The effects of adenosine A2A receptor antagonists on haloperidol-induced movement disorders in primates.

Abstract

RATIONALE:

Adenosine and dopamine interact within the striatum to control striatopallidal output and globus pallidus GABA release. Manipulating striatal adenosine transmission via blockade of the A2A receptor subtype can compensate for the reduced dopamine activity within the striatum that underlies movement disorders such as antipsychotic-induced extrapyramidal syndrome (EPS) and Parkinson's disease (PD). Preclinical studies in the rat have demonstrated that adenosine A2A receptor antagonists can attenuate behaviors reflecting reduced dopamine activity, such as haloperidol-induced catalepsy and hypoactivity.

OBJECTIVES:

In the present studies using nonhuman primates, adenosine antagonists were tested against haloperidol-induced EPS in Cebus apella and haloperidol-induced catalepsy in Saimiri sciureus (squirrel monkey). Specifically, the A2A receptor antagonists, SCH 412348 (0.3-30 mg/kg PO) and KW-6002 (3-100 mg/kg PO); the A1/A2A receptor antagonist, caffeine (1-30 mg/kg PO and IM); and the A1 receptor antagonist, DPCPX (3-30 mg/kg PO) were tested in at least one of these models.

RESULTS:

SCH 412348 (10-30 mg/kg), KW-6002 (57-100 mg/kg), and caffeine (30 mg/kg) significantly increased the time to EPS onset. Additionally, SCH 412348, KW-6002, and caffeine afforded protection from the onset of EPS for at least 6 h in some of the primates. SCH 412348 (10 mg/kg) and caffeine (10 mg/kg) significantly reduced haloperidol-induced catalepsy. DPCPX produced a very slight attenuation of EPS at 30 mg/kg, but had no effect on catalepsy.

CONCLUSIONS:

These findings suggest that adenosine A2A receptor antagonists may represent an effective treatment for the motor impairments associated with both antipsychotic-induced EPS and PD.

• Authors: Geoffrey B Varty, Robert A Hodgson, Annamarie J Pond, Michael E Grzelak, Eric M Parker, John C Hunter
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 200 Issue 3 Pg. 393-401 (Oct 2008) ISSN: 0033-3158 [Print] Germany
• PMID: 18594798 (Publication Type: Journal Article)

Chemical References

• (7-(2-(4-difluorophenyl)-1-piperazinyl)ethyl)-2-(2-furanyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine
• Adenosine A2 Receptor Antagonists
• Antipsychotic Agents
• Purines
• Pyrimidines
• Receptor, Adenosine A2A
• Triazoles
• Xanthines
• istradefylline
• Caffeine
• gamma-Aminobutyric Acid
• 1,3-dipropyl-8-cyclopentylxanthine
• Haloperidol

Topics

• Adenosine A2 Receptor Antagonists
• Animals
• Antipsychotic Agents (toxicity)
• Caffeine (pharmacology)
• Catalepsy (chemically induced, physiopathology)
• Cebus
• Corpus Striatum (drug effects, physiopathology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Dyskinesia, Drug-Induced (physiopathology)
• Globus Pallidus (drug effects, physiopathology)
• Haloperidol (toxicity)
• Neurologic Examination (drug effects)
• Purines (pharmacology)
• Pyrimidines (antagonists & inhibitors)
• Receptor, Adenosine A2A (physiology)
• Saimiri
• Triazoles (antagonists & inhibitors)
• Xanthines (pharmacology)
• gamma-Aminobutyric Acid (metabolism)