Varenicline Markedly Decreases Antipsychotic-Induced Tardive Dyskinesia in a Rodent Model

Abstract

Tardive dyskinesia is a potentially irreversible drug-induced movement disorder that arises as a side effect of antipsychotic therapy. Antipsychotics form the mainstay of treatment for schizophrenia and bipolar disorder and, in addition, are increasingly being prescribed for major depressive disorder, autism, attention deficit hyperactivity disorder, obsessive compulsive disorder and post-traumatic stress disorder. There is therefore a clear need for therapies to reduce tardive dyskinesia. Our recent studies showed that nicotine administration decreased haloperidol-induced vacuous chewing movements (VCMs) in a rat model of tardive dyskinesia. The present experiments demonstrate that nicotine (300 µg/ml in drinking water) also reduced VCMs (50%) in mice whether haloperidol was given via constant infusion (subcutaneous pellet) or daily injection. The nicotine-mediated decline is thus observed across species using various haloperidol treatment regimens. We then tested the effect of varenicline, an agonist that interacts with multiple nicotinic receptor subtypes. Low dose varenicline (0.1 mg/kg) decreased haloperidol-induced VCMs to a much greater extent (~90%) than nicotine (~50%). Since varenicline also acts at serotonergic receptors, we tested the effect of nicotine in combination with a selective serotonergic receptor drug 8-OH-DPAT (0.3 mg/kg). Nicotine or 8-OH-DPAT treatment alone decreased haloperidol-induced VCMs by ~60%, while combined administration reduced VCMs to a significantly greater extent than either drug alone (83%). These data are the first to show that drugs acting at both nicotinic and serotonergic receptors result in a pronounced decline in antipsychotic-induced VCMs. Drugs such as varenicline that act at both receptors may thus represent a novel therapy for reducing tardive dyskinesia.