Original articlesClozapine and the mitogen-activated protein kinase signal transduction pathway: Implications for antipsychotic actions
Section snippets
Drugs
Clozapine was dissolved in 5% glucose acidified with acetic acid and administered intraperitoneally (IP) at 10 mg/kg in a volume of 1 mL/kg. DOI was dissolved in 5% glucose and administered subcutaneously at 10 mg/kg in a volume of 1 mL/kg. Kinase inhibitors were dissolved in dimethylsulfoxide (DMSO) and diluted (except SL-327) to 10 μmol/mL immediately before injection (1 μL per side).
Animals
Male Sprague-Dawley rats (200–250 g) were purchased from the Sasko-Kingston colony of Charles Rivers
Clozapine increases phosphorylation of MEK1/2 and ERK
Systemic clozapine administration increased phosphorylation of MEK1/2 in the prefrontal cortex at 30 min as determined by Western blots [F(1,9) = 24.15, p < .01; Figure 1A]. This elevation of MEK1/2 phosphorylation was responsive to increasing clozapine dose (Figure 1B). The phosphorylation of p38 [F(1,9) = .33, p < .58] or c-Jun N-terminal (JNK) kinase [F(1,9) = 1.01, p < .34] was unaffected. To determine the pharmacologic specificity of clozapine-induced increase in phosphoMEK1/2, the 5-HT2A
Discussion
The JNK and p38 cascades are highly responsive to stress, as well as being involved in cell survival and growth (Hagemann and Blank 2001). In addition to being involved in differentiation (Sweatt 2001), the MEK/ERK pathway has been implicated in learning and memory (Atkins et al 1998) and long-term potentiation (LTP; Davis et al 2000). Thought to play a crucial role in learning and memory, LTP is a long-term cellular adaptation to the effect of short-term neurotransmitter action. In cell
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2018, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Lifetime antipsychotic use was inversely correlated with methylation at a CpG island 30 kb upstream of the mitogen-activated protein kinase 1 (MEK1) gene, once again demonstrating the demethylating action of antipsychotics. This is a notable finding given that clozapine selectively interacts with MEK1 to activate the mitogen- activated protein-kinase (MAPK) signaling pathway (Browning et al., 2005). The clinical relevance of this interaction is yet to be understood.