The D₁receptor‐mediated effects of the ergoline derivative LEK‐8829 in rats with unilateral 6‐hydroxydopamine lesions

Abstract

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-HTIA, 5-HT2 and D2 receptors (the ratio of pKi values 5-HT2/D2 = 1.11) and a moderate affinity to DI 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 DI receptor antagonist SCH-23390 but not the D2 receptor antagonist haloperidol or 5-HTlA antagonist pindolol, dose-dependently inhibited the turning behaviour induced by In an attempt to clarify the D,:D2 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 DI 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 DI:D2 receptor interactions and could have beneficial effects in the treatment of drug-induced psychosis in patients with Parkinson's disease.

Upregulation of Cysteine Protease Cathepsin X in the 6-Hydroxydopamine Model of Parkinson’s Disease

“…The standard procedure described by Zivin et al (1996) was used for in situ hybridization histochemistry. The 10 μm sections were incubated with 35 S-labeled oligodeoxyribonucleotide “antisense” probes (45 bases long) complementary to the rat TH mRNA (sequence 5 ′ -AAC CAA ACC AGG GCA CAC AGG GAG AAC CAT GCT CTT AAG-3 ′ ) and rat cathepsin X mRNA (sequence 5 ′ -AGG TCT CAT CGG GGA TGC CAT GCT TGT GGG CAT ACT CCC ACA CCG-3 ′ ).…”

Synaptotagmins in Neurodegeneration

“…We performed the standard procedure described in detail by Zivin et al (1996). The sections were incubated with 3′ end 35 S‐labelled oligodeoxyribonucleotide antisense probes (45 bases long) complementary to the mouse Syt 1 mRNA (sequence 5′‐GGA AAA GGC ATC TTC CTT CCC TTC CCC AGG ACT GGC TGG CTC AGT‐3′), mouse Syt 2 mRNA (sequence 5′‐TGG CCG GAG CCA CAT TTG GCT CCT GGT TCC TCT TGA AGA TGT TTC‐3′), mouse Syt 4 mRNA (sequence 5′‐CAG AGG GAG ACC AGA AGT TCA CCC CGT CCA GAA GAC TTC TTA GCA‐3′), mouse Syt 7 mRNA (sequence 5′‐CCG AGT CTG GCG TGC CCA CCG TCT CCA AGG AAT TCT TGT AGC GTT‐3′: the probe that recognizes all Syt 7 splicing variants), rat Syt 4 mRNA (sequence 5′‐CAG AGG GAG ACC AGA AGT TCA CCC CGT CCA GAA GAC TTC TTA GCA‐3′), GenBank accession numbers used to design the probes were as follows: mouse Syt 1 BC042519, mouse Syt 2 NT078297, mouse Syt 4 NM009308, mouse Syt 7 NM018801 and rat Syt 4 L38247.…”

Neuroprotective role of γ‐enolase in microglia in a mouse model of Alzheimer's disease is regulated by cathepsin X

“…The standard procedure described by Zivin et al (1996) was used for in situ hybridization. Sections were incubated with 3′ end 35 S-labelled oligodeoxyribonucleotide antisense probes (45-bases long) complementary to the mouse c-enolase mRNA (ENO2; sequence 5′-TCC TGG TAG AGT GCC CCC AGC TGG TCC CCA GTG ATG TAT CGG GAA-3′) and mouse cathepsin X mRNA (CTSZ; sequence 5′-CCC AAA TGT GCA GGC ACT CTC GAT GGC AAG GTT GTA GCT GTC ACC-3′).…”