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.

Histamine H 3 receptors modulate histamine synthesis, although little is known about the transduction mechanisms involved. To investigate this issue, we have used a preparation of rat brain cortical miniprisms in which histamine synthesis can be modulated by depolarization and by H 3 receptor ligands. When the miniprisms were incubated in presence of forskolin, dibutyryl-cAMP, or 3-isobutyl-1-methylxanthine (IBMX), histamine synthesis was stimulated in 34, 29, and 47%, respectively. These stimulations could be prevented by the selective cAMP protein kinase blocker Rp-adenosine 3Ј,5Ј-cyclic monophosphothioate triethylamine (Rp-cAMPs). Preincubation with the H 3 receptor agonist imetit prevented IBMX-(100% blockade) and forskolin-(70% blockade) induced stimulation of histamine synthesis. The H 3 inverse agonist thioperamide enhanced histamine synthesis in the presence of 1 mM IBMX or 30 mM potassium (ϩ47 and ϩ45%, respectively). Similarly, the H 3 antagonist clobenpropit enhanced histamine synthesis in the presence of 30 mM potassium (ϩ 59%). The cAMP-dependent protein kinase blockers Rp-cAMPs and PKI14 -22 could impair the effects of thioperamide and clobenpropit, respectively. These results indicate that the adenylate cyclase-protein kinase A pathway is involved in the modulation of histamine synthesis by H 3 autoreceptors present in histaminergic nerve terminals.

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