Facilitation of dopamine D 1 receptor- but not dopamine [formula omitted] receptor-dependent locomotion by glutamate antagonists in the reserpine-treated mouse

Abstract

The effects of a selection of N- methyl- D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonists on dopamine D 1 and D 2 receptor-dependent locomotor activity were studied in 24 h reserpine-treated mice. At fixed doses, determined from a previous study to be optimal for augmenting D 1-dependent locomotion, 3-[(+)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP; 1 mg/kg), R-(E)-2-amino-4-methyl-5-phosphono-3-pentanoate (CGP 40116; 1 mg/kg), ( RS)-3-amino-1-hydroxypyrrolidin-2-one (HA 966; 2 mg/kg), (+)-methyl-10,11-dihydro-5H-dibenzo-(a,d)-cyclohepten-5,10-imine (MK 801; 0.4 mg/kg) and 2,3-hydroxy-6-nitro-7-sulphamoyl-benzo(f)-quinoxaline-dione (NBQX; 0.2 mg/kg) all failed to reverse the akinesia of reserpine treatment by themselves. As expected, however, all five glutamate receptor antagonists potentiated locomotion induced by 30 mg/kg 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF 38393; D 1 receptor agonist). Only CPP and MK 801 potentiated a threshold dose of SKF 38393 (3 mg/kg). Locomotion evoked with 5 mg/kg N-n-propyl- N-phenylethyl- p (3-hydroxyphenyl) ethylamine hydrochloride (RU 24213; D 2 receptor agonist) was attenuated by HA 966 and MK 801, but not by CPP, CGP 40116 (except at higher doses) or NBQX. SKF 38393 (3 mg/kg) and RU 24213 (5 mg/kg) interacted synergistically to elicit locomotion which was unaffected by CPP, CGP 40116, HA 966 and NBQX, and inhibited by MK 801. SKF 38393 (3 mg/kg) and RU 24213 (0.5 mg/kg) represented a threshold mixed D 1 D 2 motor stimulus that was not modified by any of the glutamate receptor antagonists. These results show that doses of NMDA and AMPA receptor antagonists which are capable of facilitating robust D 1-mediated locomotor responses, do not have the same consistent effect against threshold D 1 responses, while threshold or fully active mixtures of D 1 and D 2 receptor agonists are not potentiated at all, and may even be inhibited by glutamate receptor blockade. It is concluded that an increase in D 1 responding alone is not sufficient to account for the increased antiparkinsonian efficacy of L-dihydroxyphenylalanine (L-DOPA) in the presence of glutamate receptor blockade, described in earlier studies.