Effects of clozapine and 2,5-dimethoxy-4-methylamphetamine [DOM] on 5-HT2A receptor expression in discrete brain areas

Doat-Meyerhoefer, MM; Hard, R; Winter, J.C.; Rabin, Richard A.

doi:10.1016/j.pbb.2005.05.011

Cited by 12 publications

(9 citation statements)

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“…Previous studies reported a sizable amount of 5-HT 2A receptors in the cytosol in addition to that found in the membrane (Cornea-Hébert et al, 1999). Several reports suggest a decrease in B max with no change in K d after treatment with antipsychotics (Matsubara and Meltzer, 1989;Doat-Meyerhoefer et al, 2005). A decrease in the density of 5-HT 2A receptors without any change in affinity is consistent with the receptor internalization previously reported (Roth et al, 1995;Willins et al, 1998).…”

Section: Olanzapine Increases Rgs7 Protein Via Jak-stat Activation 137supporting

confidence: 86%

“…Several studies specifically investigated changes in the transcript level of 5-HT 2A receptors with both short-term and chronic antipsychotic treatments (Burnet et al, 1996;Doat-Meyerhoefer et al, 2005). Buckland et al (1997) reported a significant decrease in receptor mRNA in hippocampus, brain stem, and midbrain, whereas no significant change was observed in other brain regions after 32 days of treatment with the atypical antipsychotic clozapine.…”

Section: Olanzapine Increases Rgs7 Protein Via Jak-stat Activation 137mentioning

confidence: 99%

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Olanzapine Increases RGS7 Protein Expression via Stimulation of the Janus Tyrosine Kinase-Signal Transducer and Activator of Transcription Signaling Cascade

Singh

Ju²,

Zemaitaitis³

et al. 2007

J Pharmacol Exp Ther

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Atypical antipsychotics such as olanzapine have high affinity for multiple monoamine neurotransmitter receptors and are the mainstay of pharmacological therapy for treatment of schizophrenia. In addition to blocking monoamine receptors, these drugs also affect intracellular signaling cascades. We now report that 24-h treatment with 300 nM olanzapine causes desensitization of serotonin (5-HT) 2A receptors in A1A1v cells, a rat cortical cell line, as indicated by a reduction in inositol phosphate accumulation following stimulation with a 5-HT 2A/2C receptor agonist (Ϫ)-1-(2,5-dimethoxy-4-lodophenyl)-2-aminopropane HCl. Olanzapine treatment for 24 h increased the levels of 5-HT 2A receptors in both cytosol (234 Ϯ 34% of control level) and membrane fractions (206 Ϯ 14% of control levels) and RGS7 proteins in both cytosol (193 Ϯ 32% of control levels) and membrane fractions (160 Ϯ 18% of control levels) as measured on Western blots. Increased phosphorylation of Janus tyrosine kinase (JAK) 2 and increased phosphorylation and nuclear translocation of signal transducer and activator of transcription (STAT) 3 with 24-h olanzapine treatment demonstrate activation of the JAK-STAT signaling cascade. Pretreatment with a JAK inhibitor, AG490 [␣-cyano-(3,4-dihydroxy)-N-benzylcinnamide], prevented the olanzapine-induced increase in membrane RGS7 protein levels; AG490 alone had no effect on RGS7 protein levels. We verified that treatment with AG490 reduced phosphorylation of JAK2 and inhibited the nuclear localization of phospho-STAT3. Interestingly, treatment with the JAK inhibitor had no effect on 5-HT 2A receptor protein levels. These data suggest that olanzapine-induced activation of the JAK-STAT signaling cascade causes increased expression of RGS7 protein, which in turn could mediate desensitization of 5-HT 2A receptor signaling caused by olanzapine because RGS7 binds to G␣ q protein and accelerates GTP hydrolysis.

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Section: Olanzapine Increases Rgs7 Protein Via Jak-stat Activation 137supporting

confidence: 86%

Section: Olanzapine Increases Rgs7 Protein Via Jak-stat Activation 137mentioning

confidence: 99%

Olanzapine Increases RGS7 Protein Expression via Stimulation of the Janus Tyrosine Kinase-Signal Transducer and Activator of Transcription Signaling Cascade

Singh

Ju²,

Zemaitaitis³

et al. 2007

J Pharmacol Exp Ther

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“…In addition, studies were inconclusive regarding the role for transcriptional regulation of 5-HT 2A receptor down-regulation with antipsychotics (Gray and Roth, 2001). Both, a decrease in receptor mRNA in hippocampus, brain stem, and midbrain and no change in mRNA levels are reported previously with atypical antipsychotics (Burnet, et al, 1996;Doat-Meyerhoefer, et al, 2005). Thus, transcriptional regulation of 5-HT 2A receptors by atypical antipsychotics does not appear to be responsible for down-regulation leading to the desensitization of 5-HT 2A receptor signaling.…”

Section: Discussionsupporting

confidence: 56%

Activation of the JAK-STAT pathway is necessary for desensitization of 5-HT2A receptor-stimulated phospholipase C signalling by olanzapine, clozapine and MDL 100907

Singh

Dai

Staudinger

et al. 2008

Int. J. Neuropsychopharm.

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We previously demonstrated that olanzapine-induced desensitization of 5-HT2A receptor-stimulated phospholipase C (PLC) activity is associated with increases in RGS7 protein levels both in vivo and in cells in culture, and the increase in RGS7 is dependent on activation of the JAK-STAT pathway in cells in culture (Muma, et al., 2007;Singh, et al., 2007). In the current study, we found that desensitization of 5-HT2A receptor-stimulated PLC activity induced by olanzapine is dependent on activation of the JAK-STAT pathway. Similar to olanzapine, clozapine-induced desensitization of 5-HT2A receptor signaling is accompanied by increases in RGS7 and activation of JAK2. Treatment with the selective 5-HT2A receptor antagonist MDL100907 also increased RGS7 protein levels and JAK2 activation. Using a JAK2 inhibitor AG490, we found that clozapine and MDL100907-induced increases in RGS7 are dependent on activation of the JAK-STAT pathway. Olanzapine, clozapine, and MDL100907 treatment increased mRNA levels of RGS7. Using a chromatin immunoprecipitation assay we found STAT3 binding to the putative RGS7 promoter region. Taken together, olanzapine-induced activation of the JAK-STAT pathway, and STAT3 binding to the RGS7 gene could underlie the increase in RGS7 mRNA which could subsequently increase protein expression. Furthermore, the increase in RGS7 protein could play a role in the desensitization of 5-HT2A receptor signaling by terminating the activated Gαq/11 proteins more rapidly. Overall, our data suggest that the complete desensitization of 5-HT2A receptor-stimulated PLC activity by olanzapine, clozapine and MDL100,907 requires activation of the JAK-STAT pathway, which in turn increases RGS7 expression likely by direct transcriptional activity of STAT3.

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“…In the PCP model, it has been shown that acute atypical drugs such as clozapine and olanzapine inhibit PCP-induced hyperlocomotion primarily due to their multiple actions on D 2 and 5-HT 2A receptors (Gleason and Shannon, 1997; Maurel-Remy et al, 1995; Millan et al, 1999). 5-HT 2A receptors may be even more important than D 2 receptors due to the fact that other 5-HT 2A antagonists such as LY53857, ritanserin, ketanserin, fananserin, and MDL 100, 907 are more effective than dopamine antagonists in suppressing PCP-induced hyperlocomotion (Gleason and Shannon, 1997; Millan et al, 1999); and repeated administration of clozapine causes a down-regulation of 5-HT 2A receptors in the prefrontal cortex (Doat-Meyerhoefer et al, 2005). Because PCP also enhances serotonergic, dopaminergic and glutamatergic neurotransmission in the nucleus accumbens and prefrontal cortex (Abekawa et al, 2007; Maurel-Remy et al, 1995; Millan et al, 1999), we have proposed that antipsychotic sensitization in the PCP-induced hyperlocomotion test is mediated by down-regulating 5- HT 2A receptors and concomitantly decreasing PCP-induced dopamine and 5-HT increases in the prefrontal cortex (Sun et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Repeated asenapine treatment produces a sensitization effect in two preclinical tests of antipsychotic activity

Qin

Chen

2013

Neuropharmacology

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Among several commonly used atypical antipsychotic drugs, olanzapine and risperidone cause a sensitization effect in the conditioned avoidance response (CAR) and phencyclidine (PCP)-induced hyperlocomotion paradigms – two well established animal tests of antipsychotic drugs, whereas clozapine causes a tolerance effect. Asenapine is a novel antipsychotic drug recently approved for the treatment of schizophrenia and manic disorders. It shares several receptor binding sites and behavioral features with other atypical antipsychotic drugs. However, it is not clear what type of repeated effect (sensitization or tolerance) asenapine would induce, and whether such an effect is transferrable to other atypicals. In this study, male adult Sprague-Dawley rats were first repeatedly tested with asenapine (0.05, 0.10 or 0.20 mg/kg, sc) for avoidance response or PCP (3.20 mg/kg, sc)-induced hyperlocomotion daily for 5 consecutive days. After 2–3 days of retraining/drug-free recovery, they were then challenged with asenapine (0.10 mg/kg, sc), followed by olanzapine (0.50 mg/kg, sc) and clozapine (2.50 mg/kg, sc). During the 5-day drug test period (the induction phase), repeated asenapine treatment progressively increased its inhibition of avoidance response and PCP-induced hyperlocomotion in a dose-dependent fashion. On the asenapine and olanzapine challenge tests (the expression phase), rats previously treated with asenapine still showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle. An increased reactivity to clozapine challenge in prior asenapine-treated rats was also found in the PCP-induced hyperlocomotion test. These findings suggest that asenapine is capable of inducing a sensitization effect and a cross-sensitization to olanzapine and clozapine (to a lesser extent). Because the behavioral profile of asenapine in both tests is similar to that of olanzapine, but different from that of clozapine, we suggest that asenapine resembles olanzapine to a greater extent than clozapine in its therapeutic and side effect profiles.

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Effects of clozapine and 2,5-dimethoxy-4-methylamphetamine [DOM] on 5-HT2A receptor expression in discrete brain areas

Cited by 12 publications

References 50 publications

Olanzapine Increases RGS7 Protein Expression via Stimulation of the Janus Tyrosine Kinase-Signal Transducer and Activator of Transcription Signaling Cascade

Olanzapine Increases RGS7 Protein Expression via Stimulation of the Janus Tyrosine Kinase-Signal Transducer and Activator of Transcription Signaling Cascade

Activation of the JAK-STAT pathway is necessary for desensitization of 5-HT2A receptor-stimulated phospholipase C signalling by olanzapine, clozapine and MDL 100907

Repeated asenapine treatment produces a sensitization effect in two preclinical tests of antipsychotic activity

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