Preventing olanzapine-induced weight gain using betahistine: a study in a rat model with chronic olanzapine treatment

Olanzapine is the one of first line antipsychotic drug for schizophrenia and other serious mental illness. However, it is associated with troublesome metabolic side-effects, particularly body weight gain and obesity. The antagonistic affinity to histamine H1 receptors (H1R) of antipsychotic drugs has been identified as one of the main contributors to weight gain/obesity side-effects. Our previous study showed that a short term (2 weeks) combination treatment of betahistine (an H1R agonist and H3R antagonist) and olanzapine (O+B) reduced (−45%) body weight gain induced by olanzapine in drug-naïve rats. A key issue is that clinical patients suffering with schizophrenia, bipolar disease and other mental disorders often face chronic, even life-time, antipsychotic treatment, in which they have often had previous antipsychotic exposure. Therefore, we investigated the effects of chronic O+B co-treatment in controlling body weight in female rats with chronic and repeated exposure of olanzapine. The results showed that co-administration of olanzapine (3 mg/kg, t.i.d.) and betahistine (9.6 mg/kg, t.i.d.) significantly reduced (−51.4%) weight gain induced by olanzapine. Co-treatment of O+B also led to a decrease in feeding efficiency, liver and fat mass. Consistently, the olanzapine-only treatment increased hypothalamic H1R protein levels, as well as hypothalamic pAMPKα, AMPKα and NPY protein levels, while reducing the hypothalamic POMC, and UCP1 and PGC-1α protein levels in brown adipose tissue (BAT). The olanzapine induced changes in hypothalamic H1R, pAMPKα, BAT UCP1 and PGC-1α could be reversed by co-treatment of O+B. These results supported further clinical trials to test the effectiveness of co-treatment of O+B for controlling weight gain/obesity side-effects in schizophrenia with chronic antipsychotic treatment

Unique effects of acute aripiprazole treatment on the dopamine D2 receptor downstream cAMP-PKA and Akt-GSK3β signalling pathways in rats

Aripiprazole is a wide-used antipsychotic drug with therapeutic effects on both positive and negative symptoms of schizophrenia, and reduced side-effects. Although aripiprazole was developed as a dopamine D2 receptor (D2R) partial agonist, all other D2R partial agonists that aimed to mimic aripiprazole failed to exert therapeutic effects in clinic. The present in vivo study aimed to investigate the effects of aripiprazole on the D2R downstream cAMP-PKA and Akt-GSK3β signalling pathways in comparison with a D2R antagonist - haloperidol and a D2R partial agonist - bifeprunox. Rats were injected once with aripiprazole (0.75mg/kg, i.p.), bifeprunox (0.8mg/kg, i.p.), haloperidol (0.1mg/kg, i.p.) or vehicle. Five brain regions - the prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CPu), ventral tegmental area (VTA) and substantia nigra (SN) were collected. The protein levels of PKA, Akt and GSK3β were measured by Western Blotting; the cAMP levels were examined by ELISA tests. The results showed that aripiprazole presented similar acute effects on PKA expression to haloperidol, but not bifeprunox, in the CPU and VTA. Additionally, aripiprazole was able to increase the phosphorylation of GSK3β in the PFC, NAc, CPu and SN, respectively, which cannot be achieved by bifeprunox and haloperidol. These results suggested that acute treatment of aripiprazole had differential effects on the cAMP-PKA and Akt-GSK3β signalling pathways from haloperidol and bifeprunox in these brain areas. This study further indicated that, by comparison with bifeprunox, the unique pharmacological profile of aripiprazole may be attributed to the relatively lower intrinsic activity at D2R

Unique effects of acute aripiprazole treatment on the dopamine D2 receptor downstream cAMP-PKA and Akt-GSK3β signalling pathways in rats

Aripiprazole is a wide-used antipsychotic drug with therapeutic effects on both positive and negative symptoms of schizophrenia, and reduced side-effects. Although aripiprazole was developed as a dopamine D2 receptor (D2R) partial agonist, all other D2R partial agonists that aimed to mimic aripiprazole failed to exert therapeutic effects in clinic. The present in vivo study aimed to investigate the effects of aripiprazole on the D2R downstream cAMP-PKA and Akt-GSK3β signalling pathways in comparison with a D2R antagonist - haloperidol and a D2R partial agonist - bifeprunox. Rats were injected once with aripiprazole (0.75mg/kg, i.p.), bifeprunox (0.8mg/kg, i.p.), haloperidol (0.1mg/kg, i.p.) or vehicle. Five brain regions - the prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CPu), ventral tegmental area (VTA) and substantia nigra (SN) were collected. The protein levels of PKA, Akt and GSK3β were measured by Western Blotting; the cAMP levels were examined by ELISA tests. The results showed that aripiprazole presented similar acute effects on PKA expression to haloperidol, but not bifeprunox, in the CPU and VTA. Additionally, aripiprazole was able to increase the phosphorylation of GSK3β in the PFC, NAc, CPu and SN, respectively, which cannot be achieved by bifeprunox and haloperidol. These results suggested that acute treatment of aripiprazole had differential effects on the cAMP-PKA and Akt-GSK3β signalling pathways from haloperidol and bifeprunox in these brain areas. This study further indicated that, by comparison with bifeprunox, the unique pharmacological profile of aripiprazole may be attributed to the relatively lower intrinsic activity at D2R

The effects of antipsychotics on the density of cannabinoid receptors in selected brain regions of male and female adolescent juvenile rats

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 [ 3 H]CP-55940 (an agonist for CB1R and CB2R) and [ 3 H]SR141716A (a selective CB1R antagonist) in the rat brains. Risperidone significantly upregulated the [ 3 H]CP55940 and [ 3 H]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 [ 3 H]SR141716A binding in the Cg and NAcS of female rats. Furthermore, there is an overall higher [ 3 H]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

Early antipsychotic exposure affects NMDA and GABAA receptor binding in the brains of juvenile rats

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

The mechanisms for reducing olanzapineinduced weight gain/obesity by betahistine: clinical implications

Olanzapine, a second generation antipsychotic drug, is widely used to treat multiple domains of schizophrenia and other mental disorders. However, it is associated with substantial body weight gain/obesity side-effects. Since the antagonistic affinity to histaminergic H1 receptor (H1 R) has been identified as a major contributor for antipsychotic-induced weight gain, this thesis investigated the effects and mechanisms of co-treatment with betahistine (a histaminergic H1 R agonist and H3 receptor antagonist) for ameliorating olanzapine-induced weight gain/obesity in a series of four experiments using a female rat model. The first experiment showed that short-term (2 weeks) combination treatment of betahistine and olanzapine (O+B) reduced (-45%) body weight gain and feeding efficiency caused by olanzapine in drug-naïve rats. Olanzapine significantly upregulated expressions of H1R, Neuropeptide Y (NPY), and AMP-activated protein kinase ɑ (AMPKɑ) phosphorylation, that were reversed by O+B co-treatment. Hypothalamic pro-opiomelanocortin (POMC) expression was decreased by olanzapine, but not affected by O+B co-treatment. These results suggest that O+B co-treatment may reduce olanzapine-induced weight gain via the H1 R-NPY and H1 R-pAMPKɑ pathways. Since patients suffering with schizophrenia and other mental disorders often face chronic, even life-time, antipsychotic treatment, I further investigated effects of chronic O+B co-treatment on preventing olanzapine-induced weight gain. Chronic coadministration of O+B significantly reduced (-51.4%) weight gain, feeding efficiency, liver and fat mass induced by olanzapine. Consistently, the chronic olanzapine-only treatment increased expressions of hypothalamic H1 R, pAMPKɑ and NPY, while reducing uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator1-alpha (PGC-1a) levels in brown adipose tissue. These olanzapineinduced changes could be reversed by chronic O+B co-treatment. Following experiments investigated the effects of O+B co-treatment on the primary therapeutic receptor binding sites of olanzapine in various brain regions. Both shortterm olanzapine-only and O+B co-treatment significantly decreased 5-HT2A receptor (5- HT2AR) bindings in the prefrontal cortex (PFC), cingulate cortex (Cg), and nucleus accumbens (NAc), but had no effects on dopamine D2 receptors (D2R). Olanzapine also significantly decreased 5-HTT bindings in the ventral tegmental area (VTA) and substantia nigra (SN). The results confirmed the important role of 5-HT2AR in the efficacy of olanzapine, which was not influenced by short-term O+B co-treatment. Both chronic olanzapine-only and O+B co-treatment significantly decreased the bindings of 5-HT2AR, 5-HT2CR, and 5-HTT in the PFC, Cg and NAc. The chronic olanzapine-only treatment significantly increased the D2R bindings in the Cg, NAc, and CPu (which might be attributed to “dopaminergic supersensitivity”), while the chronic betahistine-only treatment reduced D2R bindings. Chronic O+B co-treatment reversed the D2R bindings in the NAc and CPu that were increased by chronic olanzapine treatment. Therefore, chronic O+B co-treatment has similar effects on serotonin neurotransmission as olanzapine-only treatment, but reverses the D2R binding that is upregulated by chronic olanzapine treatment. In brief, this thesis provided sound evidence that both short-term and chronic cotreatment with betahistine would be effective combination therapy to reduce olanzapineinduced weight gain without affecting its therapeutic effects. These results support further clinical trials to test the effectiveness of betahistine co-treatment for controlling weight gain/obesity side-effects in schizophrenia patients with antipsychotic treatment

Chronic antipsychotic treatment differentially modulates protein kinase A- and glycogen synthase kinase 3 beta-dependent signaling pathways, N-methyl-D-aspartate receptor and γ-aminobutyric acid A receptors in nucleus accumbens of juvenile rats

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, β-catenin, and cAMP-responsive element-binding protein 1. In the caudate putamen, olanzapine increased β-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-β-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-β-catenin signaling and/or cAMP-responsive element-binding protein 1 activation