A synaptic mechanism underlying the behavioral abnormalities induced by manganese intoxication

In the present study we have characterized a rad: model of manganese (Mn) i ntoxication leading to behavioral disinhibition in the absence of major mot or alterations. These behavioral changes were associated with significantly increased brain Mn levels but were uncoupled to anatomical lesions of the striatum or to morphological and cytochemical changes of the nigrostriatal dopaminergic pathway. The analysis of this model at cellular level showed a n enhanced dopaminergic inhibitory control of the corticostriatal excitator y transmission via presynaptic DP-like dopamine (DA) receptors in slices ob tained from Mn-treated rats. Conversely, the use of agonists acting on pres ynaptic purinergic, muscarinic, and glutamatergic metabotropic receptors re vealed a normal sensitivity. Moreover, membrane responses recorded from sin gle dopaminergic neurons following activation of D2 DA eutoreceptors were a lso unchanged following Mn intoxication. Thus, our findings indicate a sele ctive involvement of the DP-like DA receptors located on glutamatergic cort icostriatal terminals in this pathological condition and suggest that the b ehavioral symptoms described in the "early" clinical phase of manganism may be caused by an abnormal dopaminergic inhibitory control on corticostriata l inputs. The identification of the synaptic mechanism underlying the "earl y" phase of Mn intoxication might have a critical importance to understand the causes of the progression of this pathological condition towards an "es tablished" phase characterized by motor abnormalities and anatomical lesion s of the basal ganglia. (C) 2001 Academic Press.