Haloperidol modulates midbrain-prefrontal functional connectivity in the rat brain

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.