Pharmacological characterization of psychosis-like behavior in the MPTP-lesioned nonhuman primate model of Parkinson's disease.
Investigation of the pathophysiology of psychosis in Parkinson's disease (PD), as well as the assessment of potential novel therapeutics, has been limited by the lack of a well-validated animal model. MPTP-lesioned primates exhibit abnormal behaviors that are distinct from dyskinesia and parkinsonism and may represent behavioral correlates of neural processes related to psychosis in PD. Here we assess four types of behavior--agitation, hallucinatory-like responses to nonapparent stimuli, obsessive grooming, and stereotypies that are termed "psychosis-like"--and define their pharmacology using a psychosis-like behavior rating scale. By assessing the actions of drugs known to enhance or attenuate psychosis in PD patients, we find that the pharmacology of these behaviors recapitulates, in several respects, the pharmacology of psychosis in PD. Thus, levodopa and apomorphine elicited psychosis-like behaviors. Amantadine significantly decreased levodopa-induced dyskinesia but exacerbated psychosis-like behaviors. Haloperidol reduced psychosis-like behaviors but at the expense of increased parkinsonian disability while the atypical neuroleptics clozapine and quetiapine reduced psychosis-like behaviors without significant effect on parkinsonian disability. The response of different components of the psychotomimetic behavior suggested the involvement of both dopaminergic and nondopaminergic mechanisms in their expression.
Visanji
Naomi P
NP
Toronto Western Research Institute, Toronto Western Hospital, Toronto, Ontario, Canada.
Gomez-Ramirez
Jordi
J
Johnston
Tom H
TH
Pires
Donna
D
Voon
Valerie
V
Brotchie
Jonathan M
JM
Fox
Susan H
SH
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000547:Amantadine / Q000627:therapeutic use; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000627:therapeutic use; D001058:Apomorphine / Q000009:adverse effects; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D002144:Callithrix; D004185:Disability Evaluation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D005260:Female; D006120:Grooming / Q000187:drug effects / Q000502:physiology; D006212:Hallucinations / Q000188:drug therapy / Q000209:etiology; D007980:Levodopa / Q000009:adverse effects; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D011595:Psychomotor Agitation / Q000188:drug therapy / Q000209:etiology; D011618:Psychotic Disorders / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D018709:Statistics, Nonparametric; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology
D000978:Antiparkinson Agents; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000547:Amantadine; D001058:Apomorphine