Haloperidol and clozapine differentially regulate signals upstream of glycogen synthase kinase 3 in the rat frontal cortex

Abstract

Glycogen synthase kinase 3 (GSK3) was recently suggested to be a potential target of psychotropics used in psychiatric illnesses such as schizophrenia and bipolar disorder. Relevant studies have found that antipsychotic drugs regulate GSK3 activity via an increase in either inhibitory serine phosphorylation or amount of GSK3 after acute or subchronic treatment. Recent evidence shows that GSK3 is regulated by dopaminergic or serotonergic systems implicated in the pathophysiology and treatment mechanisms of schizophrenia and bipolar disorder. Therefore, antipsychotics may regulate GSK3 via antagonizing dopaminergic or serotonergic activity. However, the signaling pathway that is involved in GSK3 regulation by dopaminergic or serotonergic systems has not been well established. Haloperidol is a typical antipsychotic with potent dopamine D 2 receptor antagonism. Clozapine is an atypical antipsychotic with potent serotonin 5HT2 receptor antagonism. We injected rats with haloperidol or clozapine and examined the phosphorylation and amount of GSK3α/β and its well-known upstream regulators Akt and Dvl in the rat frontal cortex by Western blotting. Both haloperidol and clozapine induced Ser21/9 phosphorylation of GSK3α/β. Haloperidol increased the Ser473 phosphorylation of Akt transiently, whereas clozapine maintained the increase for 1 h. Haloperidol did not affect the phosphorylation and amount of Dvl, whereas clozapine increased both phosphorylation and the amount of Dvl. Our results suggest that GSK3 activity may be regulated by both typical and atypical antipsychotics and that Akt or Dvl, depending on the D 2 -or 5HT 2 -receptor antagonism properties of typical and atypical antipsychotics, mediate the regulation differently.

Protein Phosphatase 2A and Glycogen Synthase Kinase 3 Signaling Modulate Prepulse Inhibition of the Acoustic Startle Response by Altering Cortical M-Type Potassium Channel Activity

“…Several groups have reported that systemic treatment with the D 2 antagonist haloperidol inhibits GSK3␤ activity in frontal cortex (Li et al, 2007;Roh et al, 2007). However, systemic administration of haloperidol in wild-type mice typically enhances PPI, despite increasing extracellular dopamine in the nucleus accumbens (Hernandez and Hoebel, 1989;Moghaddam and Bunney, 1990;McCaughran et al, 1997;Ouagazzal et al, 2001), whereas infusion of the D 2 agonist quinpirole directly into nucleus accumbens impairs PPI (Wan and Swerdlow, 1993).…”

A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health

“…46,47 Administration of amphetamine, methamphetamine or the nonselective DA receptor agonist apomorphine to normal mice also results in an inhibition of Akt activity and concomitant activation of GSK3, whereas striatal DA depletion has the opposite effect, thus firmly establishing the regulation of the Akt-GSK3 pathway by DA. 31,46,48,49 Further characterization of these signalling responses using selective D1 and D2 receptor antagonists, 46 the antipsychotic haloperidol 50,51 or mice lacking different subtypes of DA receptors have shown that Akt, GSK3α and GSK3β are regulated by D2 receptors. 52 More specifically, D2 receptors appear to be essential for the inhibition of striatal Akt by DA in mice.…”

“…75,77 In addition, a handful of studies also suggest a role for the disheveled Wnt signalling pathway in the regulation of GSK3 activity by antipsychotics. 51,88 Therefore, there may be more than 1 mechanism through which antipsychotic drugs affect GSK3 activity in a given cell or in different neuronal populations. Further characterizations of the role of these mechanisms and of possible functional cross-talk between them at the cellular and system levels may thus be important to understand the possible implication of GSK3-mediated signalling in the effects of these drugs.…”

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

“…Lithium can similarly substitute for Mg in other metalloproteins; its relative specificity for GSK3 and a few other enzymes (such as inositol monophosphatase and inositol polyphosphate 1-phosphatase in the phosphoinositide pathway) stems from biophysical idiosyncrasies - the distribution of positive charges, bulky coordinating residues, and solvent accessibility - of the metal-binding pocket in lithium-sensitive metalloproteins [312]. But lithium is far from the only psychiatric drug to impact GSK3: the mood stabilizer/anticonvulsant valproic acid (VPA) [313,314,315], diverse antipsychotics [316,317,318,319,320], antidepressants including tricyclics and selective serotonin reuptake inhibitors [321,322,323,324], as well as the novel acute antidepressant ketamine [325], all modulate GSK3 as one of their many downstream effects. Many orally administrable molecules with specific and selective inhibitory activity on GSK3 are commercially available and have been widely used in basic scientific studies including in live animal models, with little evidence of toxicity [326,327,328,329,330].…”