Behavioural interaction between the NMDA antagonist MK-801 and the dopaminergic antagonist haloperidol: support for a balance model

Abstract

One hundred and four male Sprague-Dawley rats were divided into three experiments. The first two experiments were to assess the effect of different MK-801 doses (0.1-0.3 mg/kg) and combinations of MK-801/ haloperidol (0.3/0.1-0.5 mg/kg) on locomotor behaviour. The animals from the third experiment were administered either saline, MK-801 (0.3 mg/kg), haloperidol (0.5 mg/kg) or MK-801/haloperidol (0.3/0.5 mg/kg). Locomotor activity measurements showed that the NMDA antagonist MK-801 induced a dose-dependent hyperactivity, while haloperidol, the D-2 dopamine receptor antagonist, induced hypoactivity. Significantly the highest doses of combined MK-801/haloperidol treatment (0.3/0.5 mg/kg) showed behavioural equivalence to the saline animals in both total locomotion, locomotion patterns and within-session habituation. Thus, the behavioural effects of each drug given alone were cancelled when the drugs were given together. This cancellation effect could not be ascribed to direct drug interference effects on dopamine metabolism since the ex vivo biochemical data revealed that the combined MK-801/haloperidol (0.3/0.5 mg/kg) treatment increased dopamine metabolism to the same extent as haloperidol given alone. None of the drug treatments, however, had any effect on brain serotonin metabolism. Serum measurement indicated that dopamine, homovanillic acid, 3,4-dihydroxyphenyl-acetic acid, 5-hydroxyindole-3-acetic acid, norepinephrine and corticosterone were not differentially affected by the drug treatment. Haloperidol-treated animals, however, had higher serum serotonin concentration than saline-treated animals. Taken together, these results support the hypothesis that the effect of MK-801 on behaviour is independent of biochemical changes in dopaminergic neuro transmission per se. Rather, the present results support the hypothesis of a glutamatergic-dopaminergic balance which when disturbed leads to behavioural changes along an excitatory-inhibitory behavioural gradient.