Pharmacological and neurochemical differences between acute and tardive vacuous chewing movements induced by haloperidol

Abstract

Late onset vacuous chewing movements (VCMs) from chronic neuroleptic treatment have been used as a rat model of tardive dyskinesia (TD). Early onset VCMs have also been observed, raising questions about the validity of this model. To assess the relationship between these two types of VCMs, pharmacological and neurochemical properties of early and late onset VCMs were compared. "Acute" VCMs were induced by daily intraperitoneal injections for 1-21 days. "Tardive" VCMs were induced by intramuscular injections of haloperidol decanoate every 3 weeks for 30 weeks followed by a 24-week withdrawal period. Suppression was attempted for both types of VCMs using several doses of intraperitoneal haloperidol. Striatonigral activation was assessed by measuring mRNA expression levels of the neuropeptides dynorphin and substance P using in situ hybridization histochemistry. Enkephalin mRNA was also measured as an index of striatopallidal activation. The results indicate that acute VCMs cannot be suppressed with increased doses of haloperidol and are associated with reduced dynorphin and substance P. This profile is similar to that seen with an animal model of parkinsonism. Tardive VCMs, in contrast, were markedly suppressed by haloperidol. They have previously been shown to be associated with increased striatonigral activation as indicated by increased dynorphin mRNA. Enkephalin mRNA was elevated following both short and long term treatment. Although superficially similar, acute and tardive VCMs appear to have different pharmacological and neurochemical profiles, suggesting they are related to acute extrapyramidal side effects and tardive dyskinesia, respectively.

Differential Effects of Within-Day Continuous Vs Transient Dopamine D2 Receptor Occupancy in the Development of Vacuous Chewing Movements (VCMs) in Rats

“…An issue that could be raised regarding this study is the shorter (8 weeks) duration of treatment compared to other VCM investigations that have been longer than 6 months (eg Egan et al, 1996). While our study was limited to 8 weeks, the decision to reduce the length of the study was based on the finding that the VCM behavior plateaus beyond 5 weeks of treatment in this study and in other VCM experiments conducted in our laboratory (Turrone et al, 2002(Turrone et al, , 2003.…”

“…Importantly, however, the evidence in support of these hypotheses is largely derived from studies where animals were treated with APs over a brief time period (o21 days) (see Turrone et al, 2002). There is some evidence that early-appearing VCMs may be more neurochemically and pharmacologically related to acute EPS than TD (Egan et al, 1996). Moreover, evidence derived from a recent long-term VCM study has demonstrated that it is not the anticholinergic challenge that reduces VCMs, but some aspect inherent to the injection procedure itself (Sakai et al, 2001).…”

“…In all, 43% (10/23) of rats given 0.25 or 1 mg/kg/day doses of haloperidol via minipump (achieving mean D 2 occupancy of 82%) developed high (beyond the eight VCM/2 min cutoff as defined by Egan et al, 1996) levels of VCMs (13 VCMs/2 min) compared to only 8% (2/24) of the rats given the same doses via daily s.c. injections, despite the fact that they also yielded high (485%), albeit transient, mean D 2 occupancy levels. The 0.1 mg/kg dose did not give rise to any VCMs beyond vehicle, regardless of the route of administration.…”

“…The inter-rater reliability is 0.84 in our laboratory, as calculated after VCM counts performed by two investigators were compared during a previous experiment. For additional analyses, VCM behavior was dichotomized as 'High' (+) vs 'Low' (À), with rats scoring X8 VCMs averaged over the last three sessions being rated as VCM(+) and those with mean scores o8 as VCM(À), following a commonly used criterion in the literature (Egan et al, 1996;Sasaki et al, 1996). In these analyses, VCM(+) rats are referred to as showing the VCM syndrome.…”

Animal models for predicting the efficacy and side effects of antipsychotic drugs

“…[14][15][16][17] Tests that predict the side effects of antipsychotic drugs As mentioned in the introduction, the short-term side effects of first-generation antipsychotic drugs include parkinsonian syndrome, dystonia and akathisia, whereas chronic treatment leads to tardive dyskinesia, which comprises abnormal, excessive, and involuntary movements. 51 Despite a large number of investigations, the mechanisms through which these effects occur remain to be elucidated. These include dopaminergic supersensitivity, excitotoxicity, free radical formation, and a decrease in dopamine transporter density.…”