title: Haloperidol modulates midbrain-prefrontal functional connectivity in the rat brain.
abstract: Dopamine D₂ receptor antagonists effectively reduce positive symptoms in schizophrenia, implicating abnormal dopaminergic neurotransmission as an underlying mechanism of psychosis. Despite the well-established, albeit incomplete, clinical efficacies of D₂ antagonists, no studies have examined their effects on functional interaction between brain regions. We hypothesized that haloperidol, a widely used antipsychotic and D₂ antagonist, would modulate functional connectivity in dopaminergic circuits. Ten male Sprague-Dawley rats received either haloperidol (1 mg/kg, s.c.) or the same volume of saline a week apart. Resting-state functional magnetic resonance imaging data were acquired 20 min after injection. Connectivity analyses were performed using two complementary approaches: correlation analysis between 44 atlas-derived regions of interest, and seed-based connectivity mapping. In the presence of haloperidol, reduced correlation was observed between the substantia nigra and several brain regions, notably the cingulate and prefrontal cortices, posterodorsal hippocampus, ventral pallidum, and motor cortex. Haloperidol induced focal changes in functional connectivity were found to be the most strongly associated with ascending dopamine projections. These included reduced connectivity between the midbrain and the medial prefrontal cortex and hippocampus, possibly relating to its therapeutic action, and decreased coupling between substantia nigra and motor areas, which may reflect dyskinetic effects. These data may help in further characterizing the functional circuits modulated by antipsychotics that could be targeted by innovative drug treatments.
authors.affiliation: Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany. Electronic address: natalia.gass@zi-mannheim.de.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gass
authors.forename: Adam James
authors.initials: AJ
authors.lastname: Schwarz
authors.forename: Alexander
authors.initials: A
authors.lastname: Sartorius
authors.forename: Dirk
authors.initials: D
authors.lastname: Cleppien
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.forename: Esther
authors.initials: E
authors.lastname: Schenker
authors.forename: Celine
authors.initials: C
authors.lastname: Risterucci
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weber-Fahr
mesh_terms: D000818:Animals; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D059907:Functional Neuroimaging; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism; D009044:Motor Cortex / Q000187:drug effects / Q000378:metabolism; D009415:Nerve Net / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism
chemical_list: D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D009419:Nerve Tissue Proteins; D017448:Receptors, Dopamine D2; D006220:Haloperidol