EFFECTS OF THE ANTIPARKINSONIAN DRUG BUDIPINE ON CENTRAL NEUROTRANSMITTER SYSTEMS

Budipine is a novel antiparkinsonian drug which is particularly benefi cial in the treatment of parkinsonian tremor. The mechanism of action of budipine is not fully understood. To study whether budipine has dop aminergic activity in vivo, we used the 6-hydroxydopamine rotational m odel of Parkinson's disease. Budipine (0.78-12.5 mg/kg i.p.) did not i nduce ipsilateral or contralateral rotations, suggesting that it does not possess direct or indirect dopaminergic activity. This conclusion is further supported by the observation that budipine (10 mg/kg) i.v. did not facilitate striatal dopamine release measured in vivo by brain microdialysis. To investigatate possible antimuscarinic and N-methyl- D-aspartic acid (NMDA) antagonistic properties of budipine, we compare d budipine with the antimuscarinic antiparkinsonian drug biperiden and the NMDA receptor antagonist +/-)-2-carboxypiperazine-4-yl]-propyl-1- phosphonic acid (CPP). In receptor-binding assays, budipine inhibited thienylcyclohexylpiperidyl-3,4-[H-3](n) ([H-3]TCP) (2.5 nM)-binding wi th an IC50 of 36 mu M and [H-3]3-quinuclidinol benzilate-binding with an IC50 of 1.1 mu M. The respective values for biperiden were 170 and 0.053 mu M. In line with these findings, budipine and CPP increased th e threshold for NMDA-induced seizures in mice with an ED(50) of 10.2 a nd 4.4 mg/kg, respectively, whereas biperiden was not effective. In 6- hydroxydopamine-lesioned rats, budipine (3.13-12.5 mg/kg) and CPP (0.1 -0.39 mg/kg) increased the number of contralateral rotations induced b y apomorphine, whereas biperiden was not effective. The present data s uggest that budipine acts by blocking muscarinic and NMDA transmission while facilitation of dopaminergic transmission does not appear to co ntribute to its in vivo action. In comparison to biperiden, which has also antimuscarinic and NMDA receptor antagonistic properties, the ant i-NMDA action of budipine is more prominent.