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

Abstract

In 24 h reserpine-treated akinetic mice, locomotion was induced by the D1-selective agonist SKF 38393 (30 mg/kg IP), or by the mixed D1/D2 agonists L-dopa (150 mg/kg IP, plus benserazide 100 mg/kg IP) and apomorphine (0.5 mg/kg SC). The non-competitive NMDA receptor antagonist MK 801 (0.01-1.6 mg/kg IP) did not induce motor activity by itself, but potentiated the motor responses to L-dopa and apomorphine at roughly 10-fold lower doses than those which facilitated D1 responding. These data cast doubt on the notion that glutamate antagonists enhance the antiparkinsonian efficacy of mixed D1/D2 agonists solely through a D1 receptor mechanism.

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

“…Nevertheless, other groups have failed to detect any such cooperativity between low doses of apomorphine (0.025-0.1mg/kg) and MK 801 (0.1-0.4mg/kg), or for that matter any other glutamate antagonist (amantadine, CPP, CGP 40116, HA 966, NBQX), in respect of either stereotypy (Verma and Kulkarni, 1992) or locomotion (Starr andStart, 1993b, 1995) in reserpinised mice. By contrast, small doses of MK 801 (0.01-0.1 mg/kg) were found to potentiate stereotyped and horizontal activities of a behaviourally effective dose of the DiD 2 agonist (0.5 mg/kg; Kaur et al, 1994;Verma and Kulkarni, 1992). Animals appeared hyperexcited, often running about the cage and showing perseverative rearing, with no signs of the muscle uncoordination commonly seen with larger doses of MK 801.…”

“…Dopamine efftux was not affected by including MK 801 (150 nM) in the perfusing solution, whereas a modest and predictable increase in extracellular dopamine was detected when L-DOPA (10 ~M) was added. The most significant finding, was an enormous potentiation of the L-DOPA response when This low concentration of MK 801, was calculated to be equivalent to the brain concentration reached by 0.01mg/kg MK 801, which we found was sufficient to enhance the L-DOPA response in behavioural experiments (Kaur et al, 1994). It did not affect dopamine output by itself in intact nigras, and so we can rule out a straightforward facilitation of the dopamine release mechanism by MK 801.…”

“…This represented a true synergism between the dopaminergic agonist and the glutamate antagonist. Kaur et al (1994) later repeated this observation with a mixture of an effective amount of L-DOPA (150mg/kg) and MK 801 (0.025-0.05mg/kg) in reserpine-treated mice. In both cases there was no appreciable loss of muscle coordination, as such low doses of MK 801 were used, suggesting that very small adjunctive doses of glutamate antagonists might be used to boost the antiparkinsonian efficacy of L-DOPA in man.…”

“…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.…”

Effects of glutamate antagonists on nigral dopamine release in the reserpine-treated rat

“…For the next experiments, 2-mm dialysis probes were constructed and implanted bilaterally in the SNR. The results of earlier behavioural studies had indicated that the noncompetitive NMDA ion channel blocker dizocilpine potentiated the motor restorative action of r.-dopa in parkinsonian rodents and primates at doses that by themselves had no effect on motor behaviour [7,8]. We therefore examined whether dizocilpine affected the rate of conversion of I,-dopa to dopamine.…”