Crucial role of the accumbens nucleus in the neurotransmitter interactions regulating motor control in mice

Abstract

Previous work, based on systemic drug administration, has shown that neurotransmitter interactions between dopaminergic, adrenergic, glutamatergic and cholinergic systems are involved in locomotor control in mice. In an attempt to identify the target sites in the brain of these interactions, we have started a series of experiments, where the drugs are administered intracerebrally in mice. The locomotor threshold doses of the competitive NMDA antagonist AP-5 and the noncompetitive NMDA antagonist 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 than in intact animals, whereas the threshold dose of MK-801 was lower in monoaminergically intact than monoamine-depleted mice. The locomotor effects of AP-5 and the AMPA-kainate receptor antagonist CNQX were registered in monamine-depleted mice after local application in the accumbens or entopeduncular nucleus (= medial pallidum). Both AP-5 and CNQX stimulated locomotor activity in the accumbens, but had no effects in the entopeduncular nucleus. We have previously shown synergistic interactions with regard to locomotor stimulation in monoamine-depleted mice, between an NMDA antagonist and an alpha 2-adrenoceptor agonist or a dopamine D1 agonist (all drugs given systemically). In the present study the alpha 2-adrenoceptor agonist alpha-methylnoradrenaline was applied intracerebrally in combination with a subthreshold dose of MK-801 given intraperitoneally: Locomotor stimulation was produced after alpha-methyl-noradrenaline injection into the accumbens nucleus, but not after injection into the dorsal striatum, prefrontal cortex or thalamus. Likewise, local application of the D1 agonist SKF 38393, in combination 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 shown a synergistic interaction between a muscarine antagonist and an alpha 2-adrenoceptor agonist in monoamine-depleted mice. Local application of the muscarine antagonist methscopolamine, in combination with the alpha 2-adrenoceptor agonist clonidine given intraperitoneally, showed that the striatum, in this case both the ventral and dorsal parts of the striatum, is an important target for the muscarine antagonist. Unilateral injection of AP-5 into the accumbens nucleus of mice induces rotational behaviour: Previous findings have shown that the rotation is ipsilateral in monoaminergically intact animals, whereas monoamine-depleted animals rotate contralaterally. In addition, these findings 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 injected into the dorsal striatum or hippocampus were investiga...

Role of Dopaminergic System in Core Part of Nucleus Accumbens in Hyperlocomotion and Rearing Induced by MK-801 in Rats: A Behavioral and In Vivo Microdialysis Study

“…It has been reported that MK-801 increases DA release in the locus coeruleus, but decreases uptake of norepinephrine in the locus coeruleus and that of 5-HT in the dorsal raphe nucleus. However, different results had been reported for effect of MK-801 on DA release in the ACC: no effect (36,37), increase (26,32,38,39) and even decrease (40). Our results indicate that MK-801at 0.1 mg /kg did not increase DA level in the cACC.…”

“…A subthreshold i.p. dose of MK-801 produces locomotor stimulation after alpha-methyl-noradrenaline injection into the ACC but not into the dorsal striatum, prefrontal cortex or thalamus (38). MK-801-hyperlocomotion is accompanied by increased DA release in the cACC, but not in the ventral pallidum (46).…”

“…However, the same dose of MK-801 has been reported to increase DA level in the sACC, but not in the cACC, due to the relative degree of NMDA-receptor antagonism in the sACC (27). Accordingly, it could be suggested that MK-801 at a low dose does not increase DA level in the cACC due to a regional selectivity, failure in inhibiting the intrinsic GABA neurons and disinhibiting DA release (38) or to lack of effect on sigma 1 and 2 receptors subtypes (41) in the cACC.…”

Acute and Chronic Effects of Methamphetamine on Tele-Methylhistamine Levels in Mouse Brain: Selective Involvement of the D2 and not D3Receptor

“…Even more, the comparison of the two temporal profiles suggests that histaminergic neurons are involved in a compensatory manner in the modulation of this response, inasmuch as t-MeHA levels were also increased in the nucleus accumbens, known to be associated with the regulation of locomotor function (Svensson et al, 1995). Consistent with this proposal, enhanced release of endogenous histamine attenuates stimulant-induced locomotor activity (Itoh et al, 1984;Clapham and Kilpatrick, 1994;Ito et al, 1997), and ciproxifan, an H 3 receptor inverse agonist known to enhance histamine neuron activity (Morisset et al, 2000a), strongly decrease methamphetamine-induced hyperlocomotion.…”

The muscarine antagonist methscopolamine and the NMDA antagonist AP-5 injected unilaterally into the nucleus accumbens cause mice to rotate in opposite directions

“…For instance, there seems to be both direct and indirect striatothalamic pathways, and accordingly both positive and negative cortico-striato-thalamo-cortical feedback circuits (see Svensson et al, 1995).…”