Olanzapine depot formulation in rat: a step forward in modelling antipsychotic-induced metabolic adverse effects

Abstract

Rats are used as animal models in the study of antipsychotic-induced metabolic adverse effects, with oral drug administration yielding hyperphagia, weight gain and, in some cases, lipogenic effects. However, the rapid half-life of these drugs in rats, in combination with development of drug tolerance after a few weeks of treatment, has limited the validity of the model. In order to prevent fluctuating drug serum concentrations seen with daily repeated administrations, we injected female rats with a single intramuscular dose of long-acting olanzapine formulation. The olanzapine depot injection yielded plasma olanzapine concentrations in the range of those achieved in patients, and induced changes in metabolic parameters similar to those previously observed with oral administration, including increased food intake, weight gain and elevated plasma triglycerides. Moreover, the sensitivity to olanzapine was maintained beyond the 2-3 wk of weight gain observed with oral administration. In a separate olanzapine depot experiment, we aimed to clarify the role of hypothalamic AMP-activated protein kinase (AMPK) in olanzapine-induced weight gain, which has been subject to debate. Adenovirus-mediated inhibition of AMPK was performed in the arcuate (ARC) or the ventromedial hypothalamic (VMH) nuclei in female rats, with subsequent injection of olanzapine depot solution. Inhibition of AMPK in the ARC, but not in the VMH, attenuated the weight-inducing effect of olanzapine, suggesting an important role for ARC-specific AMPK activation in mediating the orexigenic potential of olanzapine. Taken together, olanzapine depot formulation provides an improved mode of drug administration, preventing fluctuating plasma concentrations, reducing handling stress and opening up possibilities to perform complex mechanistic studies.

Preventing Olanzapine-Induced Weight Gain Using Betahistine: A Study in a Rat Model with Chronic Olanzapine Treatment

“…Consistent with the body weight changes in this study, the olanzapine-only group had more white fat mass and higher liver weight than the control and betahistine-only groups, which also corresponded with previous reports [31], [46], [51], [64], [65]. On the other hand, compared to the olanzapine-only treatment, chronic O+B co-treatment decreased inguinal fat mass and liver weight in this study.…”

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

“…It has been found that olanzapine and clozapine activated hypothalamic AMPK by blocking H 1 Rs to increase food intake and body weight gain [63,96,97]. In hypothalamic tissue slices, the level of pAMPK can be enhanced markedly by olanzapine, which indicates that the weight gain/obesity side-effects associated with olanzapine is mediated by activation of hypothalamic AMPK linked to blockade of the histaminergic H 1 R [63].…”

Antipsychotic-induced metabolic effects in the female rat: Direct comparison between long-acting injections of risperidone and olanzapine

“…We previously demonstrated that, in the female rat, treatment with olanzapine elevated transcription of several genes involved in lipogenesis, all target genes of the key transcription factors sterol regulatory element binding proteins 1 and 2 (SREBP1 and SREBP2), independent of nutritional status (Skrede et al, 2012(Skrede et al, , 2014.…”

“…The use of rodents facilitates screening of dysmetabolic effects in organisms not previously exposed to antipsychotic agents, but have been hampered by the short half-life of antipsychotics in rodents (Aravagiri et al, 1999). We recently circumvented this challenge by means of intramuscular injections of a long-acting olanzapine formulation, and demonstrated that such exposure gave clinically relevant plasma levels of olanzapine, associated with potent dysmetabolic effects in the female rat (Skrede et al, 2014).…”