The effects of systemic, intrastriatal, and intrapallidal injections of caffeine and systemic injections of A2A and A1 antagonists on forepaw stepping in the unilateral 6-OHDA-lesioned rat

• Published in: Psychopharmacologia Vol. 201; no. 4; pp. 529 - 539
• Main Authors: Kelsey, John E., Langelier, Nicole A., Oriel, Brad S., Reedy, Catherine
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 2009; Springer; Springer Nature B.V
• Subjects: Adenosine A1 Receptor Antagonists; Adenosine A2 Receptor Antagonists; Adult and adolescent clinical studies; Animals; Antagonist drugs; Antiparkinson Agents - pharmacology; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Caffeine; Caffeine - administration & dosage; Caffeine - pharmacology; Central Nervous System Stimulants - administration & dosage; Central Nervous System Stimulants - pharmacology; Clinical outcomes; Corpus Striatum - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Globus Pallidus - metabolism; Injections; Levodopa - pharmacology; Male; Medical sciences; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Neuropharmacology; Neurosciences; Organic mental disorders. Neuropsychology; Original Investigation; Oxidopamine; Parkinson Disease - drug therapy; Parkinson Disease - physiopathology; Parkinson's disease; Pharmacology. Drug treatments; Pharmacology/Toxicology; Psychiatry; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Rats; Rats, Long-Evans; Rodents; 6-OHDA; Exterior globus pallidus; Adenosine receptors; Dorsal striatum; Parkinson’s; Caffeine; Agonist; Rat; Psychotropic; Central nervous system; Parkinson disease; Oxidopamine; Pallidum; Encephalon; Xanthine derivatives; Degenerative disease; Antagonist; Adenosine receptors . Dorsal striatum . Exterior globus pallidus; Parkinson's; Nervous system diseases; CNS stimulant; Rodentia; Basal ganglion; Corpus striatum; Sympathomimetic; Cerebral disorder; Vertebrata; Mammalia; Animal; Central nervous system disease; Lesion; Adenosine receptor; Adrenergic receptor; Extrapyramidal syndrome
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-008-1319-0

Rationale and objectives Given that adenosine A 2A antagonists appear to be therapeutic in several animal models of Parkinson’s disease (PD), we examined the extent to which caffeine and selective A 2A and A 1 antagonists could enhance contralateral forepaw stepping in the unilateral 6-OHDA-lesioned rat. Materials and methods Following unilateral injections of 12 μg 6-OHDA into the medial forebrain bundle (MFB), frequency of stepping with both front paws was counted separately as the paws were dragged anteriorally and laterally by a treadmill. Results The MFB lesions decreased contralateral stepping by 74–83%, and 8 mg/kg 3,4-dihydroxy- l -phenylalanine (L-DOPA) increased contralateral stepping by 25–26%. Caffeine given systemically (15 mg/kg) or into the dorsal striatum or external globus pallidus (GP E ; 20–40 μg) increased contralateral forepaw stepping by 14%, 27%, and 26%, respectively, and enhanced the effect of 8 mg/kg L-DOPA on stepping. The selective A 2A antagonist SCH-58261 (2 mg/kg) also increased stepping by 13% and enhanced the therapeutic effect of L-DOPA, whereas the selective A 2A antagonist 8-cyclopentyltheophylline (3–7 mg/kg) and A 1 agonist N 6 -cyclopentyladenosine (0.03–0.2 mg/kg) had no effect. None of these drugs appeared to produce dyskinesic effects. Conclusions In this well-validated animal model of the akinesic effects of PD, caffeine and a selective A 2A , but not an A 1 , antagonist were able to provide both monotherapeutic and adjunctive therapeutic effects. These data are consistent with the hypothesis that A 2A antagonists may be therapeutic in human PD patients and indicate that the dorsal striatum and GP E are critical sites of therapeutic action.