Rationale <p>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.</p> Objectives <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>