| 1 | Ann. N. Y. Acad. Sci. 2000 Jun 911: 73-82 |
|---|---|
| PMID | 10911868 |
| Title | Molecular effects of the psychotropic NMDA receptor antagonist MK-801 in the rat entorhinal cortex: increases in AP-1 DNA binding activity and expression of Fos and Jun family members. |
| Abstract | Noncompetitive NMDA receptor antagonists such as phencyclidine and MK-801 produce psychotropic symptoms that closely resemble schizophrenic psychosis and induce the expression of immediate early genes in limbic cortical areas. We are concentrating on analyzing molecular and physiological effects that these drugs produce in the entorhinal cortex and on the potential connection between these effects and the psychotic symptoms. We show here that MK-801 increases the DNA binding activity of the activator protein-1 (AP-1) complex in the entorhinal cortex. We also observed increased expression of mRNAs for Fos and Jun transcription factor family members c-Fos, FOSB, Fra-2, and JunB, as well as Fos family proteins in the entorhinal cortex after MK-801 administration. This suggests that the activated AP-1 complex consists of these transcription factors. Genes regulated by the AP-1 complex in the entorhinal cortex might be involved in the pathophysiology of psychotic behavior and are potential targets for new antipsychotic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Exp. Neurol. 2001 Apr 168: 392-401 |
| PMID | 11259127 |
| Title | Enhancement of laminar FosB expression in frontal cortex of rats receiving long chronic clozapine administration. |
| Abstract | The frontal cortex (FrC) and cingulate cortex (CgC) are critical sites for normal cognitive function, as well as cognitive dysfunction in schizophrenia. Thus, modulation of synaptic transmission within these cortical areas may, in part, account for the therapeutic actions of antipsychotic drugs such as haloperidol and clozapine. FOSB and DeltaFOSB are immediate-early gene (IEG) products sensitive to changes in response to chronic neuroleptic drug administration. We quantitatively examine whether there are light microscopic regional and/or laminar variations in FOSB or DeltaFOSB in the FrC or CgC of normal adult rats, or animals receiving 6 months administration of either drinking water clozapine, or depot haloperidol. Only animals receiving chronic haloperidol developed vacuous chewing movements, the equivalent of tardive dyskinesia in humans. In control animals, the deep and superficial layers of the FrC showed a higher area density of FOSB, but not DeltaFOSB immunoreactive cells than the medial layers of FrC or any of the CgC layers. In animals receiving clozapine, but not haloperidol there was increase in the area density of FOSB immunoreactive neurons in all FrC layers, but the major increase occurs in medial layers. These findings suggest that FOSB expression identifies those FrC neurons that are most active during normal waking behaviors and are further activated following chronic administration of atypical neuroleptics without motor side effects. The results also indicate that the actions of clozapine are attributed in large part to modulation of the output of frontal cortical pyramidal neurons residing in the medial layers. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Eur. J. Pharmacol. 2009 Oct 620: 27-35 |
| PMID | 19695244 |
| Title | F15063, a potential antipsychotic with dopamine D(2)/D(3) receptor antagonist and 5-HT(1A) receptor agonist properties: influence on immediate-early gene expression in rat prefrontal cortex and striatum. |
| Abstract | Brain region-specific modulation of immediate-early gene (IEG) may constitute a marker of antipsychotic drug-like activity. We investigated the effects of the putative antipsychotic drug N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine (F15063), a compound that targets both dopamine D(2) and serotonin 5-HT(1A) receptors, in comparison with haloperidol and clozapine on rat mRNA expression of IEG i.e. the zinc-fingered transcription factors c-fos, FOSB, zif268, c-jun and junB, two transcription factors of the nuclear receptor family nur77 and nor1, and the effector IEG arc. F15063 (10 mg/kg) and clozapine (10 mg/kg), but not haloperidol (0.63 mg/kg), induced c-fos and FOSB mRNA expression in prefrontal cortex, a region associated with control of cognition and negative symptoms of schizophrenia. In striatum, only c-fos, FOSB, junB and nur77 were induced by clozapine whereas all IEG mRNAs were increased by haloperidol and F15063 (from 2.5 mg/kg) with similar high efficacy despite a total absence of F15063-induced catalepsy. However, at 0.63 mg/kg, F15063 induced a lower degree of striatal IEG mRNA expression than haloperidol and pretreatment with the serotonin 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl-N-(2-pyridinyl)cyclohexane carboxamide trihydrochloride (WAY100635) (0.63 mg/kg) increased the level of IEG mRNA induction by F15063. Furthermore, (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)-8-OH-DPAT] at 0.16 mg/kg decreased haloperidol-induced striatal IEG mRNA expression although it exerted no effects on its own. These results are consistent with an activation of serotonin 5-HT(1A) receptors by F15063, thus reducing D(2) blockade-induced striatal IEG mRNA. Furthermore, the substantial F15063-induced expression of IEGs such as c-fos in striatum is not related to cataleptogenic activity and may act more as a marker of efficacious dopamine D(2) receptor blockade. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Int. J. Neuropsychopharmacol. 2011 Jun 14: 631-43 |
| PMID | 20701826 |
| Title | The schizophrenia susceptibility gene neuregulin 1 modulates tolerance to the effects of cannabinoids. |
| Abstract | Cannabis increases the risk of schizophrenia in genetically vulnerable individuals. In this study we aim to show that the schizophrenia susceptibility gene neuregulin 1 (Nrg1) modulates the development of tolerance to cannabinoids in mice. Nrg1 heterozygous (HET) and wild-type (WT) mice were treated daily for 15 d with the synthetic analogue of ?9-tetrahydrocannabinol, CP55,940 (0.4 mg/kg). We measured the impact of this exposure on locomotor activity, anxiety, prepulse inhibition (PPI), body temperature and FOSB/?FOSB immunohistochemistry. Tolerance to CP55,940-induced hypothermia and locomotor suppression developed more rapidly in Nrg1 HET mice than WT mice. Conversely in the light-dark test, while tolerance to the anxiogenic effect of CP55,940 developed in WT mice over days of testing, Nrg1 hypomorphs maintained marked anxiety even after 15 d of treatment. Repeated cannabinoid exposure selectively increased FOSB/?FOSB expression in the lateral septum, ventral part (LSV) of Nrg1 HET but not WT mice. On day 1 of exposure opposite effects of CP55,940 treatment were observed on PPI, i.e. it was facilitated in Nrg1 hypomorphs and impaired in WT mice, despite the drug significantly impairing the acoustic startle reflex equally in both genotypes. These effects of CP55,940 on PPI were not maintained as both genotypes became tolerant to cannabinoid action with repeated exposure. Our results highlight that Nrg1 modulates the development of cannabinoid tolerance dependent on the parameter being measured. Furthermore, these data reinforce the notion that the VLS is an important brain region involved in Nrg1-cannabinoid interactions. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Behav Brain Funct 2012 -1 8: 15 |
| PMID | 22433906 |
| Title | Acetylcholinesterase inhibition ameliorates deficits in motivational drive. |
| Abstract | Apathy is frequently observed in numerous neurological disorders, including Alzheimer's and Parkinson's, as well as neuropsychiatric disorders including schizophrenia. Apathy is defined as a lack of motivation characterized by diminished goal-oriented behavior and self-initiated activity. This study evaluated a chronic restraint stress (CRS) protocol in modeling apathetic behavior, and determined whether administration of an anticholinesterase had utility in attenuating CRS-induced phenotypes. We assessed behavior as well as regional neuronal activity patterns using FOSB immunohistochemistry after exposure to CRS for 6 h/d for a minimum of 21 d. Based on our FOSB findings and recent clinical trials, we administered an anticholinesterase to evaluate attenuation of CRS-induced phenotypes. CRS resulted in behaviors that reflect motivational loss and diminished emotional responsiveness. CRS-exposed mice showed differences in FOSB accumulation, including changes in the cholinergic basal forebrain system. Facilitating cholinergic signaling ameliorated CRS-induced deficits in initiation and motivational drive and rescued immediate early gene activation in the medial septum and nucleus accumbens. Some CRS protocols may be useful for studying deficits in motivation and apathetic behavior. Amelioration of CRS-induced behaviors with an anticholinesterase supports a role for the cholinergic system in remediation of deficits in motivational drive. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Synapse 2013 Sep 67: 553-67 |
| PMID | 23447367 |
| Title | Moderate and severe perinatal asphyxia induces differential effects on cocaine sensitization in adult rats. |
| Abstract | Perinatal asphyxia (PA) increases the likelihood of suffering from dopamine-related disorders, such as ADHD and schizophrenia. Since dopaminergic transmission plays a major role in cocaine sensitization, the purpose of this study was to determine whether PA could be associated with altered behavioral sensitization to cocaine. To this end, adult rats born vaginally (CTL), by caesarean section (C+), or by C+ with 15 min (PA15, moderate PA) or 19 min (PA19, severe PA) of global anoxia were repeatedly administered with cocaine (i.p., 15 mg/kg) and then challenged with cocaine (i.p., 15 mg/kg) after a 5-day withdrawal period. In addition, c-Fos, FOSB/?FOSB, DAT, and TH expression were assessed in dorsal (CPu) and ventral (NAcc) striatum. Results indicated that PA15 rats exhibited an increased locomotor sensitization to cocaine, while PA19 rats displayed an abnormal acquisition of locomotor sensitization and did not express a sensitized response to cocaine. c-Fos expression in NAcc, but not in CPu, was associated with these alterations in cocaine sensitization. FOSB/?FOSB expression was increased in all groups and regions after repeated cocaine administration, although it reached lower expression levels in PA19 rats. In CTL, C+, and PA15, but not in PA19 rats, the expression of TH in NAcc was reduced in groups repeatedly treated with cocaine, independently of the challenge test. Furthermore, this reduction was more pronounced in PA15 rats. DAT expression remained unaltered in all groups and regions studied. These results suggest that moderate PA may increase the vulnerability to drug abuse and in particular to cocaine addiction. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Front Behav Neurosci 2014 -1 8: 388 |
| PMID | 25414651 |
| Title | Addiction and reward-related genes show altered expression in the postpartum nucleus accumbens. |
| Abstract | Motherhood involves a switch in natural rewards, whereby offspring become highly rewarding. Nucleus accumbens (NAC) is a key CNS region for natural rewards and addictions, but to date no study has evaluated on a large scale the events in NAC that underlie the maternal change in natural rewards. In this study we utilized microarray and bioinformatics approaches to evaluate postpartum NAC gene expression changes in mice. Modular Single-set Enrichment Test (MSET) indicated that postpartum (relative to virgin) NAC gene expression profile was significantly enriched for genes related to addiction and reward in five of five independently curated databases (e.g., Malacards, Phenopedia). Over 100 addiction/reward related genes were identified and these included: Per1, Per2, Arc, Homer2, Creb1, Grm3, FOSB, Gabrb3, Adra2a, Ntrk2, Cry1, Penk, Cartpt, Adcy1, Npy1r, Htr1a, Drd1a, Gria1, and Pdyn. ToppCluster analysis found maternal NAC expression profile to be significantly enriched for genes related to the drug action of nicotine, ketamine, and dronabinol. Pathway analysis indicated postpartum NAC as enriched for RNA processing, CNS development/differentiation, and transcriptional regulation. Weighted Gene Coexpression Network Analysis (WGCNA) identified possible networks for transcription factors, including Nr1d1, Per2, FOSB, Egr1, and Nr4a1. The postpartum state involves increased risk for mental health disorders and MSET analysis indicated postpartum NAC to be enriched for genes related to depression, bipolar disorder (BPD), and schizophrenia. Mental health related genes included: Fabp7, Grm3, Penk, and Nr1d1. We confirmed via quantitative PCR Nr1d1, Per2, Grm3, Penk, Drd1a, and Pdyn. This study indicates for the first time that postpartum NAC involves large scale gene expression alterations linked to addiction and reward. Because the postpartum state also involves decreased response to drugs, the findings could provide insights into how to mitigate addictions. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Neuropsychopharmacology 2014 Feb 39: 538-44 |
| PMID | 24067299 |
| Title | ?FosB induction in prefrontal cortex by antipsychotic drugs is associated with negative behavioral outcomes. |
| Abstract | ?FOSB, a FOSB gene product, is induced in the prefrontal cortex (PFC) by repeated exposure to several stimuli including antipsychotic drugs such as haloperidol. However, the functional consequences of increased ?FOSB expression following antipsychotic treatment have not been explored. Here, we assessed whether ?FOSB induction by haloperidol mediates the positive or negative consequences or clinical-related actions of antipsychotic treatment. We show that individuals with schizophrenia who were medicated with antipsychotic drugs at their time of death display increased ?FOSB levels in the PFC, an effect that is replicated in rats treated chronically with haloperidol. In contrast, individuals with schizophrenia who were medication-free did not exhibit this effect. Viral-mediated overexpression of ?FOSB in the PFC of rodents induced cognitive deficits as measured by inhibitory avoidance, increased startle responses in prepulse inhibition tasks, and increased MK-801-induced anxiety-like behaviors. Together, these results suggest that ?FOSB induction in the PFC by antipsychotic treatment contributes to the deleterious effects of these drugs and not to their therapeutic actions. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Endocr Regul 2015 Apr 49: 58-67 |
| PMID | 25960006 |
| Title | Impact of repeated asenapine treatment on FosB/?FosB expression in neurons of the rat central nucleus of the amygdala: colocalization with corticoliberine (CRH) and effect of an unpredictable mild stress preconditioning. |
| Abstract | FOSB/?FOSB expression in the central amygdalar nucleus (CeA) in response to repeated asenapine (ASE) treatment (an atypical antipsychotic used for the treatment of schizophrenia) was studied in normal rats and rats preconditioned with chronic unpredictable variable mild stress (CMS). The goal of this study was to reveal whether repeated ASE treatment for 14 days may: 1) induce FOSB/?FOSB expression in the amygdala, 2) activate CRH-synthesizing neurons in the CeA, and 3) interfere with 21 days lasting concomitant CMS preconditioning. Four groups of animals were studied: controls and ASE-, CMS-, and CMS+ASE-treated ones. CMS consisted of the restrain, social isolation, crowding, swimming, and cold and lasted 21 days. The ASE and CMS+ASE groups were from the 7th day of the experiment treated with ASE (0.3 mg/kg, subcutaneously - s.c.) twice a day, i.e. together for 14 days. Controls and CMS groups were treated with saline (300 µl/rat, s.c.) twice a day for 14 days. All the animals were sacrificed on the 22nd day, i.e. 16-18 hours after the last treatments. Single FOSB/?FOSB, FOSB/?FOSB colocalizations with CRH, and CRH immunolabeled perikarya were investigated in the CeA using a combined light and fluorescent immunohistochemistry. The distribution aspect of the black FOSB/?FOSB profiles was homogeneous over the whole CeA and no significant differences in the number of FOSB/?FOSB profiles between the individual groups of the rats really occurred. The level of colocalization pattern of FOSB/?FOSB in CRH perikarya was also very similar between the individual groups and in each case it reached approximately 10% of double-labeling. No differences were also seen in the number of CRH immunolabeled perikarya. The density of CRH nerve projections within the CeA was very alike in the individual groups of animals investigated. The study provides a new anatomical/functional finding about the lack of the stimulatory effect of the repeated ASE treatment on the expression of FOSB/?FOSB, FOSB/?FOSB/CRH colocalizations, and CRH immunolabeled perikarya number in the CeA. In addition, CMS preconditioning itself neither stimulated nor inhibited FOSB/?FOSB expression, nor altered the impact of ASE on the activity of CRH neurons in the CeA. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | PLoS ONE 2015 -1 10: e0116686 |
| PMID | 25658856 |
| Title | Altered gene expression in schizophrenia: findings from transcriptional signatures in fibroblasts and blood. |
| Abstract | Whole-genome expression studies in the peripheral tissues of patients affected by schizophrenia (SCZ) can provide new insight into the molecular basis of the disorder and innovative biomarkers that may be of great utility in clinical practice. Recent evidence suggests that skin fibroblasts could represent a non-neural peripheral model useful for investigating molecular alterations in psychiatric disorders. A microarray expression study was conducted comparing skin fibroblast transcriptomic profiles from 20 SCZ patients and 20 controls. All genes strongly differentially expressed were validated by real-time quantitative PCR (RT-qPCR) in fibroblasts and analyzed in a sample of peripheral blood cell (PBC) RNA from patients (n = 25) and controls (n = 22). To evaluate the specificity for SCZ, alterations in gene expression were tested in additional samples of fibroblasts and PBCs RNA from Major Depressive Disorder (MDD) (n = 16; n = 21, respectively) and Bipolar Disorder (BD) patients (n = 15; n = 20, respectively). Six genes (JUN, HIST2H2BE, FOSB, FOS, EGR1, TCF4) were significantly upregulated in SCZ compared to control fibroblasts. In blood, an increase in expression levels was confirmed only for EGR1, whereas JUN was downregulated; no significant differences were observed for the other genes. EGR1 upregulation was specific for SCZ compared to MDD and BD. Our study reports the upregulation of JUN, HIST2H2BE, FOSB, FOS, EGR1 and TCF4 in the fibroblasts of SCZ patients. A significant alteration in EGR1 expression is also present in SCZ PBCs compared to controls and to MDD and BD patients, suggesting that this gene could be a specific biomarker helpful in the differential diagnosis of major psychoses. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Int. J. Neuropsychopharmacol. 2015 Mar 18: -1 |
| PMID | 25618402 |
| Title | Cannabidiol attenuates sensorimotor gating disruption and molecular changes induced by chronic antagonism of NMDA receptors in mice. |
| Abstract | Preclinical and clinical data suggest that cannabidiol (CBD), a major non-psychotomimetic compound from Cannabis sativa, induces antipsychotic-like effects. However, the antipsychotic properties of repeated CBD treatment have been poorly investigated. Behavioral changes induced by repeated treatment with glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been proposed as an animal model of schizophrenia-like signs. In the present study, we evaluated if repeated treatment with CBD would attenuate the behavioral and molecular modifications induced by chronic administration of one of these antagonists, MK-801. Male C57BL/6J mice received daily i.p. injections of MK-801 (0.1, 0.5, or 1mg/kg) for 14, 21, or 28 days. Twenty-four hours after the last injection, animals were submitted to the prepulse inhibition (PPI) test. After that, we investigated if repeated treatment with CBD (15, 30, and 60mg/kg) would attenuate the PPI impairment induced by chronic treatment with MK-801 (1mg/kg; 28 days). CBD treatment began on the 6th day after the start of MK-801 administration and continued until the end of the treatment. Immediately after the PPI, the mice brains were removed and processed to evaluate the molecular changes. We measured changes in FOSB/?FOSB and parvalbumin (PV) expression, a marker of neuronal activity and a calcium-binding protein expressed in a subclass of GABAergic interneurons, respectively. Changes in mRNA expression of the NMDAR GluN1 subunit gene (GRN1) were also evaluated. CBD effects were compared to those induced by the atypical antipsychotic clozapine. MK-801 administration at the dose of 1mg/kg for 28 days impaired PPI responses. Chronic treatment with CBD (30 and 60mg/kg) attenuated PPI impairment. MK-801 treatment increased FOSB/?FOSB expression and decreased PV expression in the medial prefrontal cortex. A decreased mRNA level of GRN1 in the hippocampus was also observed. All the molecular changes were attenuated by CBD. CBD by itself did not induce any effect. Moreover, CBD effects were similar to those induced by repeated clozapine treatment. These results indicate that repeated treatment with CBD, similar to clozapine, reverses the psychotomimetic-like effects and attenuates molecular changes observed after chronic administration of an NMDAR antagonist. These data support the view that CBD may have antipsychotic properties. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Cereb. Cortex 2016 Mar 26: 1287-94 |
| PMID | 26637448 |
| Title | Evidence for Competition for Target Innervation in the Medial Prefrontal Cortex. |
| Abstract | Inputs to sensory cortices are known to compete for target innervation through an activity-dependent mechanism during critical periods. To investigate whether this principle also applies to association cortices such as the medial prefrontal cortex (mPFC), we produced a bilateral lesion during early development to the ventral hippocampus (vHC), an input to the mPFC, and analyzed the intensity of the projection from another input, the basolateral amgydala (BLA). We found that axons from the BLA had a higher density of "en passant" boutons in the mPFC of lesioned animals. Furthermore, the density of neurons labeled with retrograde tracers was increased, and neurons projecting from the BLA to the mPFC showed increased expression of FOSB. Since neonatal ventral hippocampal lesion has been used as an animal model of schizophrenia, we investigated its effects on behavior and found a negative correlation between the density of retrogradely labeled neurons in the BLA and the reduction of the startle response in the prepulse inhibition test. Our results not only indicate that the inputs from the BLA and the vHC compete for target innervation in the mPFC during postnatal development but also that subsequent abnormal rewiring might underlie the pathophysiology of neuropsychiatric disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |