Caffeine has greater potency and efficacy than theophylline to reverse the motor impairment caused by chronic but not acute interruption of striatal dopaminergic transmission in rats

• Published in: Neuropharmacology 2013-07, Vol.70, p.51-62
• Main Authors: Acuña-Lizama, Miguel M., Bata-García, José L., Alvarez-Cervera, Fernando J., Góngora-Alfaro, José L.
• Format: Article
• Language: English
• Subjects: Animals; Caffeine - pharmacology; Catalepsy - chemically induced; Catalepsy test; Corpus Striatum - drug effects; Dopaminergic Neurons - drug effects; Dose-Response Relationship, Drug; Haloperidol - adverse effects; Haloperidol - antagonists & inhibitors; Male; Methylxanthines; Motor Skills - drug effects; Oxidopamine - adverse effects; Oxidopamine - antagonists & inhibitors; Parkinson's disease; Parkinsonian Disorders - chemically induced; Rats; Stepping test; Theophylline - pharmacology
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2013.01.002

In order to assess whether caffeine and theophylline have the same potency and efficacy to reverse the impairment of motor function caused by acute or chronic interruption of striatal dopamine transmission, a comparison of their dose–response relationship was made in the acute model of haloperidol-induced catalepsy, and the chronic model of unilateral lesion of the dopamine nigrostriatal pathway with 6-hydroxydopamine. At equimolar doses, both drugs reduced catalepsy intensity and increased its onset latency in a dose-dependent fashion, showing comparable potencies and attaining the maximal effect at similar doses. Catalepsy intensity: caffeine ED50 = 24.1 μmol/kg [95% CI, 18.4–31.5]; theophylline ED50 = 22.0 μmol/kg [95% CI, 17.0–28.4]. Catalepsy latency: caffeine ED50 = 27.0 μmol/kg [95% CI, 21.1–34.6]; theophylline ED50 = 28.8 μmol/kg [95% CI, 22.5–36.7]. In one group of hemiparkinsonian rats (n = 5), caffeine caused a dose-dependent recovery of the contralateral forepaw stepping: ED50 = 2.4 μmol/kg/day [95% CI, 1.9–3.1]), reaching its maximum at the dose of 5.15 μmol/kg/day. When the treatment of these same rats was switched to 5.15 μmol/kg/day of theophylline, the stepping recovery was only 51 ± 12% of that induced by caffeine. Assessing the dose–response relationship of theophylline in another group of hemiparkinsonian rats (n = 7) revealed that it caused stepping recovery in an all-or-none fashion. Thus, the three lower doses had no effect, but at the dose of 5.15 μmol/kg/day theophylline suddenly increased the stepping to 56 ± 5% of the maximal effect observed when the treatment of these same rats was switched to an equimolar dose of caffeine. Increasing the dose of theophylline up to 15.45 μmol/kg/day caused no further stepping improvement since it was only 41 ± 6% of the maximal effect produced by caffeine at the dose of 5.15 μmol/kg/day. Given that theophylline showed less potency and efficacy than caffeine to reverse the motor impairment caused by chronic, but not acute, interruption of striatal dopaminergic transmission in rats, it is suggested that caffeine would provide more benefits than theophylline to improve the motor function in patients with Parkinson's disease. ► Caffeine and theophylline were tested in acute and chronic models of parkinsonism. ► Both drugs had the same potency and efficacy to reverse haloperidol-induced catalepsy. ► Caffeine was more potent and efficacious than theophylline to restore stepping in hemiparkinsonian rat