Evaluation of the Role of a Cholinergic Agonist in the Potentiating Neuroleptic Response in Animals and Tourette Patients

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Cincinnati
Investigators Name
Sanberg, Paul, PhD

The drugs of choice for Tourette Syndrome are dopamine receptor blockers such as haloperidol. However, some patients under these drugs show only marginal improvement. Furthermore, these drugs can lead to sedation, exacerbation of learning difficulties and possible tardive dyskinesia. For these reasons an agent that potentiates the effects of a drug such as haloperidol could allow for lower doses of neuroleptics and -a reduction in side effects. It is well known that haloperidol decreases movement or cause hypokinesis when administered to laboratory rats. Recently, we reported that low doses of nicotine (a drug that acts on the acetylcholine system in the brain) potentiated haloperidol-induced hypokinesia in the rat. The addition of nicotine produced almost a ten-fold increase in the hypo-kinetic response to the same dose of haloperidol. Nicotine alone was without effect. This dramatic potentiation by nicotine of the extrapyramidal actions of haloperidol suggested that nicotine might also potentiate the therapeutic effects of haloperidol in patients with extrapyramidal movement disorders. Indeed, the potential usefulness of combining nicotine with neuroleptic treatment for Tourette Syndrome was recently tried on some patients. In a preliminary examination we reported that nicotine (in the form of nicotine gum) caused a dramatic improvement in TS symptoms in two patients who responded only marginly to haloperidol. Subsequently, eight out of ten patients have demonstrated improvement with nicotine and haloperidol. The animal and human studies suggested nicotine should prove of value only when combined with a neuroleptic. The purpose of this grant is to further investigate the effects of nicotine as a therapeutic adjunct to neuroleptic treatment in animal models of extrapyramidal function and in patients with IS Together with Dr. Andrew B. Norman, we plan to examine the basic science of the effects of co-treatment of nicotine and haloperidol to determine the dose response relationship of their interaction. In addition, it is hoped to examine whether co-treatment can attenuate the dopamine receptor supersensitivity which can result following chronic neuroleptic treatment in rats. This basic information will be useful to determine whether nicotine co-administration can decrease the clinically effective dose of neuroleptics and reduce any incidence of tardive dyskinesia produced in humans following chronic administration. In addition, the grant will allow us to further study the effects of nicotine on individuals with TS in a controlled study in order to further confirm whether nicotine potentiates the therapeutic effects of haloperidol in these patients. The clinical studies will be performed with Dr. Brian J. McConville and Dr. M. Harold Fogelson at the Tourette’s Clinic, Children’s Hospital Medical Center, Cincinnati, Ohio. Paul R. Sanberg, Ph.D. University of Cincinnati, Cincinnati, OH Award: $20,180 Tourette Association of America Inc. – Research Grant Award 1989