Effects of Atypical Antipsychotic Drugs on Intralipid Intake and Cocaine-Induced Hyperactivity in Rats

Abstract

Clozapine and olanzapine have been shown to acutely stimulate consumption of a fat emulsion (Intralipid) by male Lister hooded rats. We initially investigated the extent of any sex difference in Intralipid hyperphagia associated with olanzapine treatment. We then examined the degree of Intralipid hyperphagia produced by a range of atypical antipsychotic drugs having different associations with human weight gain, and also determined their effects on cocaine-stimulated locomotor activity as a measure of functional dopamine antagonism in vivo. Olanzapine (0.1-1 mg/kg) stimulated Intralipid intake to an equal extent in male and female rats. Quetiapine (10 mg/kg) also stimulated Intralipid intake whereas ziprasidone (0.3-10 mg/kg) or risperidone (0.03-0.3 mg/kg) did not have this effect. All of the compounds, except quetiapine, reduced cocaine-stimulated locomotor activity but the relationship to the degree of Intralipid hyperphagia was variable. Since there was a positive relationship between Intralipid hyperphagia and the reported extent of human body weight gain, we conclude that Intralipid hyperphagia may have predictive value for this drug-associated side effect and is not related to the dopamine antagonist properties of these agents.

Atypical antipsychotics and effects on feeding: from mice to men

“…Studies in rodents have consistently failed to demonstrate increased food intake following ZIP treatment (Fell et al 2005a;Fell et al 2007;Fell et al 2008;Hartfield et al 2006;Kirk et al 2004;MinetRinguet et al 2006a;Park et al 2012;Shobo et al 2011b;Snigdha et al 2008;von Wilmsdorff et al 2010). Negative findings occur regardless of sex, method of drug administration, time of drug administration relative to outcome measured, or dose range.…”

“…In a similar fashion to CLO, dosing paradigms directly administering OLA acutely prior to measurements of food intake consistently demonstrate increased food consumption regardless of rodent sex (Hartfield et al 2003;Hartfield et al 2006;Kirk et al 2004;Shobo et al 2011b) and with OLA administration peripherally as well as centrally. However, studies examining repeated/ chronic dosing paradigms of OLA show interesting sex differences.…”

“…In contrast to OLA studies in rodents, it is less clear whether sex effects can alter food intake and body weight with RIS or QUE administration. In female rodents, RIS has been associated with increased food intake and body weight (Baptista et al 2002;Cope et al 2007;Cope et al 2009;Kaur and Kulkarni 2002;Lian et al 2015;Ota et al 2002), although not all studies have shown a positive association (Fell et al 2007;Fell et al 2008;Hartfield et al 2006). Interestingly, a recent study suggested that female mice treated over 4 weeks with RIS-containing peanut butter pills gained weight but did not exhibit increased food intake, in contrast to concomitant hyperphagia with weight gain in animals treated with OLA or QUE (Cope et al 2007).…”

“…Conversely, Baptista et al (2002) failed to find a dose relationship with RIS; all doses examined (0.125-0.5 mg/kg/day subcutaneously) increased food intake in female, but not male, rats. Hartfield et al (2006) examined effects of QUE (0.3-10 mg/kg intraperitoneally (IP) 30 min prior to testing) on food intake and weight in an acute paradigm, finding that both male and female rats acutely increased intralipid consumption, while RIS (across a range of doses between 0.1 and 3 mg/kg IP, 30 min prior to testing) failed to have any effects on intake.…”

Ziprasidone versus Olanzapine in the weight gain associated with the treatment of schizophrenia: A six-month double-blind randomized parallel group study

“…Tschoner et al found higher fasting glucose and an increased score in an insulin resistance model in patients treated with olanzapine, while this effect could not be observed in ziprasidone treated patients, indicating the involvement of this effect in olanzapine-induced weight gain 6 . Animal studies have shown that olanzapine, but not ziprasidone, stimulates the consumption of fat 36 and that chronic treatment with olanzapine impairs lipolysis by adipocytes 37 . Also, previous studies have found cholesterol, triglycerides and LDL-cholesterol increase in olanzapine treated patients, and not in ziprasidone treated individuals 6,38 .…”