title: Calcium-dependent, D2 receptor-independent induction of c-fos by haloperidol in dopamine neurons.
abstract: Antipsychotic drugs such as haloperidol act as dopamine D2 receptor antagonists to produce a number of cellular effects including the induction of immediate-early genes such as c-fos. It has been hypothesized that blockade of D2 receptors by antipsychotics is responsible for the induction of c-fos, but the mechanism has not been determined. Using cultured ventral tegmental area (VTA) dopaminergic neurons as a model, we report that nanomolar concentrations of haloperidol cause a time-dependent increase in Fos expression in dopaminergic neurons.Surprisingly, this induction was not mimicked by sulpiride, a selective D2 receptor antagonist, and was not blocked by Rp-cAMPS, an antagonist of protein kinase A (PKA), thus suggesting that D2 receptors and the cAMP cascade are not required. The induction of Fos expression was blocked by tetrodotoxin, BAPTA and KN-93, thus showing that it is activity- and calcium-dependent and requires the activation of a calmodulin-dependent kinase (CaMK). Together, these results suggest that haloperidol induces Fos expression in dopaminergic neurons through a D2 receptor-independent increase in intracellular calcium, leading to CaMK activation.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Université de Montréal, 2900 Boulevard Edouard-Montpetit, Montréal, Québec H3T 1J4, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Jomphe
authors.forename: D
authors.initials: D
authors.lastname: Lévesque
authors.forename: L-E
authors.initials: LE
authors.lastname: Trudeau
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D005576:Colforsin / Q000037:antagonists & inhibitors / Q000378:metabolism; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D016762:Genes, fos / Q000187:drug effects* / Q000235:genetics; D006220:Haloperidol / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis* / Q000187:drug effects; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013873:Thionucleotides / Q000378:metabolism / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D002118:Calcium; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D005576:Colforsin; D000242:Cyclic AMP; D004298:Dopamine; D006220:Haloperidol; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D017480:Receptors, sigma; D013449:Sulfonamides; D013779:Tetrodotoxin; D013873:Thionucleotides; C072105:KN 93; D000096926:Benzenesulfonamides; C016957:adenosine-3',5'-cyclic phosphorothioate