CRUCIAL ROLE OF THE ACCUMBENS NUCLEUS IN THE NEUROTRANSMITTER INTERACTIONS REGULATING MOTOR CONTROL IN MICE

Previous work, based on systemic drug administration, has shown that n eurotransmitter interactions between dopaminergic, adrenergic, glutama tergic and cholinergic systems are involved in locomotor control in mi ce. In an attemp to identify the target sites in the brain of these in teractions, we have started a series of experiments, where the drugs a re administered intracerebrally in mice.The locomotor threshold doses of the competitive NMDA antagonist AP-5 and the noncompetitive NMDA an tagonist MK-801 were investigated by means of local application in the accumbens nucleus of monoamine-depleted and monoaminergically intact mice, respectively. The threshold dose of AP-5 was lower in depleted t han in intact animals, whereas the threshold dose of MK-801 was lower in monoaminergically intact than monoamine-depleted mice. The locomoto r effects of AP-5 and the AMPA-kainate receptor antagonist CNQX were r egistered in monaomine-depleted mice after local application in the ac cumbens or entopedunular nucleus (= medial pallidum). Both AP-5 and CN QX stimulated locomotor activity in the accumbens, but had no effects in the entopedunular nucleus. We have previously shown synergistic int eractions with regard to locomotor stimulation in monoamine-depleted m ice, between an NMDA antagonist and an alpha(2)-adrenoceptor agonist o r a dopamine D1 agonist (all drugs given systemically). In the present study the alpha(2)-adrenoceptor agonist alpha-methyl-noradrenaline wa s applied intracerebrally in combination with a subthreshold dose of M K-801 given intraperitoneally: Locomotor stimulation was produced afte r alpha-methyl-noradrenaline injection into the accumbens nucleus, but not after injection into the dorsal striatum, prefrontal cortex or th alamus. Likewise, local application of the D1 agonist SKF 38393, in co mbination with a subthreshold dose of MK-801 given intraperitoneally, point to an important role of the accumbens nucleus in motor control. Previous experiments based on systemic drug administration have also s hown a synergistic interaction between a muscarine antagonist and an a lpha(2)-adrenoceptor agonist in monoamine-depleted mice. Local applica tion of the muscarine antagonist methscopolamine, in combination with the alpha(2)-adrenoceptor agonist clonidine given intraperitoneally; s howed that the striatum, in this case both the ventral and dorsal part s of the striatum, is an important target for the muscarine antagonist . Unilateral injection of AP-5 into the accumbens nucleus of mice indu ces rotational behaviour: Previous findings have shown that the rotati on is ipsilateral in monoaminergically intact animals, whereas monoami ne-depleted animals rotate contralaterally. In addition, these finding s have shown that dopamine D2 receptor stimulation seems to determine whether AP-5 will induce ipsilateral or contralateral rotation. In the present study we report further evidence for a crucial role of the D2 receptor in this respect. Finally, the rotational effects of AP-5 inj ected into the dorsal striatum or hippocampus were investigated: As af ter AP-5 application into the accumbens nucleus, monoaminergically int act mice rotated ipsilaterally, whereas monoamine-depleted animals rot ated contralaterally, following AP-5 application in the dorsal striatu m or the hippocampus. The present data show that the accumbens nucleus has an important role in motor control. Both glutamatergic, muscarine cholinergic, dopaminergic and alpha-adrenergic systems are involved i n the control of motor functions in the accumbens nucleus.