A synaptic mechanism underlying the behavioral abnormalities induced by manganese intoxication.
In the present study we have characterized a rat model of manganese (Mn) intoxication leading to behavioral disinhibition in the absence of major motor 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 an enhanced dopaminergic inhibitory control of the corticostriatal excitatory transmission via presynaptic D2-like dopamine (DA) receptors in slices obtained from Mn-treated rats. Conversely, the use of agonists acting on presynaptic purinergic, muscarinic, and glutamatergic metabotropic receptors revealed a normal sensitivity. Moreover, membrane responses recorded from single dopaminergic neurons following activation of D2 DA autoreceptors were also unchanged following Mn intoxication. Thus, our findings indicate a selective involvement of the D2-like DA receptors located on glutamatergic corticostriatal terminals in this pathological condition and suggest that the behavioral symptoms described in the "early" clinical phase of manganism may be caused by an abnormal dopaminergic inhibitory control on corticostriatal inputs. The identification of the synaptic mechanism underlying the "early" phase of Mn intoxication might have a critical importance to understand the causes of the progression of this pathological condition towards an "established" phase characterized by motor abnormalities and anatomical lesions of the basal ganglia.
Calabresi
P
P
Clinica Neurologica, Dipartemente Neuroscienze, Universita' di Roma Tor Vergata, Via di Tor Vergata 135, Rome, 00133, Italy.
Ammassari-Teule
M
M
Gubellini
P
P
Sancesario
G
G
Morello
M
M
Centonze
D
D
Marfia
G A
GA
Saulle
E
E
Passino
E
E
Picconi
B
B
Bernardi
G
G
D000818:Animals; D001479:Basal Ganglia / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry; D004298:Dopamine / Q000494:pharmacology; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D008099:Liver / Q000737:chemistry; D008297:Male; D008345:Manganese / Q000032:analysis / Q000494:pharmacology; D020149:Manganese Poisoning / Q000503:physiopathology*; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D020734:Parkinsonian Disorders / Q000139:chemically induced; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D013378:Substantia Nigra / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects
D017448:Receptors, Dopamine D2; D008345:Manganese; D004298:Dopamine