Abstract

The long term objective of this research is to determine the neurochemical mechanisms underlying antipsychotic-induced dyskinesias. Antipsychotics, such as haloperidol, are widely used in the treatment of schizophrenia and in agitated elderly patients. However, a substantial proportion of patients receiving antipsychotic medication experience motor disorders, often referred to as extrapyramidal side effects (EPS). In fact, the incidence of EPS can approach 100 percent in the elderly. Currently, no antipsychotics exist which are both safe to use and free of EPS liability. It is hoped that by understanding how these drugs affect neuronal systems involved in motor control, safer compounds with no motoric side effects can be developed. One neurotransmitter involved in motor control and implicated in mediating EPS, is serotonin (5-hydroxytryptamine; 5-HT). Drugs which increase central serotonergic activity can elicit orofacial dyskinesias in both non-human primates and rats which have received antipsychotic treatment, but not in vehicle-pretreated animals. Similar orofacial dyskinesias are often seen in patients on antipsychotic medication. While experimental data suggests that the serotonin 5-HT2c receptor mediates orofacial dyskinesias, the effects of antipsychotics on 5-HT2c mediated motor control and 5-HT2c-linked signal transduction in the brain have not been studied. In this proposal it is hypothesized that 5-HT2c receptor supersensitivity in the basal ganglia contributes to the EPS caused by antipsychotic drugs. The first specific aim is to determine that 21 day administration of haloperidol to rats increases 5-HT2c mediated motor activity in vivo. This will be accomplished by comparing 5-HT2c-mediated orofacial dyskinesias between haloperidol- treated and vehicle-treated rats. The effects of haloperidol on 5-HT2c receptor-mediated signal transduction in basal ganglia will also be assessed in Aim I. For this purpose, 5-HT2c-stimulated phospholipase C activity in caudate and substantia nigra of haloperidol-treated and vehicle treated rats will be assayed. To determine the receptor transduction mechanism through which supersensitivity occurs, radioligand binding assays will assess changes in the 5-HT2c ligand recognition site and immunoblotting techniques will assess changes in guanine-nucleotide binding regulatory proteins which couple the 5-HT2c site to phospholipase C. The second specific aim is to attenuate the induction of dyskinesias and receptor supersensitivity by chronically co-administering agents known to down-regulate the 5-HT2c receptor. The success of this approach will be determined biochemically and behaviorally as Aim I.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036410-03
Application #
6165520
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Sheehy, Paul A
Project Start
1998-03-01
Project End
2002-08-31
Budget Start
2000-03-01
Budget End
2002-08-31
Support Year
3
Fiscal Year
2000
Total Cost
$135,545
Indirect Cost

  Institution

Name
Loyola University Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153