title: Lack or inhibition of dopaminergic stimulation induces a development increase of striatal tyrosine hydroxylase-positive interneurons.
abstract: We examined the role of endogenous dopamine (DA) in regulating the number of intrinsic tyrosine hydroxylase-positive (TH(+)) striatal neurons using mice at postnatal day (PND) 4 to 8, a period that corresponds to the developmental peak in the number of these neurons. We adopted the strategy of depleting endogenous DA by a 2-day treatment with α-methyl-p-tyrosine (αMpT, 150 mg/kg, i.p.). This treatment markedly increased the number of striatal TH(+) neurons, assessed by stereological counting, and the increase was highly correlated to the extent of DA loss. Interestingly, TH(+) neurons were found closer to the clusters of DA fibers after DA depletion, indicating that the concentration gradient of extracellular DA critically regulates the distribution of striatal TH(+) neurons. A single i.p. injection of the D1 receptor antagonist, SCH23390 (0.1 mg/kg), the D2/D3 receptor antagonist, raclopride (0.1 mg/kg), or the D4 receptor antagonist, L-745,870 (5 mg/kg) in mice at PND4 also increased the number of TH(+) neurons after 4 days. Treatment with the D1-like receptor agonist SKF38393 (10 mg/kg) or with the D2-like receptor agonist, quinpirole (1 mg/kg) did not change the number of TH(+) neurons. At least the effects of SCH23390 were prevented by a combined treatment with SKF38393. Immunohistochemical analysis indicated that striatal TH(+) neurons expressed D2 and D4 receptors, but not D1 receptors. Moreover, treatment with the α4β2 receptor antagonist dihydro-β-erythroidine (DHβE) (3.2 mg/kg) also increased the number of TH(+) neurons. The evidence that DHβE mimicked the action of SCH23390 in increasing the number of TH(+) neurons supports the hypothesis that activation of D1 receptors controls the number of striatal TH(+) neurons by enhancing the release of acetylcholine. These data demonstrate for the first time that endogenous DA negatively regulates the number of striatal TH(+) neurons by direct and indirect mechanisms mediated by multiple DA receptor subtypes.
authors.affiliation: IRCCS Neuromed, Pozzilli, Italy.
authors.forename: Carla Letizia
authors.initials: CL
authors.lastname: Busceti
authors.forename: Domenico
authors.initials: D
authors.lastname: Bucci
authors.forename: Gemma
authors.initials: G
authors.lastname: Molinaro
authors.forename: Paola
authors.initials: P
authors.lastname: Di Pietro
authors.forename: Luca
authors.initials: L
authors.lastname: Zangrandi
authors.forename: Roberto
authors.initials: R
authors.lastname: Gradini
authors.forename: Rosario
authors.initials: R
authors.lastname: Moratalla
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.forename: Valeria
authors.initials: V
authors.lastname: Bruno
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Francesco
authors.initials: F
authors.lastname: Fornai
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000008:administration & dosage; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010641:Phenotype; D011954:Receptors, Dopamine / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
chemical_list: D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine