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

Abstract

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective Increases in Phosphoinositide Signaling Activity and G Protein Levels in Postmortem Brain from Subjects with Schizophrenia or Alcohol Dependence

“…Prior drug use is clearly a major concern, and a number of psychoactive compounds, including antipsychotic drugs, were detected in some of these schizophrenic brain samples. In several previous studies in animals, treatments with antipsychotic drugs have been reported to decrease phosphoinositide signaling (Friedel and Knauer, 1981;Edwards et al, 1991;Li et al, 1992Li et al, , 1994. If this action of antipsychotic drugs also occurs in humans, these drugs would be predicted to dampen the increased phosphoinositide signaling detected in schizophrenic brain in this study.…”

Pharmacology of signaling induced by dopamine D1-like receptor activation

“…These observations have been made in preparations of the rat kidney (Felder et al, 1989a; Felder et al, 1989b; Vyas et al, 1992a; Hussain and Lokhandwala, 1997), rat brain (Alexander and Crutcher, 1990; Undie and Friedman, 1990a; Undie and Friedman, 1990b; Arias-Montano et al, 1993; Martin and Waszczak, 1993; Li et al, 1994), mouse brain (Friedman et al, 1997; Undie, 1998), postmortem human brain (Wallace and Claro, 1993; Pacheco and Jope, 1997), fresh monkey brain (Panchalingam and Undie, 2001) and clonal cell lines of rat hippocampal origin (Jin et al, 1998). The findings are in contrast with some earlier reports that had implied a lack of association of dopamine with phosphoinositide hydrolysis in neural tissues or clonal cell lines (Pizzi et al, 1987; Cubitt et al, 1987; Pizzi et al, 1988; Rubinstein and Hitzemann, 1990).…”

“…Multiple laboratories have demonstrated that dopamine as well as D 1 -like receptor agonists can activate PLC-mediated phosphoinositide hydrolysis in native mammalian tissues (Felder et al, 1989a; Felder et al, 1989b; Dyck, 1990; Chen et al, 1992; Vyas et al, 1992a; Martin and Waszczak, 1993; Li et al, 1994; Kansra et al, 1995; Pacheco and Jope, 1997; Hussain and Lokhandwala, 1997; Friedman et al, 1997; Rosengarten and Friedhoff, 1998; Jin et al, 1998; Jope et al, 1998). These observations have been made in preparations of the rat kidney (Felder et al, 1989a; Felder et al, 1989b; Vyas et al, 1992a; Hussain and Lokhandwala, 1997), rat brain (Alexander and Crutcher, 1990; Undie and Friedman, 1990a; Undie and Friedman, 1990b; Arias-Montano et al, 1993; Martin and Waszczak, 1993; Li et al, 1994), mouse brain (Friedman et al, 1997; Undie, 1998), postmortem human brain (Wallace and Claro, 1993; Pacheco and Jope, 1997), fresh monkey brain (Panchalingam and Undie, 2001) and clonal cell lines of rat hippocampal origin (Jin et al, 1998).…”