Calcium-dependent, D2 receptor-independent induction of c-fos by haloperidol in dopamine neurons

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 367; no. 5; pp. 480 - 489
• Main Authors: Jomphe, C, Lévesque, D, Trudeau, L-E
• Format: Journal Article
• Language: English
• Published: Germany 01.05.2003
• Subjects: Animals; Benzylamines - pharmacology; Calcium - physiology; Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinases - drug effects; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cells, Cultured; Colforsin - antagonists & inhibitors; Colforsin - metabolism; Cyclic AMP - analogs & derivatives; Cyclic AMP - metabolism; Cyclic AMP - pharmacology; Dopamine - physiology; Gene Expression - drug effects; Gene Expression - genetics; Genes, fos - drug effects; Genes, fos - genetics; Haloperidol - administration & dosage; Haloperidol - antagonists & inhibitors; Haloperidol - pharmacokinetics; Neurons - drug effects; Neurons - physiology; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2 - biosynthesis; Receptors, Dopamine D2 - drug effects; Receptors, sigma - drug effects; Receptors, sigma - metabolism; RNA, Messenger - metabolism; Second Messenger Systems - drug effects; Second Messenger Systems - physiology; Signal Transduction; Sulfonamides - pharmacology; Tetrodotoxin - pharmacology; Thionucleotides - metabolism; Thionucleotides - pharmacology; Ventral Tegmental Area - cytology; Ventral Tegmental Area - drug effects; Ventral Tegmental Area - physiology
• ISSN: 0028-1298
• DOI: 10.1007/s00210-003-0742-3

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.