Chronic Olanzapine or Sertindole Treatment Results in Reduced Oral Chewing Movements in Rats Compared to Haloperidol

Abstract

Chronic haloperidol treatment typically produces late-onset, purposeless oral chewing movements in laboratory rats with a prevalence of 40 to 60%. Chronic clozapine does not produce these movements. Based on the phenomenologic and pharmacologic similarities between these rat chewing movements and human tardive dyskinesia (TD), the animal movements are often used as a model of tardive dyskinesia (TD). Here we report results of the association of oral chewing movements in rats withTraditional antipsychotics, such as haloperidol or fluphenazine, induce purposeless oral chewing movements in rats when they are administered chronically (Clow et al. 1980;Ellison et al. 1987;Waddington 1990;Glenthoj and Hemmingsen 1989). These dyskinesias appear gradually, and they occur in only some of the animals. Because characteristics of these neuroleptic-induced rat movements parallel certain features (although not all) of the human neuroleptic-induced dyskinetic syndrome tardive dyskinesia (TD), they are often used in its study.General criteria for using an animal preparation as a model for a human condition have previously been proposed (McKinney and Bunney 1969) and refined (Weiss and Kilts 1995). Scientists have stressed that the most critical elements for comparison are similarities in etiology, phenomenology, biochemistry, and pharmacology between the animal and the human condition. The etiology of these rat oral dyskinesias (i.e., the chronic antipsychotic treatment) matches the etiology of TD, as do some of the demographic aspects of the rat movements, such as slow symptom onset, delayed offset, and jerky quality (Tamminga et al. 1990;Waddington 1990). Moreover, whereas traditional neuroleptics cause these purposeless movements in rats and tardive dyskinesia in humans, clozapine fails to produce dyskinesias in ei- Chronic Olanzapine or Sertindole in Rats 429 ther rats or humans (Gunne et al. 1982;Kakigi et al. 1995). The difficulty of distinguishing types of antipsychotic-induced movements in rats, along with the limited oral distribution of the movements in rats, and disagreements about the anticholinergic suppressability of the rat movements, have maintained a proper skepticism about using this preparation without reservation as an animal model of human TD. In this report, we have attempted to expand the pharmacology of these rat dyskinesias by testing whether two of the new antipsychotic drugs, olanzapine and sertindole, which have known low acute motor side effect profiles in humans, would induce purposeless oral chewing in rats.Olanzapine is a new antipsychotic drug developed by Lilly Laboratories, Inc., a thio[1,5]benzo-diazepine (Bymaster et al. 1996). It has potent antipsychotic actions in schizophrenic psychosis, comparable to traditional neuroleptics, and is active against both positive and negative symptoms (Beasley et al. 1996). One of the unusual characteristics of olanzapine is its low potency in producing Parkinsonian side effects and akathisia in humans. Olanzapine is a clozapine-like drug with respect to i...

Olanzapine-Induced Weight Gain and Increased Visceral Adiposity is Blocked by Melatonin Replacement Therapy in Rats

“…Details of olanzapine solution preparation have been described previously (Gao et al, 1998). The olanzapine concentration in the drinking water was initially 0.033 mg/ml; this concentration was modified according to measured daily water intake and body weight during the course of the experiment to maintain a dosage of approximately 2 mg/kg/day.…”

“…The olanzapine concentration in the drinking water was initially 0.033 mg/ml; this concentration was modified according to measured daily water intake and body weight during the course of the experiment to maintain a dosage of approximately 2 mg/kg/day. This olanzapine dose and method of administration have been demonstrated to maintain rat plasma olanzapine levels in the human therapeutic range (Gao et al, 1998). Melatonin was dissolved in 100% ethanol and added to the drinking water at a final concentration of 0.4 mg/ml.…”

Multidose Risperidone Treatment Evaluated in a Rodent Model of Tardive Dyskinesia

“…Laboratory rats chronically treated with the traditional antipsychotic drug haloperidol or other similar drugs gradually develop VCMs over a time course of 3-6 months (Clow et al, 1980a, b, c;Ellison et al, 1987;Glenthoj and Hemmingsen, 1989;Gao et al, 1998;Andreassen et al, 2003). Several characteristics of these movements, including aspects of their phenomenology, etiology, and pharmacology, resemble TD in humans (Tamminga et al, 1990;Waddington, 1990).…”

Blind, controlled, long-term study of the comparative incidence of treatment-emergent tardive dyskinesia with olanzapine or haloperidol

“…Observations with the atypical antipsychotic clozapine have led to a hypothesis that an imbalance between D 1 and D 2 receptor activity in the basal ganglia may underlie tardive dyskinesia (29). Several studies support a distinctly different D 1-4 binding profile relative to conventional neuroleptic drugs for both olanzapine and clozapine (7)(8)(9)(10)(30)(31)(32)(33)(34). Regardless, the existing data suggest at least a secondary or modulatory role for dopamine in the pathophysiology of tardive dyskinesia.…”

“…More recently, a model of spontaneous vacuous chewing movements has been proposed as a proxy for tardive dyskinesia. Gao et al (33) reported that olanzapine, unlike conventional neuroleptic drugs, did not induce vacuous chewing movements. In support of these preclinical data, in vivo human imaging studies have demonstrated lower D 2 striatal receptor occupancy with olanzapine than with haloperidol (34).…”