Pharmacological characterization of psychosis‐like behavior in the MPTP‐lesioned nonhuman primate model of Parkinson's disease

Abstract

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.

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…Thus, in the MPTP-lesioned macaque killed 1 hour after L-DOPA administration, 5-HT 2A receptor levels were increased in the motor cortex and striatum of dyskinetic animals (Huot et al, 2012b). Moreover, antagonizing 5-HT 2A receptors with the atypical antipsychotics clozapine and quetiapine led to a reduction of established AIMs severity in the 6-OHDA-lesioned rat (Lundblad et al, 2002) and LID in the MPTPlesioned primate (Oh et al, 2002;Visanji et al, 2006). It should be noted though that both clozapine and quetiapine bind to several other serotonergic and nonserotonergic receptors (Huot et al, 2011a) and that, although their antidyskinetic efficacy is usually attributed to antagonizing 5-HT 2A receptors, a contribution of these other targets cannot be excluded, therefore limiting the interpretation of these pharmacological studies.…”

Anatomically Selective Serotonergic Type 1A and Serotonergic Type 2A Therapies for Parkinson's Disease: An Approach to Reducing Dyskinesia without Exacerbating Parkinsonism?

“…The nonselective 5-HT 2A antagonist clozapine reduced L-DOPA-induced dyskinesia in MPTP-lesioned, parkinsonian nonhuman primates (Visanji et al, 2006) and patients with PD (Durif et al, 2004). However, clozapine may exacerbate parkinsonism (Wolters et al, 1990).…”

Characterization of 3,4-Methylenedioxymethamphetamine (MDMA) EnantiomersIn Vitroand in the MPTP-Lesioned Primate:R-MDMA Reduces Severity of Dyskinesia, WhereasS-MDMA Extends Duration of ON-Time

“…Methods for assessment of behavior were described previously in detail Gomez-Ramirez et al, 2006;Visanji et al, 2006;Fox et al, 2010). Briefly, parkinsonian disability was rated for 5 min every 10 min using a parkinsonian disability scale combining measures of range of movement, bradykinesia, posture, and attention/alertness.…”

“…Previous pharmacological studies have suggested that 5-HT 2A receptors might be involved in the genesis of dyskinesia and thus might support the involvement of R-MDMA in antidyskinetic actions. For example, the nonselective 5-HT 2A antagonists clozapine and quetiapine reduced dyskinesia-associated behaviors in the 6-OHDA-lesioned rodent and dyskinesia in the MPTP-lesioned primate (Oh et al, 2002;Visanji et al, 2006). In human studies, low-dose clozapine alleviated dyskinesia (Durif et al, 2004).…”