Differential anti-parkinsonian effects of benzazepine D1 dopamine agonists with varying efficacies in the MPTP-treated common marmoset

Abstract

In common marmosets systemically treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), the behavioural effects of benzazepine D1 dopamine (DA) agonists with full/supramaximal (SKF 80723 and SKF 82958), partial (SKF 38393, SKF 75670 and SKF 83565) and no efficacies (SKF 83959) in stimulating adenylate cyclase (AC) activity were investigated. The benzazepine derivatives, with the exception of SKF 82958 (8 fold D1 DA receptor selectivity), demonstrated high D1 DA receptor affinity and selectivity (approximately 100 fold or more) in rat striatal homogenates. Administration of MPTP in marmosets induced locomotor hypoactivity, rigidity and motor disability. SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine) and SKF 75670 (3-CH3 analogue) further reduced locomotor activity (by -70 to -80%) and increased motor disability (by +22 to +67%) in these animals. SKF 83565 (6-Cl, 3-CH3, 3'-Cl analogue) and SKF 82958 (6-Cl, 3-C3H5 analogue) had only a slight effect on locomotor activity but decreased motor disability at high doses (-46 to -60%). In contrast, SKF 83959 (6-Cl, 3-CH3, 3'-CH3 analogue) and SKF 80723 (6-Br analogue) produced pronounced increases in locomotion (6-10 fold) and a reversal in motor disability (by -64 to -77%). Oral activity, consisting largely of abnormal, 'dyskinetic' tongue protrusions and vacuous chews, was increased in animals treated with SKF 38393, SKF 83565, SKF 82958 and more especially with SKF 80723 and SKF 83959. Grooming was increased with SKF 82958 and more especially with SKF 80723 and SKF 83959. In contrast, quinpirole (D2 DA agonist), reversed the MPTP-induced motor deficits in the marmoset, with no effect on grooming and oral activity. The present findings further demonstrate the antiparkinsonian actions of some D1 DA agonists in MPTP-treated primates. However, in general the behavioural effects of benzazepines failed to correlate with either their D1 DA receptor affinity/selectivity or their efficacy in stimulating adenylate cyclase (AC) activity. These observations further implicate a behavioural role for D1 DA receptors uncoupled to AC and/or a role for extrastriatal D1 DA receptors in mediating the behavioural response to D1 DA agonists.

Mapping the Effects of Three Dopamine Agonists with Different Dyskinetogenic Potential and Receptor Selectivity Using Pharmacological Functional Magnetic Resonance Imaging

“…Studies performed in MPTP-lesioned monkeys are to some extent contradictory on this matter, yet most emphasize that D1/D5 agonists induce significant dyskinesia (Blanchet et al, 1996;Pearce et al, 1999;Goulet and Madras, 2000) and the D1/D5 agonist ABT-431 is as potent as levodopa in inducing dyskinesia in patients (Rascol et al, 2001). Remarkably, we found that SKF-81297 induced significantly more MD than apomorphine and quinpirole, what is consistent with reports showing that D1/D5 agonists increase oral movements in rats and monkeys with intact dopaminergic pathways (Bedard and Boucher, 1989;Waddington et al, 1995) and produce abnormal dyskinetic oral movements in MPTP-lesioned marmosets (Gnanalingham et al, 1995). Overall, these findings are well in line with recent research showing altered D1 receptor signaling in the striatum of parkinsonian rats (Gerfen et al, 2002) and MPTP monkeys rendered dyskinetic by chronic levodopa administration (Aubert et al, 2005), and further support the usefulness of rodent models of PD for the study of dopamine agonistinduced dyskinesia.…”

“…But the neural mechanisms of dopamine agonist-induced dyskinesia are thought to essentially concern the indirect pathway (Crossman, 1990;Obeso et al, 2000) and our findings suggest a primary involvement of the D1 receptor regulated direct pathway. A primary involvement of D1 receptors and the direct basal ganglia pathway is suggested by other recent studies too (Aubert et al, 2005;Fiorentini et al, 2006), and by the fact that D2 family agonists are less likely to induce dyskinesia in patients and animal models of PD than unselective and D1/D5 selective agonists (present findings; Gnanalingham et al, 1995;Blanchet et al, 1996;Pearce et al, 1999;Goulet and Madras, 2000;Nutt, 2000;Rascol et al, 2001;Lundblad et al, 2002;Monville et al, 2005). A recent study established that levodopa-induced dyskinesia in the rat 6-OHDA model is related to increased synchronization of afferent activity to the basal ganglia output nuclei (Meissner et al, 2006).…”

Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons: a modeling study

“…It has been shown that SKF83959 produces potent antiparkinsonian effects in primate and rodent models [5][6][7] . Furthermore, SKF83959 has been reported to attenuate L-DOPAinduced dyskinesia (LID) in 6-OH-DOPA-lesioned rat models [5,8] .…”

“…It has been shown that SKF83959 produces potent antiparkinsonian effects in primate and rodent models [5][6][7] . Furthermore, SKF83959 has been reported to attenuate L-DOPAinduced dyskinesia (LID) in 6-OH-DOPA-lesioned rat models [5,8] . Recently, SKF83959 has been shown to be an identified allosteric modulator of the sigma-1 receptor and to have antidepressant effects [9] ; moreover, SKF83959 has also been shown to improve the survival of pheochromocytoma cells (PC12 cells) subjected to H 2 O 2 insult [10] .…”

“…Recently, SKF83959 has been shown to be an identified allosteric modulator of the sigma-1 receptor and to have antidepressant effects [9] ; moreover, SKF83959 has also been shown to improve the survival of pheochromocytoma cells (PC12 cells) subjected to H 2 O 2 insult [10] . Both D1 receptor-dependent and -independent mechanisms have been suggested to be responsible for the range of the drug's effects [5][6][7][8]10] .…”