Involvement of Cholinergic System in Hyperactivity in Dopamine-Deficient Mice

Abstract

Dopaminergic systems have been known to be involved in the regulation of locomotor activity and development of psychosis. However, the observations that some Parkinson's disease patients can move effectively under appropriate conditions despite low dopamine levels (eg, kinesia paradoxia) and that several psychotic symptoms are typical antipsychotic resistant and atypical antipsychotic sensitive indicate that other systems beyond the dopaminergic system may also affect locomotor activity and psychosis. The present study showed that dopamine-deficient (DD) mice, which had received daily L-DOPA injections, could move effectively and even be hyperactive 72 h after the last L-DOPA injection when dopamine was almost completely depleted. Such hyperactivity was ameliorated by clozapine but not haloperidol or ziprasidone. Among multiple actions of clozapine, muscarinic acetylcholine (ACh) activation markedly reduced locomotor activity in DD mice. Furthermore, the expression of choline acetyltransferase, an ACh synthase, was reduced and extracellular ACh levels were significantly reduced in DD mice. These results suggest that the cholinergic system, in addition to the dopaminergic system, may be involved in motor control, including hyperactivity and psychosis. The present findings provide additional evidence that the cholinergic system may be targeted for the treatment of Parkinson's disease and psychosis.

Unilateral Lesion of Dopamine Neurons Induces Grooming Asymmetry in the Mouse

“…L-DOPA administration also had effects on other grooming parameters. The main effect was a general increase in total grooming duration, an effect that could be related to the increase of general activity stimulated by L-DOPA [ 28 ]. In addition, we did not observe any L-DOPA effect on the frequency of complete grooming, suggesting a lack of efficiency of L-DOPA to restore sequence completion that was altered by the 6-OHDA lesion.…”

Opioid and nondopamine reward circuitry and state‐dependent mechanisms

“…We previously found that dopamine‐deficient mice became hypoactive 24 h after the last l ‐DOPA injection, when striatal dopamine levels were low but could be detected. Unexpectedly, dopamine‐deficient mice became hyperactive in a novel environment 72 h after the last l ‐DOPA injection (Fig. ).…”

Early manifestation of depressive‐like behavior in transgenic mice that express dementia with Lewy body‐linked mutant β‐synuclein

“…Nest building (Data S3) was assessed by leaving a mouse in a cage that was covered with a Palsoft Sheet Type (ie, a sheet‐type bedding material; Oriental Yeast, Tokyo, Japan) for one night, followed by visual examination of the formation of a nest. Locomotor activity (Data S1) was assessed in a novel environment as described previously using a Supermex apparatus (Muromachi Kikai, Tokyo, Japan) and a sensor monitor that was mounted above the chamber. Each mouse was exposed to an illuminated chamber (30 cm × 40 cm × 25 cm).…”