Haloperidol - norepinephrine synergy in stimulation of vacuous chewing movements in rats: Enhancement by nicotine

Tardive dyskinesia (TD), a late onset involuntary repetitive movements, is a complication of antipsychotic therapy. The mechanism of TD development is currently obscure. In TD patients, an increased brain level of norepinephrine was found; the pathogenic significance of this abnormality is unclear. The chronic administration of haloperidol in rodents induces a specific stereotyped behavior called vacuous chewing movements (VCM) that resembles TD and is used as a routine TD model. Meanwhile, this model does not mirror such a feature of TD as an exacerbation by tobacco smoking.

We examined the hypotheses that (i) sustained brain norepinephrine hyperactivity influences the development of haloperidol-induced VCM; and (ii) VCM induced by haloperidol-norepinephrine combination, are enhanced by nicotine.

Male Sprague-Dawley rats were used. VCM were exerted by 25-day administration of haloperidol; to simulate an increase in brain norepinephrine levels this agent was injected intracerebroventricularly for 14 consecutive days. Nicotine was given daily concurrently with norepinephrine.

Separated administration of haloperidol and norepinephrine at low doses resulted in no effect; however, their co-administration induced a clear stimulation of VCM. The chronic nicotine treatment did not affect the haloperidol-induced VCM but strongly enhanced the effect induced by the haloperidol + norepinephrine combination.

It was found for the first time that haloperidol and norepinephrine synergistically stimulate VCM; this finding can advance our understanding of TD pathogenesis. In the light of these results, norepinephrine may be a promising therapeutic target in TD. Given the obtained results, the haloperidol + norepinephrine-induced VCM seem to be more reasonable model for TD than haloperidol-only one.