Elsevier

Biological Psychiatry

Volume 57, Issue 4, 15 February 2005, Pages 406-411
Biological Psychiatry

Original articles
Continuous but not intermittent olanzapine infusion induces vacuous chewing movements in rats

https://doi.org/10.1016/j.biopsych.2004.10.023Get rights and content

Background

Continuous, but not intermittent, infusion with a conventional antipsychotic (haloperidol, HAL) can induce the vacuous chewing movement (VCM) syndrome in rats. The objective of this study was to determine whether continuous, versus intermittent, olanzapine (OLZ) infusion differently affects the development of VCMs.

Methods

Experiment 1: Animals were treated with 7.5 mg/kg/day of OLZ or vehicle (VEH) via either minipump (MP) or daily subcutaneous (SC) injections for 8 weeks. Experiment 2: A separate group of rats were treated with 15 mg/kg/day of OLZ, or 1 mg/kg/day of HAL or VEH via MP for 8 weeks. Dopamine D2 receptor occupancy levels were measured, ex vivo, with [3H]-raclopride.

Results

Experiment 1: Rats receiving 7.5 mg/kg/day of OLZ via MP (51% D2 occupancy), but not those receiving the same dose via daily SC injections (94% peak D2 occupancy), showed significant VCM levels compared with control animals (p = .02). Experiment 2: Both OLZ (67% D2 occupancy) and HAL (79% D2 occupancy) led to similar increases in VCMs compared with VEH (p = .005).

Conclusions

This study provides strong evidence that even an atypical antipsychotic like OLZ, which rarely gives rise to tardive dyskinesia in the clinic, can lead to the VCM syndrome in rats if the antipsychotic is administered in a method (via MP) that leads to continuous presence of the drug in the brain.

Section snippets

Animals

Adult male Sprague-Dawley rats (Charles River, Montreal, Canada), weighing 175–200 g at the start of the experiment, were housed two per cage in 19 × 10.5 × 8 inches transparent polycarbonate cages (Lab Products, Seaforth, Delaware) and maintained on a 12-hour light/dark cycle with continuous access to food and water. All procedures were carried out in accordance with The Animals for Research Act 1968–1969 of the Province of Ontario and the Guidelines of the Canadian Council on Animal Care.

Drug treatments

In

VCM behavior

A repeated-measures analysis of variance (ANOVA) comparing VCMs between treatment groups during the 8 weeks of treatment (Figure 1) revealed a significant dose effect [F(2,248) = 7.26, p = .003], a significant time effect [F(8,248) = 5.38, p < .001], and a significant dose × time effect [F(16,248) = 4.03, p < .001]. An ANOVA comparing average VCMs between different treatment groups over the last three test sessions was also significant [F(2,33) = 4.43, p = .02]. Post hoc Bonferroni analyses

Discussion

The results of the present study demonstrate a clear association between the emergence of the VCM syndrome and continuous versus transient D2 receptor occupancy and use of the atypical antipsychotic OLZ. Animals that received OLZ via daily SC injections did not develop VCMs beyond placebo values; however, rats that received OLZ via MP (a method that gives rise to continuous D2 occupancy) developed a high level of VCMs that was comparable to the HAL-treated group.

We suggest that the reason

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      As illustrated in Fig. 2A, this can be modelled in rats by administering antipsychotic drugs via a subcutaneously implanted osmotic minipump (Kapur et al., 2003; Samaha et al., 2007) or via a long-acting injectable formulation (Turrone et al., 2003b). Using these continuous-treatment approaches, clinically-representative doses [i.e., doses producing 65 to 80% of striatal D2 receptor occupancy (Wadenberg et al., 2000; Natesan et al., 2006)] promote dopamine supersensitivity to the behavioural effects of dopamine agonists (Ericson et al., 1996; Samaha et al., 2007, 2008; Bedard et al., 2011, 2013), tolerance to the effects of antipsychotics in tests of antipsychotic-like efficacy (Samaha et al., 2007, 2008; Amato et al., 2018), and increased probability of vacuous chewing movements (Turrone et al., 2003a; b, 2005) in laboratory rats. A different outcome emerges if clinically-representative antipsychotic doses are given regularly, but intermittently such that striatal D2 occupancy is high for a few hours following antipsychotic administration, and then decreases until the next injection [see Fig. 2B; Kapur et al. (2003)].

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