Chronic Antipsychotic Drug Treatment Induces Long-lasting Expression of fos and jun Family Genes and Activator Protein 1 Complex in the Rat Prefrontal Cortex

Kontkanen, Outi; Lakso, Merja; Wong, Garry; Ċastrén, Eero

doi:10.1016/s0893-133x(02)00289-0

Cited by 42 publications

(30 citation statements)

References 38 publications

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“…However, in contrast to the observations in humans, there were no significant differences in the levels of c-Jun protein in haloperidol-or risperidone-treated rats and controls. A very recent study has shown that chronic 17-day treatment with haloperidol and clozapine increased the expression levels of jun and fos family immediate-early genes in the rat prefrontal cortex using in situ hybridization (Kontkanen et al, 2002). Taken together, these results indicate a differential and brain region-specific regulation of jun and fos genes by antipsychotic drug treatment.…”

Section: Discussionmentioning

confidence: 75%

Increased Expression of c-Jun Transcription Factor in Cerebellar Vermis of Patients with Schizophrenia

Тодорова

Elbein

Kyosseva

2003

Neuropsychopharmacol

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Section: Discussionmentioning

confidence: 75%

Increased Expression of c-Jun Transcription Factor in Cerebellar Vermis of Patients with Schizophrenia

Тодорова

Elbein

Kyosseva

2003

Neuropsychopharmacol

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“…), calculated as salts, were clozapine, 1.5, 10.0, or 25.0 mg/kg; haloperidol, 1.0 mg/kg; and LSD, 0.24 mg/kg. These doses were selected based on previous findings with clozapine, haloperidol, and LSD in rodent models (Kuoppamaki et al 1993; Kontkanen et al 2002a, b; Gonzalez-Maeso et al 2008; Gray et al 2009). These doses represent approximately 12.5, 3.3, and 0.03 % of the LD50 of clozapine (200 mg/kg), haloperidol (30 mg/kg), and LSD (800 mg/kg) after i.p.…”

Section: Methodsmentioning

confidence: 99%

Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice

et al. 2012

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Rationale In schizophrenia patients, optimal treatment with antipsychotics requires weeks to months of sustained drug therapy. However, single administration of antipsychotic drugs can reverse schizophrenia-like behavioral alterations in rodent models of psychosis. This raises questions about the physiological relevance of such antipsychotic-like activity. Objective This study evaluates the effects of chronic treatment with clozapine on the cellular and behavioral responses induced by the hallucinogenic serotonin 5-HT2A receptor agonist lysergic acid diethylamide (LSD) as a mouse model of psychosis. Method Mice were treated chronically (21 days) with 25 mg/kg/day clozapine. Experiments were conducted 1, 7, 14, and 21 days after the last clozapine administration. [3H]Ketanserin binding and 5-HT2A mRNA expression were determined in mouse somatosensory cortex. Head-twitch behavior, expression of c-fos, which is induced by all 5-HT2A agonists, and expression of egr-1 and egr-2, which are LSD-like specific, were assayed. Results Head-twitch response was decreased and [3H]ketanserin binding was downregulated in 1, 7, and 14 days after chronic clozapine. 5-HT2A mRNA was reduced 1 day after chronic clozapine. Induction of c-fos, but not egr-1 and egr-2, was rescued 7 days after chronic clozapine. These effects were not observed after short treatment (2 days) with clozapine or chronic haloperidol (1 mg/kg/day). Conclusion Our findings provide a murine model of chronic atypical antipsychotic drug action and suggest downregulation of the 5-HT2A receptor as a potential mechanism involved in these persistent therapeutic-like effects.

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“…It has been suggested that extinction of fear may be compromised in these disorders (Charney, 2004). Interestingly, longterm treatment with anti-psychotic medications in rats increased the levels of c-Fos in the mPFC (Kontkanen et al, 2002), suggesting that these drugs may stimulate an endogenous fear-reduction system. A better understanding of molecular mechanisms of fear extinction could lead to new pharmacological treatments for anxiety disorders targeting the mPFC.…”

Section: )mentioning

confidence: 99%

Consolidation of Fear Extinction Requires Protein Synthesis in the Medial Prefrontal Cortex

Santini¹,

Ge²,

Ren³

et al. 2004

J. Neurosci.

437

331

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Extinction of conditioned fear is thought to form a long-term memory of safety, but the neural mechanisms are poorly understood. Consolidation of extinction learning in other paradigms requires protein synthesis, but the involvement of protein synthesis in extinction of conditioned fear remains unclear. Here, we show that rats infused intraventricularly with the protein synthesis inhibitor anisomycin extinguished normally within a session but were unable to recall extinction the following day. Anisomycin-treated rats showed no savings in the rate of re-learning of extinction, consistent with amnesia for extinction training. The identical effect was observed when anisomycin was microinfused into the medial prefrontal cortex (mPFC) but not the insular cortex. Furthermore, we observed that extinction training increased c-Fos levels in the mPFC but not in the insular cortex, consistent with extinction-induced gene expression in the mPFC. These findings extend previous lesion and unit-recording data by demonstrating that the mPFC is a critical storage site for extinction memory, rather than simply a pathway for expression of extinction. Understanding consolidation of fear extinction could lead to new treatments for anxiety disorders in which fear extinction is thought to be compromised.

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Chronic Antipsychotic Drug Treatment Induces Long-lasting Expression of fos and jun Family Genes and Activator Protein 1 Complex in the Rat Prefrontal Cortex

Abstract: We have characterized the effects of chronic clozapine and haloperidol treatments on the expression of fos ( c-fos , fosB , fra-2 ) and jun ( c-jun , junB, junD ) family genes in the rat forebrain. The effects of chronic (17d)

Cited by 42 publications

References 38 publications

Increased Expression of c-Jun Transcription Factor in Cerebellar Vermis of Patients with Schizophrenia

Increased Expression of c-Jun Transcription Factor in Cerebellar Vermis of Patients with Schizophrenia

Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice

Consolidation of Fear Extinction Requires Protein Synthesis in the Medial Prefrontal Cortex

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