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

Ilya D Ionov; Maria D Krasilova; Niсholas P Gorev; Victor I Tulchinskiy; Sergey A Gabov; Margarita O Lyubimova; Lyudmila I Maltseva; Piotr N Komikarov

doi:10.1007/s00213-025-06935-3

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

Psychopharmacology (Berl). 2025 Oct 25. doi: 10.1007/s00213-025-06935-3. Online ahead of print.

Authors

Ilya D Ionov¹, Maria D Krasilova², Niсholas P Gorev², Victor I Tulchinskiy², Sergey A Gabov², Margarita O Lyubimova², Lyudmila I Maltseva², Piotr N Komikarov³

Affiliations

¹ Department of Neurometabolic Analysis, Centre on Theoretical Problems in Physical and Chemical Pharmacology, Russian Academy of Sciences, Srednyaya Kalitnikovskaya 30, Moscow, 109029, Russia. newrology@yandex.ru.
² Department of Neurometabolic Analysis, Centre on Theoretical Problems in Physical and Chemical Pharmacology, Russian Academy of Sciences, Srednyaya Kalitnikovskaya 30, Moscow, 109029, Russia.
³ Timpharm LTD, Moscow, 117513, Russia.

PMID: 41137941
DOI: 10.1007/s00213-025-06935-3

Abstract

Rationale: 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.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Haloperidol; Nicotine; Norepinephrine; Synergy; Tardive dyskinesia; Vacuous chewing movements.