Effect of chronic haloperidol treatment on dopamine-induced inositol phosphate formation in rat brain slices

The effects of chronic haloperidol administration on the accumulation of inositol phosphates were examined in rat brain slices pre-labeled with [³H]myo-inositol and incubated with various dopaminergic drugs. Rats were treated with haloperidol-decanoate or its vehicle (sesame oil) for two, four or six weeks. Dopamine and the selective D₁ agonist, SKF38393, induced a significant increase in lithium-dependent accumulation of [³H]inositol monophosphate (IP₁) in the frontal cortex, hippocampus and striatum of vehicle-treated animals, while the selective D₂ agonist quinpirole did not show any effect on IP₁ accumulation. The actions of dopamine and SKF38393 were blocked by the D₁ antagonist, SCH23390, but not by the D₂ antagonist, spiperone, in all three brain regions. Haloperidol treatment did not affect basal phosphoinositide turnover in the three brain regions. Four or six weeks of haloperidol treatment significantly decreased dopamine-induced IP₁ accumulation in the striatum (by 30% and 25%, respectively), but not in the frontal cortex and the hippocampus. Four weeks of treatment with haloperidol significantly decreased IP₁ levels in the striatal slices when measured in the presence of quinpirole. However, the accumulation of IP₁ measured in the presence of SKF38393 was not significantly altered after haloperidol treatment. The loss of dopamine-sensitive IP accumulation was not observed in the presence of spiperone after haloperidol treatment. The number, but not the affinity, of [³H]sulpiride binding sites in the striatum was significantly increased (by 34–46%) after chronic haloperidol treatment. A timecourse study suggests that the inhibition by chronic haloperidol treatment of dopamine-induced phosphoinositide hydrolysis may involve an effect secondary to an increase in the number of dopamine D₂ receptors in the striatum.