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1.
Biomedicines ; 12(7)2024 Jun 25.
Article in English | MEDLINE | ID: mdl-39061977

ABSTRACT

Olanzapine is an atypical antipsychotic drug and a potent muscarinic M3 receptor (M3R) antagonist. Olanzapine has been reported to cause metabolic disorders, including dyslipidemia. Anaplastic lymphoma kinase (Alk), a tyrosine kinase receptor well known in the pathogenesis of cancer, has been recently identified as a key gene in the regulation of thinness via the regulation of adipose tissue lipolysis. This project aimed to investigate whether Olanzapine could modulate the hepatic Alk pathway and lipid metabolism via M3R. Female rats were treated with Olanzapine and/or Cevimeline (an M3R agonist) for 9 weeks. Lipid metabolism and hepatic Alk signaling were analyzed. Nine weeks' treatment of Olanzapine caused metabolic disturbance including increased body mass index (BMI), fat mass accumulation, and abnormal lipid metabolism. Olanzapine treatment also led to an upregulation of Chrm3, Alk, and its regulator Ptprz1, and a downregulation of Lmo4, a transcriptional repressor of Alk in the liver. Moreover, there were positive correlations between Alk and Chrm3, Alk and Ptprz1, and a negative correlation between Alk and Lmo4. However, cotreatment with Cevimeline significantly reversed the lipid metabolic disturbance and adipose tissue accumulation, as well as the upregulation of the hepatic Alk signaling caused by Olanzapine. This study demonstrates evidence that Olanzapine may cause metabolic disturbance by modulating hepatic Alk signaling via M3R, which provides novel insight for modulating the hepatic Alk signaling and potential interventions for targeting metabolic disorders.

3.
Int J Mol Sci ; 24(11)2023 May 23.
Article in English | MEDLINE | ID: mdl-37298094

ABSTRACT

As a partial histamine H1 receptor agonist and H3 antagonist, betahistine has been reported to partially prevent olanzapine-induced dyslipidemia and obesity through a combination therapy, although the underlying epigenetic mechanisms are still not known. Recent studies have revealed that histone regulation of key genes for lipogenesis and adipogenesis in the liver is one of the crucial mechanisms for olanzapine-induced metabolic disorders. This study investigated the role of epigenetic histone regulation in betahistine co-treatment preventing dyslipidemia and fatty liver caused by chronic olanzapine treatment in a rat model. In addition to abnormal lipid metabolism, the upregulation of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (C/EBPα), as well as the downregulation of carnitine palmitoyltransferase 1A (CPT1A) in the liver induced by olanzapine, were significantly attenuated by betahistine co-treatment. In addition, betahistine co-treatment significantly enhanced the global expression of H3K4me and the enrichment of H3K4me binding on the promoter of Cpt1a gene as revealed by ChIP-qPCR, but inhibited the expression of one of its site-specific demethylases, lysine (K)-specific demethylase 1A (KDM1A). Betahistine co-treatment also significantly enhanced the global expression of H3K9me and the enrichment of H3K9me binding on the promoter of the Pparg gene, but inhibited the expression of two of its site-specific demethylases, lysine demethylase 4B (KDM4B) and PHD finger protein 2 (PHF2). These results suggest that betahistine attenuates abnormal adipogenesis and lipogenesis triggered by olanzapine through modulating hepatic histone methylation, and thus inhibiting the PPARγ pathway-mediated lipid storage, while at the same time promoting CP1A-mediated fatty acid oxidation.


Subject(s)
Betahistine , Dyslipidemias , Rats , Animals , Olanzapine/adverse effects , Betahistine/pharmacology , PPAR gamma/genetics , PPAR gamma/metabolism , Histones/metabolism , Methylation , Carnitine O-Palmitoyltransferase/genetics , Carnitine O-Palmitoyltransferase/metabolism , Lysine/metabolism , Benzodiazepines/pharmacology , Dyslipidemias/genetics , Epigenesis, Genetic
4.
Front Cell Neurosci ; 16: 1037105, 2022.
Article in English | MEDLINE | ID: mdl-36519081

ABSTRACT

Introduction: Neuroinflammation in the central nervous system, particularly the prefrontal cortex (PFC), plays a role in the pathogenesis of schizophrenia, which has been found to be associated with maternal immune activation (MIA). Recent evidence suggests that epigenetic regulation involves in the MIA-induced neurodevelopmental disturbance. However, it is not well-understood how epigenetic modulation is involved in the neuroinflammation and pathogenesis of schizophrenia. Methods: This study explored the modulation of histone acetylation in both neuroinflammation and neurotransmission using an MIA rat model induced by prenatal polyriboinosinic-polyribocytidylic acid (Poly I:C) exposure, specifically examining those genes that were previously observed to be impacted by the exposure, including a subunit of nuclear factor kappa-B (Rela), Nod-Like-Receptor family Pyrin domain containing 3 (Nlrp3), NMDA receptor subunit 2A (Grin2a), 5-HT2A (Htr2a), and GABAA subunit ß3 (Gabrb3). Results: Our results revealed global changes of histone acetylation on H3 (H3ace) and H4 (H4ace) in the PFC of offspring rats with prenatal Poly I:C exposure. In addition, it revealed enhancement of both H3ace and H4ace binding on the promoter region of Rela, as well as positive correlations between Rela and genes encoding histone acetyltransferases (HATs) including CREB-binding protein (CBP) and E1A-associated protein p300 (EP300). Although there was no change in H3ace or H4ace enrichment on the promoter region of Nlrp3, a significant enhancement of histone deacetylase 6 (HDAC6) binding on the promoter region of Nlrp3 and a positive correlation between Nlrp3 and Hdac6 were also observed. However, prenatal Poly I:C treatment did not lead to any specific changes of H3ace and H4ace on the promoter region of the target genes encoding neurotransmitter receptors in this study. Discussion: These findings demonstrated that epigenetic modulation contributes to NF-κB/NLRP3 mediated neuroinflammation induced by prenatal Poly I:C exposure via enhancement of histone acetylation of H3ace and H4ace on Rela and HDAC6-mediated NLRP3 transcriptional activation. This may further lead to deficits in neurotransmissions and schizophrenia-like behaviors observed in offspring.

5.
Pharmacol Biochem Behav ; 219: 173453, 2022 09.
Article in English | MEDLINE | ID: mdl-36029928

ABSTRACT

Second generation antipsychotic drugs including aripiprazole, olanzapine and risperidone are prescribed increasingly (mostly off-label) to treat various mental disorders in children and adolescents. Early treatment with antipsychotics during this period may have long-lasting behavioural impacts, but to date there have been only limited investigations. Maternal infection could be implicated in the aetiology of various mental disorders including schizophrenia. Exposure of pregnant rodents to polyriboinosinic-polyribocytidylic acid (Poly I:C) causes schizophrenia-like behavioural abnormalities and neurodevelopmental conditions such as autism spectrum disorders in offspring. This study, using a Poly I:C rat model, investigated the long-lasting effects of early aripiprazole, olanzapine and risperidone treatment in the childhood/adolescent period (postnatal day 22-50) on adult behaviours of male rats. The study showed that early treatment with three antipsychotics had different effects on long-term behavioural changes in adults. Prenatal Poly I:C exposure (5 mg/kg) at gestation day 15 caused deficits in pre-pulse inhibition and social interaction, as well as cognitive impairments, that could be partially improved by early antipsychotic treatment in the juvenile period. Early antipsychotic treatment during the childhood-adolescent period resulted in similar long-lasting effects on pre-pulse inhibition, anxiety- and depressive-related behaviours in both Poly I:C and healthy (control) male rats. Overall, these results suggest that both prenatal Poly I:C exposure and early antipsychotic treatment in the childhood/adolescent period had long-lasting effects on adult behaviours of male rats, while early antipsychotic treatment could partly prevent the onset of behavioural abnormalities resulting from prenatal insult.


Subject(s)
Antipsychotic Agents , Animals , Antipsychotic Agents/pharmacology , Antipsychotic Agents/therapeutic use , Aripiprazole , Female , Humans , Male , Olanzapine , Poly I-C/pharmacology , Pregnancy , Rats , Risperidone/pharmacology , Risperidone/therapeutic use
6.
Biomolecules ; 12(5)2022 05 23.
Article in English | MEDLINE | ID: mdl-35625659

ABSTRACT

The ventral tegmental area (VTA) in the ventral midbrain is the origin of the dopaminergic neurotransmission pathways. Although GABAA receptors and AKT-GSK3ß signaling are involved in the pathophysiology of mental disorders and are modulated by antipsychotics, an unmet task is to reveal the pathological changes in these biomarkers and antipsychotic modulations in the VTA. Using a juvenile polyriboinosinic-polyribocytidylic acid (Poly I:C) psychiatric rat model, this study investigated the effects of adolescent risperidone treatment on GABAA receptors and AKT/GSK3ß in the VTA. Pregnant female Sprague-Dawley rats were administered Poly I:C (5mg/kg; i.p) or saline at gestational day 15. Juvenile female offspring received risperidone (0.9 mg/kg, twice per day) or a vehicle from postnatal day 35 for 25 days. Poly I:C offspring had significantly decreased mRNA expression of GABAA receptor ß3 subunits and glutamic acid decarboxylase (GAD2) in the VTA, while risperidone partially reversed the decreased GAD2 expression. Prenatal Poly I:C exposure led to increased expression of AKT2 and GSK3ß. Risperidone decreased GABAA receptor ß2/3, but increased AKT2 mRNA expression in the VTA of healthy rats. This study suggests that Poly I:C-elicited maternal immune activation and risperidone differentially modulate GABAergic neurotransmission and AKT-GSK3ß signaling in the VTA of adolescent rats.


Subject(s)
Antipsychotic Agents , Ventral Tegmental Area , Animals , Antipsychotic Agents/pharmacology , Female , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Poly I-C/pharmacology , Pregnancy , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/genetics , Receptors, GABA-A/metabolism , Risperidone/metabolism , Risperidone/pharmacology , Ventral Tegmental Area/metabolism , gamma-Aminobutyric Acid/metabolism
7.
Int J Neuropsychopharmacol ; 25(2): 160-171, 2022 02 11.
Article in English | MEDLINE | ID: mdl-34893855

ABSTRACT

BACKGROUND: Exposure to polyriboinosinic-polyribocytidylic acid (Poly I:C) in pregnant rats has been reported to cause schizophrenia-like behaviors and abnormal neurotransmissions in adult, particularly male, offspring. However, what is less well understood are the effects of maternal Poly I:C exposure on adolescent behaviors and neurotransmission in female juvenile rats. METHODS: Female adolescent Poly I:C offspring were constructed by treating with 5 mg/kg Poly I:C on timed pregnant rats (gestation day 15). A battery of behavioral tests was conducted during postnatal day 35-60. Neurotransmitter receptors and inflammation markers in brain regions were evaluated by RT-qPCR on postnatal day 60. RESULTS: Open field, elevated plus maze, and forced swimming tests revealed that prenatal Poly I:C exposure led to elevated anxiety-like and depression-like behaviors in female adolescent offspring. Deficits in pre-pulse inhibition and social interaction were also observed. However, the Poly I:C rats had better performance than the controls in the novel object recognition memory test, which demonstrated a behavioral phenotype with improved cognitive function. Prenatal Poly I:C exposure caused brain region-specific elevation of the P2X7 receptor- and NF-κB-NLRP3-IL-1ß inflammatory signaling in female juvenile rats. Prenatal Poly I:C exposure decreased expression of GABAA receptor subunits Gabrb3 in the prefrontal cortex and Gabrb1 and dopamine D2 receptor in the hippocampus, but increased NMDA receptor subunit Grin2a in the prefrontal cortex, 5-HT2A in the hippocampus, and Gabrb3 and D2 receptor in the nucleus accumben. CONCLUSIONS: Prenatal Poly I:C challenge causes behavioral deficits and brain-specific neurotransmission changes via elevated neuroinflammation responses in female adolescent offspring rats.


Subject(s)
Neuroinflammatory Diseases/metabolism , Poly I-C/pharmacology , Prenatal Exposure Delayed Effects/metabolism , Synaptic Transmission/drug effects , Animals , Behavior, Animal , Brain/drug effects , Cognition/drug effects , Disease Models, Animal , Female , Hippocampus/drug effects , Memory, Short-Term/drug effects , Prefrontal Cortex/metabolism , Pregnancy , Prepulse Inhibition/drug effects , Rats , Receptors, Dopamine D2/metabolism , Schizophrenia/metabolism
8.
J Psychopharmacol ; 36(2): 202-213, 2022 02.
Article in English | MEDLINE | ID: mdl-34694173

ABSTRACT

BACKGROUND: Olanzapine is one of the most commonly used antipsychotic drugs; however, its metabolic disorders are the main obstacle in the clinic. Olanzapine is a potent antagonist of the M3 acetylcholine muscarinic receptor (M3R), while the downregulated hepatic M3R-AMPKα signalling pathway is involved in metabolic disorders. AIM: This study investigated the effects of chronic co-treatment with cevimeline (an agonist of M3Rs) in attenuating olanzapine-induced metabolic disorders and the underlying mechanisms. METHODS: Forty-eight adult female Sprague-Dawley rats were treated orally with olanzapine (2 mg/kg, 3 times/day (t.i.d.)) and/or cevimeline (9 mg/kg, t.i.d.), or control (vehicle) for 9 weeks. RESULTS: Cevimeline co-treatment significantly attenuated olanzapine-induced body weight gain and glucolipid metabolic disorders. Importantly, cevimeline co-treatment attenuated olanzapine-induced upregulation of M3Rs, while the co-treatment improved olanzapine-induced downregulation of AMPKα in the liver. Cevimeline co-treatment attenuated olanzapine-induced dyslipidaemia by modulating the hepatic M3R-AMPKα downstream pathways. Cevimeline co-treatment also improved lower activated AKT-GSK3ß signalling to reverse impairment of glucose metabolism and insulin resistance caused by chronic olanzapine treatment. CONCLUSION: These results not only support the important role of M3R antagonism and its related AMPKα and downstream pathways in antipsychotic-induced metabolic disorders but also indicate that these pathways might be promising targets for pharmacological intervention to control these side effects caused by antipsychotic therapy.


Subject(s)
Antipsychotic Agents/toxicity , Metabolic Diseases/prevention & control , Olanzapine/toxicity , Quinuclidines/pharmacology , Thiophenes/pharmacology , AMP-Activated Protein Kinases/metabolism , Animals , Female , Liver/drug effects , Liver/metabolism , Metabolic Diseases/chemically induced , Muscarinic Agonists/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Muscarinic M3/agonists , Receptor, Muscarinic M3/antagonists & inhibitors , Signal Transduction/drug effects , Weight Gain/drug effects
9.
Psychiatry Res ; 305: 114196, 2021 11.
Article in English | MEDLINE | ID: mdl-34488011

ABSTRACT

The positive role of ketone bodies in the treatment for mental disorders has been demonstrated. Ketogenesis can be triggered by not only exercise and diet but also metabolic disorders. This study aimed to explore the role of risperidone and exercise in ketogenesis. Thirty-two juvenile female Sprague Dawley rats were randomly assigned into four groups: Vehicle-Sedentary, Risperidone (0.9 mg/kg; b.i.d)-Sedentary, Vehicle-Exercise (three hours daily access to running wheels) and Risperidone-Exercise groups for four weeks. Exercise-intervention significantly ameliorated the risperidone-induced increase in white adipose mass, fasting plasma triglyceride and insulin levels. Compared to the vehicle-exercise group, the risperidone-exercise group had significantly higher plasma ß-hydroxybutyrate (ß-HB) level, which had a positive correlation with plasma non-esterified fatty acid levels. Risperidone-treatment upregulated expression of ketogenic key enzyme, mitochondrial 3-hydroxy-3-methyl-glutaryl-CoA synthase 2 (HMGCS2) in the kidney rather than liver. Exercise-intervention significantly enhanced renal carnitine palmitoyltransferase1A (CPT1A) expression. These results suggested that the kidney plays an important role in ketogenesis associated with risperidone and exercise. Therefore, it is important to monitor the levels of plasma ketone bodies while exercise intervention is utilized to prevent risperidone-induced metabolic disorders in young people.


Subject(s)
Ketone Bodies , Risperidone , Animals , Fasting , Female , Ketone Bodies/metabolism , Kidney/metabolism , Rats , Rats, Sprague-Dawley , Risperidone/pharmacology
10.
Pharmacol Biochem Behav ; 191: 172878, 2020 04.
Article in English | MEDLINE | ID: mdl-32112786

ABSTRACT

Olanzapine has been used for the treatment of schizophrenia and other mental disorders. However, it is associated with serious weight gain and other metabolic side-effects. The antagonistic affinity of olanzapine to muscarinic M3 receptors has been evidenced as one of the main contributors for its weight gain and other metabolic side-effects. Therefore, this study investigated whether the co-treatment of cevimeline (a M3 receptor agonist) could prevent the metabolic side-effects associated with olanzapine medication. Female Sprague Dawley rats were treated orally with olanzapine (2 mg/kg, t.i.d.) and/or cevimeline at 3 dosages (3, 6, 9 mg/kg, t.i.d.), or vehicle for two weeks. Weight gain and food/water intake were measured throughout the drug treatment period. Intraperitoneal glucose tolerance tests and open field tests were conducted. Olanzapine-treated rats demonstrated significantly elevated body weight gain, food intake, feeding efficiency, total white fat mass, liver mass, and plasma triglyceride levels, which could be partly reversed by the co-treatment with cevimeline in a dosage-dependent manner. In general, the body weight gain can only be reversed by the co-treatment of 9 mg/kg cevimeline. The cevimeline co-treatment decreased plasma triglyceride and glucose levels compared with olanzapine only treatment. The results suggested a dosage-dependent effect of cevimeline in ameliorating olanzapine-induced weight gain and metabolic side-effects, which supports further clinical trials using cevimeline to control weight gain and metabolic side-effects caused by antipsychotic medications.


Subject(s)
Metabolic Syndrome/chemically induced , Metabolic Syndrome/prevention & control , Olanzapine/adverse effects , Quinuclidines/administration & dosage , Thiophenes/administration & dosage , Adipose Tissue/drug effects , Adiposity/drug effects , Animals , Behavior, Animal/drug effects , Blood Glucose/drug effects , Dose-Response Relationship, Drug , Drug Interactions , Eating/drug effects , Female , Locomotion/drug effects , Metabolic Syndrome/blood , Olanzapine/pharmacology , Open Field Test , Quinuclidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Muscarinic M3/agonists , Receptor, Muscarinic M3/antagonists & inhibitors , Thiophenes/pharmacology , Treatment Outcome , Triglycerides/blood , Weight Gain/drug effects
11.
Pharmacol Res ; 155: 104703, 2020 05.
Article in English | MEDLINE | ID: mdl-32068120

ABSTRACT

The antipsychotic drug olanzapine is widely used in the treatment of schizophrenia, bipolar and other mental disorders; however, it causes serious metabolic disorders, including dyslipidemia. Our previous studies have identified that olanzapine activated expression of the sterol regulatory element binding transcription factor 1 (SREBP-1) gene, a key transcriptional factor for lipogenesis in the liver and adipocytes. SREBP-1 has been reported to positively regulate the peroxisome proliferator-activated receptor gamma (PPARγ), a master regulator in the process of adipogenesis. This study aimed to investigate epigenetic modulations of the hepatic PPARγ pathway in olanzapine-induced lipid dysfunctions. Olanzapine led to significant increases of body weight gain, white adipose tissue, fasting triglyceride, and fat accumulation in the liver. A significant upregulation of PPARγ was observed in olanzapine-treated rats. ChIP-deep sequencing showed the increase of H3K4me2 binding on the whole gene loci of key regulators of adipogenesis and lipogenesis, the Pparg, Srebp-1, Cebps families (Cebpa, Cebpb and Cebpd), the Signal transducer and activator of transcription 5 families (Stat5a and Stat5b) and Klfs families (Klf9 and Klf15), as well as muscarinic M3 receptor (Chrm3). ChIP-qPCR revealed that H3K9me3 binding on the promoter of Pparg2 was significantly decreased. Consistently, KDM4B, KDM1A and PHF2, the three histone demethylases responsible for site-specific erasure of H3K9me, was increased in olanzapine-treated rats. These results suggested that olanzapine acted as stimuli to trigger the cascade of adipogenesis and lipogenesis through modulating hepatic histone modifications and subsequently upregulating key transcriptional factors. These findings provided new insight into effective strategies for the prevention and treatment of metabolic side-effects induced by antipsychotic medication.


Subject(s)
Antipsychotic Agents/adverse effects , Histones/metabolism , Metabolic Diseases/chemically induced , Metabolic Diseases/metabolism , Olanzapine/adverse effects , PPAR gamma/metabolism , Adipogenesis/drug effects , Animals , Epigenesis, Genetic , Female , Histone Demethylases/metabolism , Homeodomain Proteins/metabolism , Lipogenesis/drug effects , Rats, Sprague-Dawley , Signal Transduction
12.
Psychiatry Res ; 273: 739-745, 2019 03.
Article in English | MEDLINE | ID: mdl-31207861

ABSTRACT

Antipsychotics were developed to treat schizophrenia in adults; however they have been increasingly prescribed in children and adolescents. The NMDA and GABAA receptors are involved in neurodevelopment and the pathophysiology of various mental disorders in children and adolescents. Male and female juvenile rats were treated orally with risperidone (0.3 mg/kg, 3 times/day), aripiprazole (1 mg/kg), olanzapine (1 mg/kg) or vehicle (control), starting from postnatal day (PD) 23 (±1 day) for 3 weeks (corresponding to the childhood-adolescent period in humans). Quantitative autoradiography was used to detect the binding density of [3H]MK-801 (an NMDA receptor antagonist) and [3H]muscimol (a selective GABAA receptor agonist). Aripiprazole elevated the [3H]MK801 binding levels in the NAcC of male rats, and the NAcS and CPu of female rats. Risperidone increased [3H]MK801 levels in the CPu of female rats, and the NAcS of male rats. Aripiprazole upregulated [3H]muscimol binding levels in the CPu and NAcC of male rats, while it elevated the [3H]muscimol levels in the PFC of female rats, compared to controls. These results suggest that early treatment with these antipsychotics modulates NMDA and GABAA neurotransmission in juveniles, which may play a role in their clinical efficacy in the control of mental disorders in children and adolescents.


Subject(s)
Antipsychotic Agents/metabolism , Antipsychotic Agents/pharmacology , Brain/drug effects , Brain/metabolism , Receptors, GABA-A/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Antipsychotic Agents/therapeutic use , Autoradiography/methods , Female , Male , Pregnancy , Protein Binding/drug effects , Protein Binding/physiology , Rats , Rats, Sprague-Dawley , Schizophrenia/drug therapy
13.
J Psychopharmacol ; 32(11): 1252-1263, 2018 11.
Article in English | MEDLINE | ID: mdl-30136620

ABSTRACT

BACKGROUND: Antipsychotics are developed to treat mental disorders in adults; however, the prescription (mostly "off-label") of antipsychotics for children/adolescents has been constantly increasing over years. The influences of antipsychotics on juveniles requires investigation to validate their clinic use. Antipsychotics mainly exert their effects via several receptors and signaling pathways. AIMS: This study examined the effects of aripiprazole, olanzapine, and risperidone on selected signaling pathways, N-methyl-D-aspartate, and γ-aminobutyric acid A receptors in juveniles. METHODS: Rats were orally administered aripiprazole (1 mg/kg), olanzapine (1 mg/kg), risperidone (0.3 mg/kg), or vehicle three times/day from postnatal day 23 (±1 day) for three weeks. The effects of antipsychotics in the nucleus accumbens and caudate putamen were measured by Western blots. RESULTS: In the nucleus accumbens, all three drugs differentially increased N-methyl-D-aspartate and γ-aminobutyric acid A receptor expression. Additionally, all three antipsychotics differentially elevated the phosphorylation of glycogen synthase kinase 3 beta, ß-catenin, and cAMP-responsive element-binding protein 1. In the caudate putamen, olanzapine increased ß-catenin phosphorylation; and aripiprazole and olanzapine elevated γ-aminobutyric acid A receptor levels. Correlation analysis indicated that antipsychotics might modulate N-methyl-D-aspartate receptors via glycogen synthase kinase 3 beta-ß-catenin signaling and/or cAMP-responsive element-binding protein 1 activation. CONCLUSIONS: These findings suggest that antipsychotics can affect protein kinase A- and glycogen synthase kinase 3 beta-dependent signaling pathways in juveniles; and their modulation on N-methyl-D-aspartate and γ-aminobutyric acid A receptors is probably through glycogen synthase kinase 3 beta-ß-catenin signaling and/or cAMP-responsive element-binding protein 1 activation.


Subject(s)
Antipsychotic Agents/administration & dosage , Aripiprazole/administration & dosage , Olanzapine/administration & dosage , Risperidone/administration & dosage , Animals , Antipsychotic Agents/pharmacology , Aripiprazole/pharmacology , Blotting, Western , Cyclic AMP-Dependent Protein Kinases/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Male , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Olanzapine/pharmacology , Phosphorylation/drug effects , Rats , Rats, Sprague-Dawley , Receptors, GABA/drug effects , Receptors, GABA/metabolism , Receptors, N-Methyl-D-Aspartate/drug effects , Receptors, N-Methyl-D-Aspartate/metabolism , Risperidone/pharmacology , Signal Transduction/drug effects
14.
Psychiatry Res ; 266: 317-322, 2018 08.
Article in English | MEDLINE | ID: mdl-29576413

ABSTRACT

Antipsychotic drugs have been increasingly prescribed to children and adolescents for treating various mental disorders, such as childhood-onset schizophrenia. The abnormality of endocannabinoid system is involved in the pathophysiology of these disorders in juveniles. This study investigated the effect of antipsychotics on the cannabinoid (CB) receptors in the brain of both male and female juvenile rats. The postnatal rats (PD23±1) were administered aripiprazole (1 mg/kg), olanzapine (1 mg/kg), risperidone (0.3 mg/kg) or vehicle (control) for 3 weeks. Quantitative autoradiography was used to investigate the binding densities of [3H]CP-55940 (an agonist for CB1R and CB2R) and [3H]SR141716A (a selective CB1R antagonist) in the rat brains. Risperidone significantly upregulated the [3H]CP55940 and [3H]SR141716A bindings in the prefrontal cortex (PFC), nucleus accumbens core (NAcC), nucleus accumbens shell (NAcS), cingulate cortex (Cg), and the caudate putamen (CPu) in male rats. Moreover, aripiprazole significantly elevated the [3H]SR141716A binding in the Cg and NAcS of female rats. Furthermore, there is an overall higher [3H]SR141716A binding level in the brain of female rats than male rats. Therefore, treatment with aripiprazole, olanzapine and risperidone could induce differential and gender specific effects on the binding density of cannabinoid receptors in the selected brain regions of childhood/adolescent rats.


Subject(s)
Antipsychotic Agents/pharmacology , Brain Chemistry , Brain/drug effects , Receptors, Cannabinoid/drug effects , Sex Factors , Animals , Aripiprazole/pharmacology , Autoradiography , Benzodiazepines/pharmacology , Female , Male , Nucleus Accumbens/metabolism , Olanzapine/pharmacology , Prefrontal Cortex/drug effects , Rats , Rats, Sprague-Dawley , Risperidone/pharmacology
15.
Sci Rep ; 7(1): 2762, 2017 06 05.
Article in English | MEDLINE | ID: mdl-28584269

ABSTRACT

Chronic treatment with second-generation antipsychotic drugs (SGAs) has been associated with an increased risk of metabolic syndrome. To evaluate the longitudinal changes in glucose-lipid homeostasis after SGA use, we studied the time-dependent effects of olanzapine (OLZ) (3 mg/kg, b.i.d.) or clozapine (CLZ) (20 mg/kg, b.i.d.) treatment on metabolic profiles for 9 weeks in rats. Although only OLZ significantly increased body weight in rats, both OLZ and CLZ elevated blood lipid levels. Chronic OLZ treatment induced significant weight gain leading to a higher fasting insulin level and impaired glucose tolerance, whereas CLZ lowered fasting insulin levels and impaired glucose tolerance independent of weight gain. Treatment with both drugs deranged AKT/GSK phosphorylation and up-regulated muscarinic M3 receptors in the rats' livers. Consistent with an elevation in lipid levels, both OLZ and CLZ significantly increased the protein levels of nuclear sterol regulatory element-binding proteins (SREBPs) in the liver, which was associated with improvement in hepatic histamine H1R. However, enhanced carbohydrate response element binding protein (ChREBP) signalling was observed in only CLZ-treated rats. These results suggest that SGA-induced glucose-lipid metabolic disturbances could be independent of weight gain, possibly through activation of SREBP/ChREBP in the liver.


Subject(s)
Antipsychotic Agents/adverse effects , Clozapine/adverse effects , Glucose Metabolism Disorders/etiology , Glucose Metabolism Disorders/metabolism , Lipid Metabolism Disorders/etiology , Lipid Metabolism Disorders/metabolism , Adipose Tissue, White/drug effects , Adipose Tissue, White/metabolism , Animals , Antipsychotic Agents/administration & dosage , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Blood Glucose/drug effects , Clozapine/administration & dosage , Disease Models, Animal , Glucose/metabolism , Humans , Lipid Metabolism/drug effects , Liver/drug effects , Liver/metabolism , Metabolic Networks and Pathways/drug effects , Olanzapine/administration & dosage , Olanzapine/adverse effects , Rats , Sterol Regulatory Element Binding Proteins/metabolism , Weight Gain
16.
Int J Mol Sci ; 17(11)2016 Nov 22.
Article in English | MEDLINE | ID: mdl-27879654

ABSTRACT

Prescription of antipsychotic drugs (APDs) to children has substantially increased in recent years. Whilst current investigations into potential long-term effects have uncovered some alterations to adult behaviours, further investigations into potential changes to neurotransmitter systems are required. The current study investigated potential long-term changes to the adult dopamine (DA) system following aripiprazole, olanzapine and risperidone treatment in female and male juvenile rats. Levels of tyrosine hydroxylase (TH), phosphorylated-TH (p-TH), dopamine active transporter (DAT), and D1 and D2 receptors were measured via Western blot and/or receptor autoradiography. Aripiprazole decreased TH and D1 receptor levels in the ventral tegmental area (VTA) and p-TH levels in the prefrontal cortex (PFC) of females, whilst TH levels decreased in the PFC of males. Olanzapine decreased PFC p-TH levels and increased D2 receptor expression in the PFC and nucleus accumbens (NAc) in females only. Additionally, risperidone treatment increased D1 receptor levels in the hippocampus of females, whilst, in males, p-TH levels increased in the PFC and hippocampus, D1 receptor expression decreased in the NAc, and DAT levels decreased in the caudate putamen (CPu), and elevated in the VTA. These results suggest that early treatment with various APDs can cause different long-term alterations in the adult brain, across both treatment groups and genders.


Subject(s)
Antipsychotic Agents/adverse effects , Aripiprazole/adverse effects , Benzodiazepines/adverse effects , Dopamine/metabolism , Risperidone/adverse effects , Synaptic Transmission/drug effects , Animals , Antipsychotic Agents/administration & dosage , Aripiprazole/administration & dosage , Benzodiazepines/administration & dosage , Caudate Nucleus/drug effects , Caudate Nucleus/metabolism , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Dopamine Plasma Membrane Transport Proteins/genetics , Dopamine Plasma Membrane Transport Proteins/metabolism , Female , Gene Expression Regulation , Hippocampus/drug effects , Hippocampus/metabolism , Male , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Olanzapine , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Putamen/drug effects , Putamen/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D1/antagonists & inhibitors , Receptors, Dopamine D1/genetics , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/genetics , Receptors, Dopamine D2/metabolism , Risperidone/administration & dosage , Time Factors , Tyrosine 3-Monooxygenase/antagonists & inhibitors , Tyrosine 3-Monooxygenase/genetics , Tyrosine 3-Monooxygenase/metabolism , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/metabolism
17.
Pharmacol Rep ; 68(5): 1028-35, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27428765

ABSTRACT

BACKGROUND: Antipsychotic drugs (APDs) were developed to treat schizophrenia in adults; however they have been increasingly prescribed (mostly "off-label") for children and adolescents. This study aimed to investigate the effects of aripiprazole, olanzapine and risperidone on the binding of serotonin (5-HT) and dopamine receptors in juvenile rat brain regions that are involved in antipsychotic efficacy. METHODS: Male and female rats were treated orally with aripiprazole (1mg/kg), olanzapine (1mg/kg), risperidone (0.3mg/kg) or vehicle 3 times/day starting from postnatal day 23 (±1day) for 20 days. Quantitative autoradiography was performed to examine the receptor binding densities. RESULTS: Olanzapine significantly decreased 5-HT2A (5-HT2AR) and 5-HT2C receptor (5-HT2CR) binding in the prefrontal cortex (PFC), cingulate cortex (Cg) and nucleus accumbens (NAc) of both male and female rats. In the caudate putamen (CPu), olanzapine attenuated 5-HT2AR binding in both genders, and reduced 5-HT2CR binding in male rats. Olanzapine increased D2 receptor (D2R) binding in the NAcS of male rats, but decreased it in females. Olanzapine increased D1 receptor (D1R) binding in the Cg, while aripiprazole decreased D1R binding in the PFC of males. Aripiprazole significantly reduced 5-HT2AR binding in the male PFC. Risperidone decreased 5-HT2AR binding in the PFC of female rats, while attenuating D1R binding in the PFC and Cg of males. However, APDs have no effects on the binding of serotonin and dopamine transporters. CONCLUSION: This study revealed that aripiprazole, olanzapine and risperidone affected 5-HT2AR, 5-HT2CR, 5-HTT, D1R and D2R bindings differently in the brains of juvenile male and female rats.


Subject(s)
Antipsychotic Agents/adverse effects , Nucleus Accumbens/drug effects , Prefrontal Cortex/drug effects , Protein Binding/drug effects , Receptors, Dopamine/metabolism , Receptors, Serotonin/metabolism , Animals , Aripiprazole/adverse effects , Autoradiography/methods , Benzodiazepines/adverse effects , Female , Male , Nucleus Accumbens/metabolism , Olanzapine , Prefrontal Cortex/metabolism , Rats , Rats, Sprague-Dawley , Risperidone/adverse effects , Schizophrenia/metabolism
18.
Pharmacol Res ; 106: 51-63, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26892184

ABSTRACT

Second generation antipsychotic drugs (SGAs) cause substantial body weight gain/obesity and other metabolic side-effects such as dyslipidaemia. Their antagonistic affinity to the histaminergic H1 receptor (H1R) has been identified as one of the main contributors to weight gain/obesity side-effects. The effects and mechanisms of betahistine (a histaminergic H1R agonist and H3 receptor antagonist) have been investigated for ameliorating SGA-induced weight gain/obesity in both animal models and clinical trials. It has been demonstrated that co-treatment with betahistine is effective in reducing weight gain, associated with olanzapine in drug-naïve patients with schizophrenia, as well as in the animal models of both drug-naïve rats and rats with chronic, repeated exposure to olanzapine. Betahistine co-treatment can reduce food intake and increase the effect of thermogenesis in brown adipose tissue by modulating hypothalamic H1R-NPY-AMPKα (NPY: neuropeptide Y; AMPKα: AMP-activated protein kinase α) pathways, and ameliorate olanzapine-induced dyslipidaemia through modulation of AMPKα-SREBP-1-PPARα-dependent pathways (SREBP-1: Sterol regulatory element binding protein 1; PPARα: Peroxisome proliferator-activated receptor-α) in the liver. Although reduced locomotor activity was observed from antipsychotic treatment in rats, betahistine did not affect locomotor activity. Importantly, betahistine co-treatment did not influence the effects of antipsychotics on serotonergic receptors in the key brain regions for antipsychotic therapeutic efficacy. However, betahistine co-treatment reverses the upregulated dopamine D2 binding caused by chronic olanzapine administration, which may be beneficial in reducing D2 supersensitivity often observed in chronic antipsychotic treatment. Therefore, these results provide solid evidence supporting further clinical trials in treating antipsychotics-induced weight gain using betahistine in patients with schizophrenia and other mental disorders.


Subject(s)
Antipsychotic Agents/adverse effects , Betahistine/pharmacology , Betahistine/therapeutic use , Histamine Agonists/pharmacology , Histamine Agonists/therapeutic use , Weight Gain/drug effects , AMP-Activated Protein Kinases/metabolism , Animals , Benzodiazepines/adverse effects , Humans , Olanzapine , Receptors, Histamine H1/metabolism
19.
J Mol Neurosci ; 59(1): 36-47, 2016 May.
Article in English | MEDLINE | ID: mdl-26894264

ABSTRACT

The GABAA receptor is implicated in the pathophysiology of schizophrenia and regulated by PKA signalling. Current antipsychotics bind with D2-like receptors, but not the GABAA receptor. The cAMP-responsive element-binding protein 1 (CREB1) is also associated with PKA signalling and may be related to the positive symptoms of schizophrenia. This study investigated the effects of antipsychotics in modulating D2-mediated PKA signalling and its downstream GABAA receptors and CREB1. Rats were treated orally with aripiprazole (0.75 mg/kg, ter in die (t.i.d.)), bifeprunox (0.8 mg/kg, t.i.d.), haloperidol (0.1 mg/kg, t.i.d.) or vehicle for 1 week. The levels of PKA-Cα and p-PKA in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) were detected by Western blots. The mRNA levels of Gabrb1, Gabrb2, Gabrb3 and Creb1, and their protein expression were measured by qRT-PCR and Western blots, respectively. Aripiprazole elevated the levels of p-PKA and the ratio of p-PKA/PKA in the NAc, but not the PFC and CPu. Correlated with this elevated PKA signalling, aripiprazole elevated the mRNA and protein expression of the GABAA (ß-1) receptor and CREB1 in the NAc. While haloperidol elevated the levels of p-PKA and the ratio of p-PKA/PKA in both NAc and CPu, it only tended to increase the expression of the GABAA (ß-1) receptor and CREB1 in the NAc, but not the CPu. Bifeprunox had no effects on PKA signalling in these brain regions. These results suggest that aripiprazole has selective effects on upregulating the GABAA (ß-1) receptor and CREB1 in the NAc, probably via activating PKA signalling.


Subject(s)
Antipsychotic Agents/pharmacology , Aripiprazole/pharmacology , Cyclic AMP Response Element-Binding Protein/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Nucleus Accumbens/drug effects , Receptors, GABA-A/metabolism , Animals , Benzoxazoles/pharmacology , Cyclic AMP Response Element-Binding Protein/genetics , Cyclic AMP-Dependent Protein Kinases/genetics , Haloperidol/pharmacology , Male , Nucleus Accumbens/metabolism , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/genetics , Signal Transduction
20.
J Psychopharmacol ; 30(2): 204-14, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26577063

ABSTRACT

Childhood/adolescent antipsychotic drug (APD) use is exponentially increasing worldwide, despite limited knowledge of the long-term effects of early APD treatment. Whilst investigations have found that early treatment has resulted in some alterations to dopamine and serotonin neurotransmission systems (essential to APD efficacy), there have only been limited studies into potential long-term behavioural changes. This study, using an animal model for childhood/adolescent APD treatment, investigated the long-term effects of aripiprazole, olanzapine and risperidone on adult behaviours of male and female rats. Open-field/holeboard, elevated plus maze (EPM), social interaction and forced swim (FS) tests were then conducted in adult rats. Our results indicated that in the male cohort, early risperidone and olanzapine treatment elicited long-term hyper-locomotor effects (open-field/holeboard and FS tests), whilst a decrease in depressive-like behaviour (in FS test) was observed in response to olanzapine treatment. Furthermore, anxiolytic-like behaviours were found following testing in the open-field/holeboard and EPM in response to all three drug treatments. Effects in the female cohort, however, were to a far lesser extent, with behavioural attributes indicative of an increased depressive-like behaviour and hypo-locomotor activity exhibited in the FS test following early risperidone and olanzapine treatment. These results suggest that various APDs have different long-term effects on the behaviours of adult rats.


Subject(s)
Antipsychotic Agents/pharmacology , Behavior, Animal/drug effects , Motor Activity/drug effects , Age Factors , Animals , Antipsychotic Agents/administration & dosage , Anxiety/epidemiology , Aripiprazole/administration & dosage , Aripiprazole/pharmacology , Benzodiazepines/administration & dosage , Benzodiazepines/pharmacology , Depression/epidemiology , Female , Male , Olanzapine , Rats , Rats, Sprague-Dawley , Risperidone/administration & dosage , Risperidone/pharmacology , Sex Factors , Time Factors
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