Parallels between behavioral and neurochemical variability in the rat vacuous chewing movement model of tardive dyskinesia

The widely accepted rat vacuous chewing movement model for tardive dyskinesia could be more fully mined through greater focus on individual variability in vulnerability to this neuroleptic-induced behavior. We have examined parallels between behavioral and neurobiological variability within a cohort in order to evaluate the role that neurobiological factors might play in determining susceptibility to tardive dyskinesia. Inter-observer reliability and individual consistency across time, in both spontaneous and neuroleptic-induced vacuous chewing movements, were empirically demonstrated. While this behavior increased across 8 months of observation in both vehicle controls and haloperidol-treated rats, pre-treatment baselines were predictive of final levels across individuals only in the vehicle control group, not the haloperidol-treated group. Haloperidol-induced elevations in neostriatal D2 and GAD67 mRNA were not correlated with individual variability in haloperidol-induced vacuous chewing movements. Ambient noise during the observations was found to exacerbate chronic haloperidol-induced, but not spontaneous vacuous chewing movements. Significant correlations were found among the haloperidol-treated rats between nigral and tegmental GAD67 and tegmental α7 mRNA levels, measured by in situ hybridization histochemistry, and vacuous chewing movements, specifically in the noisy conditions. Variability in these secondary responses to primary striatal dopamine and GABA perturbations may play a role in determining vulnerability to vacuous chewing movements, and by analogy, tardive dyskinesia. Both the differential predictive value of baseline vacuous chewing movements and the differential effect of noise, between controls and haloperidol-treated rats, add to evidence that haloperidol-induced vacuous chewing movements are regulated, in part, by different mechanisms than those mediating spontaneous vacuous chewing movements.

► Rats vary in predisposition toward consistent spontaneous vacuous chewing movements.
► This predisposition is altered by the consequences of chronic neuroleptic exposure.
► Ambient noise selectively enhances neuroleptic-induced vacuous chewing movements.
► Effects of haloperidol on nigral and tegmental GABA and acetylcholine function vary.
► This neurochemical variability is correlated with haloperidol-induced dyskinesia.