title: Postnatal manganese exposure alters the expression of D2L and D2S receptor isoforms: relationship to PKA activity and Akt levels.
abstract: Postnatal manganese chloride (Mn) exposure causes persistent changes in presynaptic dopamine (DA) functioning (e.g., Mn reduces DA transporter levels and DA uptake), but evidence that Mn affects postsynaptic DA receptors and their associated second messenger systems is equivocal. Therefore, a goal of the present study was to determine whether exposing rats to Mn on postnatal days (PD) 1-21 would cause long-term alterations in D2 long (D2L) and D2 short (D2S) receptors that were detectible in adulthood (i.e., on PD 90). Signaling systems associated with D2 receptors were also assessed. Specifically, we measured protein kinase A (PKA) activity in the dorsal striatum and prefrontal cortex (PFC), whereas immunoblotting was used to quantify phosphorylated Akt (p-Akt) and phosphorylated ERK. Results showed that early Mn exposure caused a persistent elevation of D2L and D2S protein expression in the dorsal striatum, as well as an increase in the number of D2 binding sites. Conversely, Mn reduced D2 specific binding in the PFC on PD 90. PKA activity of Mn-treated rats was enhanced in both the dorsal striatum and PFC, whereas p-Akt levels were elevated in the dorsal striatum. When considered together, these results suggest that postnatal Mn exposure either directly or indirectly alters the functioning of postsynaptic DA receptors. One possibility is that early Mn exposure depresses presynaptic dopaminergic functioning and reduces DA levels, thereby causing an up-regulation of D2 receptors and a dysregulation of DA-associated signaling pathways. An alternative explanation is that early Mn exposure affects D2 receptors and PKA/p-Akt levels via independent mechanisms.
authors.affiliation: Department of Psychology, California State University, San Bernardino, California 92407, USA. smcdouga@csusb.edu
authors.forename: Sanders A
authors.initials: SA
authors.lastname: McDougall
authors.forename: Taleen
authors.initials: T
authors.lastname: Der-Ghazarian
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Britt
authors.forename: Fausto A
authors.initials: FA
authors.lastname: Varela
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Crawford
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002712:Chlorides / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D008297:Male; D017895:Manganese Compounds / Q000494:pharmacology*; D020033:Protein Isoforms / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D002712:Chlorides; D017895:Manganese Compounds; D020033:Protein Isoforms; D017448:Receptors, Dopamine D2; C113776:dopamine D2L receptor; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; C025340:manganese chloride