Katrina Weston-Green

The role of histaminergic H1 and H3 receptors in food intake: a mechanism for atypical antipsychotic-induced weight gain?

Atypical antipsychotics such as olanzapine and clozapine are effective at treating the multiple domains of schizophrenia, with a low risk of extra-pyramidal side-effects. However a major downfall to their use is metabolic side-effects particularly weight gain/obesity, which occurs by unknown mechanisms. The present paper explores the potential candidature of histaminergic neurotransmission in the mechanisms of atypical antipsychotic-induced weight gain, with a focus on the histaminergic H1 and H3 receptors. Olanzapine and clozapine have a high affinity for the H1 receptor, and meta-analyses show a strong correlation between risk of weight gain and H1 receptor affinity. In addition, olanzapine treatment decreases H1 receptor binding and mRNA expression in the rat hypothalamus. Furthermore, a complex role is emerging for the histamine H3 receptor in the control of hunger. The H3 receptor is a pre-synaptic autoreceptor that inhibits the synthesis and release of histamine, and a heteroreceptor that inhibits other neurotransmitters such as serotonin (5-HT), noradrenaline (NA) and acetylcholine (ACh), which are also implicated in the regulation of food intake. Thus, the H3 receptor is in a prime position to regulate food intake, both through its control of histamine and its influence on other feeding pathways. We proposed that a mechanism for atypical antipsychotic-induced weight gain may be partly through the H3 receptor, as a drug-induced decrease in H1 receptor activity may decrease histamine tone through the H3 autoreceptors, compounding the weight gain problem. In addition, atypical antipsychotics may affect food intake by influencing 5-HT, NA and ACh release via interactions with the H3 heteroreceptor.

Olanzapine treatment and metabolic dysfunction: a dose response study in female Sprague Dawley rats

Second generation antipsychotics are commonly prescribed for the treatment of schizophrenia, however some can induce metabolic dysfunction side-effects such as weight gain, obesity and diabetes. Clinical reports suggest olanzapine alters satiety signals, although findings appear conflicting. Previous animal model studies have utilised a range of olanzapine dosages, however the dosage that better mimics the human scenario of olanzapine-induced weight gain is unclear. Female Sprague-Dawley rats were treated orally, three times daily with olanzapine (0.25mg/kg, 0.5mg/kg, 1.0mg/kg, 2.0mg/kg), self-administered in a sweet cookie dough pellet at eight-hourly intervals) or vehicle (n=12/group) for 14-days. Olanzapine orally self-administered in multiple doses (eight-hourly intervals) may circumvent a drop in plasma drug concentration and ensure the maintenance of a consistently high olanzapine level in the rat. Olanzapine increased body weight (0.5mg/kg, 1.0mg/kg, 2.0mg/kg), food intake (2.0mg/kg) and feeding efficiency (0.5-2.0mg/kg), with no effect on water intake. Subcutaneous inguinal (1.0mg/kg, 2.0mg/kg) and intra-abdominal perirenal fat were increased (2.0mg/kg), but not interscapula brown adipose tissue. Olanzapine increased circulating ghrelin and cholecystokinin, but had no effect on peptide YY((3-36)). Olanzapine decreased insulin (0.25-2.0mg/kg) and locomotor activity in the open field arena (0.5-2.0mg/kg). A low dosage of 0.25mg/kg olanzapine had no effect on most parameters measured. Olanzapine-induced weight gain is associated with hyperphagia, enhanced feeding efficiency and adiposity, decreased locomotor activity and altered satiety signaling. The animal model used in the present study of self-administered oral olanzapine treatment (t.i.d.) at a dosage range of 0.5-2.0mg/kg (but not 0.25mg/kg) mimics aspects of the clinic.

Alterations to melanocortinergic, GABAergic and cannabinoid neurotransmission associated with olanzapine-induced weight gain

Background/Aim Second generation antipsychotics (SGAs) are used to treat schizophrenia but can cause serious metabolic side-effects, such as obesity and diabetes. This study examined the effects of low to high doses of olanzapine on appetite/metabolic regulatory signals in the hypothalamus and brainstem to elucidate the mechanisms underlying olanzapine-induced obesity. Methodology/Results Levels of pro-opiomelanocortin (POMC), neuropeptide Y (NPY) and glutamic acid decarboxylase (GAD65, enzyme for GABA synthesis) mRNA expression, and cannabinoid CB1 receptor (CB1R) binding density (using [3H]SR-141716A) were examined in the arcuate nucleus (Arc) and dorsal vagal complex (DVC) of female Sprague Dawley rats following 0.25, 0.5, 1.0 or 2.0 mg/kg olanzapine or vehicle (3×/day, 14-days). Consistent with its weight gain liability, olanzapine significantly decreased anorexigenic POMC and increased orexigenic NPY mRNA expression in a dose-sensitive manner in the Arc. GAD65 mRNA expression increased and CB1R binding density decreased in the Arc and DVC. Alterations to neurotransmission signals in the brain significantly correlated with body weight and adiposity. The minimum dosage threshold required to induce weight gain in the rat was 0.5 mg/kg olanzapine. Conclusions Olanzapine-induced weight gain is associated with reduced appetite-inhibiting POMC and increased NPY. This study also supports a role for the CB1R and GABA in the mechanisms underlying weight gain side-effects, possibly by altering POMC transmission. Metabolic dysfunction can be modelled in the female rat using low, clinically-comparable olanzapine doses when administered in-line with the half-life of the drug.

Olanzapine treatment decreases the density of muscarinic M2 receptors in the dorsal vagal complex of rats

In this study, we investigated the effects of antipsychotic drugs, olanzapine and haloperidol, on the density of the muscarinic M2 receptors in the dorsal vagal complex (DVC) and hypoglossal nucleus (HN). Female Sprague Dawley rats were treated with olanzapine, haloperidol or vehicle (control) for 1 (short-term) or 12 weeks (long-term). Quantitative autoradiography was used to investigate the M2 receptor density in the DVC and HN using a muscarinic antagonist [(3)H] AF-DX384. Olanzapine, but not haloperidol, treatment induced a significant decrease in the binding density of M2 receptors in the DVC compared to control groups. Although the HN showed a higher density of [(3)H] AF-DX384 binding than the DVC, treatment with both olanzapine and haloperidol did not induce any significant changes in [(3)H] AF-DX384 binding in the HN. These results suggest that olanzapine-induced body weight gain may be associated with functional changes in the muscarinic neurotransmission in the DVC.

Second generation antipsychotic-induced type 2 diabetes: a role for the muscarinic M3 receptor

Second generation antipsychotics (SGAs) are widely prescribed to treat various disorders, most notably schizophrenia and bipolar disorder; however, SGAs can cause abnormal glucose metabolism that can lead to insulin-resistance and type 2 diabetes mellitus side-effects by largely unknown mechanisms. This review explores the potential candidature of the acetylcholine (ACh) muscarinic M3 receptor (M3R) as a prime mechanistic and possible therapeutic target of interest in SGA-induced insulin dysregulation. Studies have identified that SGA binding affinity to the M3R is a predictor of diabetes risk; indeed, olanzapine and clozapine, SGAs with the highest clinical incidence of diabetes side-effects, are potent M3R antagonists. Pancreatic M3Rs regulate the glucose-stimulated cholinergic pathway of insulin secretion; their activation on β-cells stimulates insulin secretion, while M3R blockade decreases insulin secretion. Genetic modification of M3Rs causes robust alterations in insulin levels and glucose tolerance in mice. Olanzapine alters M3R density in discrete nuclei of the hypothalamus and caudal brainstem, regions that regulate glucose homeostasis and insulin secretion through vagal innervation of the pancreas. Furthermore, studies have demonstrated a dynamic sensitivity of hypothalamic and brainstem M3Rs to altered glucometabolic status of the body. Therefore, the M3R is in a prime position to influence glucose homeostasis through direct effects on pancreatic β-cells and by potentially altering signalling in the hypothalamus and brainstem. SGA-induced insulin dysregulation may be partly due to blockade of central and peripheral M3Rs, causing an initial disruption to insulin secretion and glucose homeostasis that can progressively lead to insulin resistance and diabetes during chronic treatment.

The Effects of Antipsychotics on the Density of Cannabinoid Receptors in the Dorsal Vagal Complex of Rats: Implications for Olanzapine-induced Weight Gain

Some atypical antipsychotics clinically used to treat schizophrenia induce weight gain by unknown mechanisms. The dorsal vagal complex (DVC) of the brainstem and the endogenous cannabinoid system are implicated in the regulation of appetite signalling and food intake. We investigated whether antipsychotic drugs alter cannabinoid receptor-binding density in the DVC. Female Spraguewk (short-term) or 120.83, p=0.01). In addition, only chronic olanzapine treatment increased food intake. These results show that olanzapine, an antipsychotic with a high risk of weight gain as a side-effect, significantly decreased cannabinoid receptor binding in the DVC, whilst aripiprazole and haloperidol, antipsychotics with a low risk of weight gain had little or no effect on binding. These results suggest that a mechanism for antipsychotic-induced weight gain may be through the modulation of cannabinoid receptors in the DVC.

Sensitivity of the female rat to olanzapine-induced weight gain - far from the clinic?

Dear Editor, The recent paper by Chintoh and colleagues (2008) reporting olanzapine-induced dysfunction in glucose metabolism, enhanced visceral fat and reduced locomotor activity in female rats was highly interesting as it illustrated olanzapine’s ability to replicate aspects of metabolic dysfunction in the rodent model in a similar manner to the human scenario. However, contrary to previous reports in the rat and the clinic, the authors reported no change in body weight or food intake following olanzapine treatment, questioning the validity of the rat model

A systematic review of the effect of cannabidiol on cognitive function: relevance to schizophrenia

Background and objectives: Cognitive impairment is a core symptom domain of schizophrenia, neurological disorders and substance abuse. It is characterised by deficits in learning, memory, attention and executive functioning and can severely impact daily living. Antipsychotic drugs prescribed to treat schizophrenia provide limited cognitive benefits and novel therapeutic targets are required. Cannabidiol (CBD), a component of the cannabis plant, has anti‐inflammatory and antipsychotic‐like properties; however, its ability to improve cognitive impairment has not been thoroughly explored. The aim of this systematic review was to evaluate preclinical and clinical literature on the effects of CBD in cognitive domains relevant to schizophrenia. Methods: A systematic literature search was performed across numerous electronic databases for English language articles (January 1990–March 2016), with 27 articles (18 preclinical and 9 clinical studies) included in the present review. Results: CBD improves cognition in multiple preclinical models of cognitive impairment, including models of neuropsychiatric (schizophrenia), neurodegenerative (Alzheimers disease), neuro‐inflammatory (meningitis, sepsis and cerebral malaria) and neurological disorders (hepatic encephalopathy and brain ischemia). To date, there is one clinical investigation into the effects of CBD on cognition in schizophrenia patients, with negative results for the Stroop test. CBD attenuates &Dgr;9‐THC‐induced cognitive deficits. Conclusions: The efficacy of CBD to improve cognition in schizophrenia cannot be elucidated due to lack of clinical evidence; however, given the ability of CBD to restore cognition in multiple studies of impairment, further investigation into its efficacy in schizophrenia is warranted. Potential mechanisms underlying the efficacy of CBD to improve cognition are discussed. HIGHLIGHTSEvidence assessing the effect of CBD on cognition in schizophrenia is limited.Acute and chronic CBD treatment improves cognition in Alzheimers disease models.CBD improves cognitive impairment in neuro‐inflammatory and neurological disorders.There is no significant effect of CBD on cognitive function in ‘healthy’ states.

Improved Social Interaction, Recognition and Working Memory with Cannabidiol Treatment in a Prenatal Infection (poly I:C) Rat Model

Neuropsychiatric disorders such as schizophrenia are associated with cognitive impairment, including learning, memory and attention deficits. Antipsychotic drugs are limited in their efficacy to improve cognition; therefore, new therapeutic agents are required. Cannabidiol (CBD), the non-intoxicating component of cannabis, has anti-inflammatory, neuroprotective and antipsychotic-like properties; however, its ability to improve the cognitive deficits of schizophrenia remains unclear. Using a prenatal infection model, we examined the effect of chronic CBD treatment on cognition and social interaction. Time-mated pregnant Sprague-Dawley rats (n=16) were administered polyinosinic-polycytidilic acid (poly I:C) (POLY; 4 mg/kg) or saline (CONT) at gestation day 15. Male offspring (PN56) were injected twice daily with 10 mg/kg CBD (CONT+CBD, POLY+CBD; n=12 per group) or vehicle (VEH; CONT+VEH, POLY+VEH; n=12 per group) for 3 weeks. Body weight, food and water intake was measured weekly. The Novel Object Recognition and rewarded T-maze alternation tests assessed recognition and working memory, respectively, and the social interaction test assessed sociability. POLY+VEH offspring exhibited impaired recognition and working memory, and reduced social interaction compared to CONT+VEH offspring (p<0.01). CBD treatment significantly improved recognition, working memory and social interaction deficits in the poly I:C model (p<0.01 vs POLY+VEH), did not affect total body weight gain, food or water intake, and had no effect in control animals (all p>0.05). In conclusion, chronic CBD administration can attenuate the social interaction and cognitive deficits induced by prenatal poly I:C infection. These novel findings present interesting implications for potential use of CBD in treating the cognitive deficits and social withdrawal of schizophrenia.

The effects of maternal antidepressant use on offspring behaviour and brain development: Implications for risk of neurodevelopmental disorders

Approximately 10% of pregnant women are prescribed antidepressant drugs (ADDs), with selective serotonin reuptake inhibitors (SSRIs) the most widely prescribed. SSRIs bind to the serotonin transporter (SERT), blocking the reabsorption of serotonin by the presynaptic neuron and increasing serotonin levels in the synaptic cleft. The serotonergic system regulates a range of brain development processes including neuronal proliferation, migration, differentiation and synaptogenesis. Given the presence of SERT in early brain development, coupled with the ability of SSRIs to cross the placenta and also enter breast milk, concerns have been raised regarding the effects of SSRI exposure on the developing foetus and newborns. In this review, we evaluate preclinical and clinical studies that have examined the effects of maternal SSRI exposure and the risk for altered neurodevelopment and associated behaviours in offspring. While the current body of evidence suggests that maternal SSRI treatment may cause perturbations to the neurobiology, behaviour and ultimately risk for neurodevelopmental disorders in exposed offspring, conflicting findings do exist and the evidence is not conclusive. However, given the increasing incidence of depression and number of women prescribed ADDs during pregnancy, further investigation into this area is warranted.