Decreased medial entorhinal cortical thickness in olanzapine exposed female rats is not ameliorated by exercise.

Aerobic exercise has been associated with hippocampal plasticity, both in healthy adults and in psychosis patients, but its impact on cortical regions remains unclear. The entorhinal cortex serves as a critical gateway for the hippocampus, and recent studies suggest that this region may also be impacted following an exercise regime. In order to investigate the effects of antipsychotic medications and exercise on the entorhinal cortex, female rats were chronically administered either olanzapine or vehicle and were either sedentary or had access to a running wheel for 9 weeks. Olanzapine-treated rats had decreased medial entorhinal cortical thickness compared to vehicle-treated rats. A statistically significant interaction was observed for layer II of the entorhinal cortex, with exercising rats having significantly greater thickness compared to sedentary rats in the vehicle group, but not the olanzapine group. Greater total entorhinal and lateral entorhinal cortical thickness was associated with greater average activity. In exercising rats, decreasing glucose intolerance was associated with larger total entorhinal and layer II cortical thickness. Lower fasting insulin levels were associated with greater total entorhinal, lateral entorhinal, and layer II cortical thickness. The relationship between increased activity and greater entorhinal cortical thickness was mediated by reduced fasting insulin, indicating that regulation of metabolic risk factors may contribute to impact of aerobic exercise on the entorhinal cortex. Aerobic exercise may be helpful in counteracting metabolic side effects of antipsychotic medications and managing these side effects may be key to promoting entorhinal cortical plasticity in patients treated with second-generation antipsychotic drugs.

Exercise prevents downregulation of hippocampal presynaptic proteins following olanzapine-elicited metabolic dysregulation in rats: Distinct roles of inhibitory and excitatory terminals.

Schizophrenia patients treated with olanzapine, or other second-generation antipsychotics, frequently develop metabolic side-effects, such as glucose intolerance and increased adiposity. We previously observed that modeling these adverse effects in rodents also resulted in hippocampal shrinkage. Here, we investigated the impact of olanzapine treatment, and the beneficial influence of routine exercise, on the neurosecretion machinery of the hippocampus. Immunodensities and interactions of three soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (syntaxin-1, synaptosome-associated protein of 25kDa (SNAP-25) and vesicle-associated membrane protein (VAMP)), synaptotagmin and complexins-1/2 were quantified in the hippocampus of sedentary and exercising rats exposed over 9weeks to vehicle (n=28) or olanzapine (10mg/kg/day, n=28). In addition, brain sections from subgroups of sedentary animals (n=8) were co-immunolabeled with antibodies against vesicular GABA (VGAT) and glutamate (VGLUT1) transporters, along with syntaxin-1, and examined by confocal microscopy to detect selective olanzapine effects within inhibitory or excitatory terminals. Following olanzapine treatment, sedentary, but not exercising rats showed downregulated (33-50%) hippocampal densities of SNARE proteins and synaptotagmin, without altering complexin levels. Strikingly, these effects had no consequences on the amount of SNARE protein-protein interactions. Lower immunodensity of presynaptic proteins was associated with reduced CA1 volume and glucose intolerance. Syntaxin-1 depletion appeared more prominent in VGAT-positive terminals within the dentate gyrus, and in non-VGAT/VGLUT1-overlapping areas of CA3. The present findings suggest that chronic exposure to olanzapine may alter hippocampal connectivity, especially in inhibitory terminals within the dentate gyrus, and along the mossy fibers of CA3. Together with previous studies, we propose that exercise-based therapies might be beneficial for patients being treated with olanzapine.

Routine exercise ameliorates the metabolic side-effects of treatment with the atypical antipsychotic drug olanzapine in rats.

Second generation antipsychotic (SGA) drugs are effective treatments for psychosis. Common side-effects of SGAs include metabolic dysregulation and risk of cardiometabolic disorders. Metabolic side-effects, including glucose intolerance, can be accurately modelled in rodents. The benefits of interventions used for treating metabolic side-effects of SGAs are mostly unknown. In a 9 wk longitudinal study, female rats were given daily olanzapine (10 mg/kg s.c.) or vehicle. Animals were either sedentary or allowed 1 or 3 h daily access to a running wheel, with total wheel revolutions electronically quantified to reflect exercise intensity. Glucose tolerance tests were performed once weekly to measure glycemic control. Drug levels were measured at week 4. At week 9, abdominal fat and skeletal muscle levels of Glucose Transporter 4 (GLUT4) were measured. Exercise intensity progressively increased over time in all groups given access to running wheels; however, rats treated with olanzapine consistently exercised less than those given the vehicle. Olanzapine caused acute and persistent glucose intolerance throughout the study, which was markedly, though incompletely, ameliorated by exercise. Exercise did not affect glycemic regulation in vehicle-treated rats. Olanzapine-treated rats showed greater central adiposity. Levels of GLUT4 in skeletal muscle were higher in both groups of exercising than in sedentary rats, and GLUT4 values were negatively correlated with glucose intolerance. Routine exercise reduced olanzapine-induced glucose intolerance and increased skeletal muscle levels of GLUT 4, the insulin-responsive transporter that mediates glucose uptake into cells. The current animal model is suitable for evaluating physiological pathways involved with glucose intolerance.

Effects of chronic exercise and treatment with the antipsychotic drug olanzapine on hippocampal volume in adult female rats.

Numerous studies have reported that the hippocampus in schizophrenia patients is reduced in volume compared to the normal population. Antipsychotic medications have had mixed benefits in maintaining hippocampal volume or reversing volume loss. Recent evidence indicates that routine aerobic exercise represents a promising intervention for reversing hippocampal loss and cognitive deficits. In the present study, we measured the effects of chronic treatment with olanzapine and daily exercise on the hippocampal volumes of rats. Adult female rats were treated during the week with either olanzapine (10mg/kg) or vehicle for 9 consecutive weeks. Subgroups of animals were provided access to exercise running wheels for 1 or 3h per day during the same period, or were sedentary. Metabolic indices, including glucose tolerance, were measured on a weekly basis. At the conclusion of the study, brains were perfused and hippocampal sections were Nissl stained. Total hippocampal volume was measured using the Cavalieri estimator. Treatment with olanzapine caused a significant decrease in hippocampal volume in sedentary rats. However, exercise was able to reverse most of this volume loss. The hippocampal sub-regions of the dentate gyrus and CA1 were most strongly affected by olanzapine and exercise. Of interest, there was a strong and highly significant negative correlation between glucose intolerance and hippocampal volume, whereby greater glucose intolerance was associated with a smaller hippocampal volume. These findings indicate that exercise may have beneficial effects on the hippocampus when antipsychotic medication can contribute to changes in volume.

Peripheral adrenoceptors: the impetus behind glucose dysregulation and insulin resistance.

It is now accepted that several pharmacological drug treatments trigger clinical manifestations of glucose dysregulation, such as hyperglycaemia, glucose intolerance and insulin resistance, in part through poorly understood mechanisms. Persistent sympathoadrenal activation is linked to glucose dysregulation and insulin resistance, both of which significantly increase the risk of emergent endocrinological disorders, including metabolic syndrome and type 2 diabetes mellitus. Through the use of targeted mutagenesis and pharmacological methods, preclinical and clinical research has confirmed physiological glucoregulatory roles for several peripheral α- and ß-adrenoceptor subtypes. Adrenoceptor isoforms in the pancreas (α(2A) and ß(2) ), skeletal muscle (α(1A) and ß(2) ), liver (α(1A & B) and ß(2) ) and adipose tissue (α(1A) and ß(1 & 3) ) are convincing aetiological targets that account for both immediate and long-lasting alterations in blood glucose homeostasis. Because significant overlap exists between the therapeutic applications of numerous classes of drugs and their associated adverse side-effects, a better understanding of peripheral adrenoceptor-mediated glucose metabolism is thus warranted. Therefore, at the same time as providing a brief review of glucose homeostasis in the periphery, the present review addresses both functional and pathophysiological roles of the mammalian α(1) , α(2) , and ß-adrenoceptor isoforms in whole-body glucose turnover. We highlight evidence relating to the clinical use of common adrenergic drugs and their impacts on glucose metabolism.

Intermittent treatment with olanzapine causes sensitization of the metabolic side-effects in rats.

The second generation antipsychotic drugs are effective treatments for psychotic disorders. Many of these compounds, including the drug olanzapine, have been associated with metabolic side-effects, including weight gain, impaired glucose tolerance and insulin resistance, which increase the risk of developing cardiometabolic disorders. Rodent models of olanzapine-induced metabolic side-effects have been used to study the physiology of these effects, but only at a single time point after drug treatment. The purpose of the present study was to examine longitudinal changes with chronic antipsychotic drug treatment. Adult female rats were treated with either olanzapine (15 mg/kg) or vehicle for five consecutive days each week, followed by a 48 h washout period. Animals were then challenged with either olanzapine (15 mg/kg) or vehicle, and fasting glucose and insulin values were recorded, as well as glucose clearance in the glucose tolerance test. Treatment with olanzapine was continued for 10 weeks, with weekly tests of metabolic indices. Rats treated acutely with olanzapine showed both glucose dysregulation and insulin resistance; for the group treated during the week with olanzapine, these effects did not change by the end of ten weeks of treatment. However, in the group of animals challenged only once per week with olanzapine, the metabolic side-effects markedly intensified with the passage of time, whereby glucose intolerance and insulin resistance increased significantly compared to both baseline values and all other treatment groups. This previously unreported sensitization phenomenon represents a novel finding that may have clinical implications for patients receiving intermittent antipsychotic drug dosing or with variable adherence to treatment.