Glutamate antagonists modify the motor stimulant actions of D1 and D2 agonists in reserpine-treated mice in complex ways that are not predictive of their interactions with the mixed D1/D2 agonist apomorphine

Abstract

In 24h reserpine-treated mice, the locomotion induced by the D1 dopamine agonist SKF 38393 (30 mg/kg IP) was facilitated by the NMDA antagonists MK 801 (0.4 mg/kg IP), CPP (1 mg/kg IP), CGP 40116 (1 mg/kg IP) and HA 966 (2 mg/kg IP), and by the AMPA antagonist NBQX (0.2 mg/kg IP). By contrast, CPP, CGP 40116 and NBQX had no effect on, while MK 801 and HA 966 suppressed, the locomotion elicited by the selective D2 agonist RU 24213 (5 mg/kg SC). When these same doses of glutamate antagonists were tested against the locomotion induced by a threshold (0.025 mg/kg SC), intermediate (0.1 mg/kg SC) or large dose (0.5 mg/kg SC) of the mixed D1/D2 agonist apomorphine, CPP, CGP 40116 and HA 966 were found to have no significant effect, whilst MK 801 was strongly inhibitory and NBQX potentiated the response to 0.1 mg/kg apomorphine only. It is evident from these data that the behavioural interaction profiles between glutamate antagonists and dopamine agonists are complex and depend on the receptor selectivities of the drugs concerned. The manner of the interaction between these glutamate antagonists and selective D1 or D2 agonists, is not predictive of the way that blockade of glutamate transmission interferes with the actions of drugs which have combined D1 and D2 motor stimulant properties.

Role of D1 receptor mechanisms in the potentiation of motor responses to L-DOPA and apomorphine by MK 801 in the reserpine-treated mouse

“…This finding has given rise to speculation that antagonists of glutamate receptors might be used in conjunction with dopamine agonists, to correct basal ganglia pathophysiology and to relieve parkinsonian akinesia (Greenamayre, 1993;Klockgether and Turski, 1989;Schmidt et al, 1992). In line with this prediction, compounds which selectively block NMDA or AMPA-type glutamate receptors, have demonstrated little or no antiparkinsonian efficacy by themselves, but they have been found to greatly facilitate the motor restorative actions of L-DOPA (Klockgether et al, , 1991L6schmann et al, 1992;Maj et al, 1993;Morelli et al, 1992;Morelli and Di Chiara, 1990;Wtillner et al, 1992) and apomorphine (Carlsson and Carlsson, 1989;Morelli and Di Chiara, 1990;Starr and Starr, 1993b;Wachtel et al, 1992), although not in all cases (Starr and Starr, 1993b;Svensson et al, 1992;Wachtel et al, 1992).…”

“…However. we found recently with the noncompetitive NMDA receptor antagonist MK 801, that doses which were optimum for potentiating SKF 38393 alone (Goodwin et al, 1992), had a deleterious effect on motor responses evoked with the mixed DID2 receptor agonist apomorphine {Starr and Starr, 1993b), or with a mixture of SKF 38393 (D 1 agonist) and Ru 24213 (D2 agonist) (Starr and Starr, 1993a). Carlsson's group observed a similar discrepancy between the capacity of MK 801 to accentuate motility induced by SKF 38393 in monoamine-depleted mice, and the attenuation of motility induced by an effective dose of apomorphine under these conditions (Svensson et aL, 1992).…”

Effect of coadministration of glutamate receptor antagonists and dopaminergic agonists on locomotion in monoamine-depleted rats

“…Stereotaxical injections of glutamate agonists into the striatum, substantia nigra compacta/globus pallidus internus and subthalamic nucleus reveal, by causing parkinsonian symptoms possible sites of action for glutamate receptor antagonists (Klockgether and Turski, 1993). However, the precise site of action of glutamate receptor antagonists administered systemically and their mode of interaction with dopamine agonists is far from being clear (Starr and Starr, 1993).…”

Antiparkinsonian actions of glutamate antagonists — alone and with L-DOPA: A review of evidence and suggestions for possible mechanisms

“…This is illustrated by the fact that a slightly lower dose of CGP 37849 (7.5mg/kg), neither accentuated nor attenuated the responses of reserpinised mice to the mixed DI/D 2 agonists CI 201-678 and SDZ 205-152 (Kannari and Markstein, 1991). Other glutamate antagonists (CGP 40116, CPP, HA 966 and NBQX) were found not to affect the sensitivity of monoamine-depleted mice to apomorphine, when used at doses that optimally potentiated SKF 38393 (Starr and Starr, 1993b). This result has to be viewed cautiously, however, in light of the more recent finding that the optimal dose of MK 801 required to increase D1/D 2 motor responding, was >10 times less than the optimal dose that facilitated Dl-dependent locomotion.…”

“…Greater than additive motor interactions have also been described with MK 801 and the mixed DiD 2 agonist pergolide (Smg/kg; Goodwin et al, 1992), and between CPPene (Smg/kg) and CI 210-678 (0.1mg/kg), but not between CPPene and SDZ 205-152 (0.5 mg/kg; Kannari and Markstein, 1991) in the reserpine model. With other combinations of MK 801 and apomorphine, however, it is not uncommon to see the two drugs interacting in a negative fashion (Kaur and Starr, 1994;Starr and Starr, 1993b;Svensson et al 1992b). Thus, 0.4 mg/kg MK 801, which was optimal for increasing SKF 38393-induced locomotion, suppressed locomotion evoked by apomorphine.…”