Oral Dyskinesias In Rats Research Articles

Intermittent and continuous haloperidol regimens produce different types of oral dyskinesias in rats

Rats were administered equivalent doses of haloperidol for either 28 days or 8 months using one of two different drug regimens: intermittent (i.e., weekly injections) or continuously (via drinking water and osmotic mini-pumps). Oral movements were determined by human observers and by a computerized video analysis system, which determined number and amplitude of jaw openings and closings (computer-scored movelets "CSMs") as well as the slope (amplitude/duration) and frequency spectrum (fourier transform) of oral activity. The two drug groups developed distinctively different changes over time. Continuous administration resulted in late-onset oral activity changes at 1-3 Hz and withdrawal increases in CSMs, a pattern expected of tardive dyskinesia. Intermittent treatment produced a primed dystonia-like pattern: large amplitude CSMs which had steep onset slopes and a peak energy at 4-7 Hz. These results demonstrate the importance of drug regimen in determining the type of neuroleptic-induced dyskinesias which develop with prolonged neuroleptic treatment in rodents.

Selective dopamine D 2 receptor reduction enhances A D 1 mediated oral dyskinesia in rats

We have previously shown, through the use of selective D 1 and D 2 dopamine receptor interactive drugs, that repetitive jaw movements in rats can be produced by activation of the D 1 system or blockade of the D 2 system. In the present study we have shown that genetic or developmental factors resulting in a lesser number of D 2 - relative to D 1 - receptors is associated with repetitive jaw movements. We have found in two strains of rats with different striatal D 2 to D 1 ratios, the strain with fewer D 2 sites had more jaw movements. We also found that experimental reduction of D 2 receptors via prenatal intervention resulted in an increase in spontaneous jaw movements, as did aging, which is accompanied by a decrease in the number of D 2 receptors. The findings of these studies carried out in rats, parallel, in a number of ways, findings in human oral dyskinesia associated with either aging or neuroleptic treatment.

A Model for Oral Dyskinesia in Rats

Rats subjected to bifrontal cortical ablations developed vacuous chewing movements and jaw tremors that began 22 weeks after surgery, reached a peak rate of 4 to 8 per minute, and remained stable for an 8-week observation period. Chronic haloperidol administration to rats with bifrontal cortical ablations produced 15 to 20 movements per minute that persisted for 7 weeks after drug withdrawal. Drugs given to decrease dopaminergic, cholinergic, and gamma-aminobutyric acid (GABA)-ergic neurotransmission suppressed the movements, whereas cholinergic agonists increased them. This model of oral dyskinesia in rats may be useful in developing drugs for the treatment of facial dyskinesias in humans.

Oral dyskinesia in rats following brain lesions and neuroleptic drug administration.

After 10-12 weeks of chronic haloperidol administration rats with frontal cortex ablations or lesions induced by intracerebroventricular infection of 6-hydroxydopamine developed vacuous chewing behavior at a fairly stable frequency (bifrontal ablations had 15-20, 6-hydroxy-dopamine lesioned rats 7-12 chewing movements/min). This behavior persisted for 10 weeks after the last injection of haloperidol decanoate. However, rats with frontal cortex lesions developed a low rate of vacuous chewings (4-8 chewings/min) even without haloperidol administration. Bilateral intrastriatal injections of kainic acid in combination with chronic haloperidol administration did not cause chewing movements in excess of unlesioned haloperidol-treated controls. Pharmacological tests of this animal model for tardive dyskinesia (TD) revealed similarities to human TD, but also differences. Dopamine agonists (apomorphine) and antagonists (haloperidol) both lowered chewing behavior analogous to reported effects on TD and so did gabaculine. The cholinergic drugs physostigmine and pilocarpine, however, increased chewing in rats, while anticholinergics (atropine) reduced it, in contrast to reported effects on human TD.