug-induced psychosis in patients with Parkinson's disease.