Elsevier

Neuropharmacology

Volume 45, Issue 4, September 2003, Pages 493-503
Neuropharmacology

Caffeine and muscarinic antagonists act in synergy to inhibit haloperidol-induced catalepsy

https://doi.org/10.1016/S0028-3908(03)00202-8Get rights and content

Abstract

The possible synergism between caffeine and muscarinic antagonists to inhibit haloperidol-induced catalepsy was investigated with the bar test in rats. Pretreatment with low doses of caffeine (1–3 mg/kg), a non-selective adenosine antagonist, dose dependently reduced the intensity and increased the onset latency of catalepsy induced by haloperidol (0.5–2 mg/kg). Similar effects were produced by the muscarinic antagonists atropine (4.1 mg/kg), and trihexyphenidyl (THP, 0.01–3 mg/kg). THP inhibited catalepsy intensity with an ED50 of 0.38 mg/kg, and increased its onset latency with an ED50 of 0.52 mg/kg. The anticataleptic effect of anticholinergics was potentiated when a low dose of caffeine (1 mg/kg) was applied simultaneously. In the presence of caffeine, THP inhibited catalepsy intensity with an ED50 of 0.19 mg/kg, and prolonged the latency with an ED50 of 0.30 mg/kg. The synergism was more evident when THP was administered at subthreshold doses that were unable to modify haloperidol-induced catalepsy when applied alone, but produced a clear inhibition of catalepsy when injected with caffeine. To assess whether repeated administration of caffeine could induce tolerance to the synergism with THP, a group of rats was pretreated with three daily doses of caffeine (1 mg/kg) for seven days, and the catalepsy test was performed on the eighth day. In these animals, caffeine was still able to enhance the anticataleptic actions of THP, suggesting that repeated administration of 1 mg/kg caffeine does not induce tolerance to the synergism with anticholinergics. These results indicate that low doses of caffeine enhance the anticataleptic actions of muscarinic antagonists, and leave open the possibility of using caffeine as adjunctive therapy to reduce the doses and the adverse effects of anticholinergics in Parkinson’s disease.

Introduction

Muscarinic antagonists were the first pharmacological treatment for Parkinson’s disease (Fahn et al., 1990). However, their usefulness has been seriously limited by their numerous systemic and CNS side-effects, which are particularly intense in elderly patients afflicted by this neurodegenerative disease (Fahn et al., 1990). At therapeutic doses, anticholinergics often produce amnesia and cognitive impairment (Pondal et al., 1996, Nishiyama et al., 1993, Van Spaendonck et al., 1993), and exacerbate the subcortico-frontal syndrome often associated with Parkinson’s disease (Bédard et al., 1999). Thus, it would be desirable to reduce the doses of anticholinergics to the minimum necessary to relieve Parkinsonian symptoms without causing memory impairment. Theoretically, this could be achieved through the simultaneous administration of another drug capable of reducing the enhanced striatal cholinergic transmission caused by the loss of dopamine innervation (Fahn et al., 1990, Stoof et al., 1992, De Boer et al., 1993), but through a mechanism other than the blockade of muscarinic receptors.

Caffeine is an alkaloid widely consumed for its CNS stimulating properties (Fredholm et al., 1999). Experimental evidence suggests that caffeine has potential antiparkinsonian properties through the blockade of striatal adenosine A2A receptors (Richardson et al., 1997, Svenningsson et al., 1999, Ferré et al., 2001). Functional studies have shown that striatal acetylcholine (ACh) release can be enhanced by adenosine A2A agonists, effect that is blocked by selective adenosine A2A antagonists (Kirkpatrick and Richardson, 1993, Kirk and Richardson, 1994, Kurokawa et al., 1996). Since caffeine is also an antagonist for A2A receptors (Fredholm et al., 1999, Svenningsson et al., 1999), it might reduce striatal ACh release, thus enhancing the antiparkinsonian effects of anticholinergics.

Neuroleptic-induced catalepsy is a behavioural test widely used to screen potential antiparkinsonian drugs (Sanberg et al., 1996). In this model, the muscarinic antagonists (Ezrin-Waters et al., 1976), as well as caffeine (Malec, 1997), are able to inhibit haloperidol-induced catalepsy. Here we used the bar test (Sanberg et al., 1996) to evaluate the hypothesis that the anticataleptic actions of the antimuscarinic drugs atropine and THP can be enhanced by the simultaneous administration of the non-selective adenosine antagonist caffeine, at the dose of 1 mg/kg, which selectively enhances the local cerebral glucose utilization in the caudate-putamen of rats (Nehlig and Boyet, 2000). This dose of caffeine lies within the range of daily human consumption in coffee and other beverages (Fredholm et al., 1999). Since continuous intake of caffeine induces tolerance to its locomotor stimulating actions (Lau and Falk, 1994, Holtzman, 1983, Holtzman et al., 1991, Finn and Holtzman, 1987), we also tested whether repeated administration of caffeine for one week, at the dose of 1 mg/kg three times a day, could lead to the loss of its anticataleptic actions, and of its synergism with anticholinergics. Part of this work has been presented in abstract form (Góngora-Alfaro et al., 2002).

Section snippets

Animals

Male Wistar rats (240–320 g) bred in our facilities were used throughout the experiments. Groups of five animals were housed in acrylic cages (length, 38 cm; width, 24 cm; height, 20 cm) at constant room temperature (23±1 °C) and maintained on a 12:12 h light/dark cycle (lights on at 07:00) for at least one week. Food and water were available ad libitum. All efforts were made to minimize animal discomfort according to the recommendations of the Guide for the Care and Use of Laboratory Animals (

Experiment 1. Effect of atropine, either alone or with caffeine, on the intensity and latency of haloperidol-induced catalepsy

In vehicle-pretreated animals, haloperidol (0.5 mg/kg) caused a progressive increase of the descent time measured in the bar test (Fig. 1A), with a mean CDT[4h] of 3582±130 s (n=6). By contrast, the animals injected only with haloperidol vehicle had a mean CDT[4h] of 108±25 s (n=4). The difference between both means (3474 s) was taken as 100% catalepsy. Pretreatment either with atropine (4.1 mg/kg, n=6) or with caffeine (1 mg/kg, n=6) significantly reduced the mean CDT[4h] by 34±7% and 23±7%,

Discussion

The main finding of the present study was that the acute administration of caffeine, at the dose of 1 mg/kg, potentiates the abilities of the prototype muscarinic antagonist atropine and of the antiparkinsonian drug THP, to reduce the intensity and to prolong the onset latency of haloperidol-induced catalepsy. As previously reported for other anticholinergics (Ezrin-Waters et al., 1976), here we found that THP was able to reverse neuroleptic-induced catalepsy in a dose-dependent fashion.

Acknowledgements

This work was supported by the Universidad Autónoma de Yucatán, and CONACYT-México grants 31377-N to JLGA and 34424-N to JCP. Rosa E. Moo-Puc received a M.Sc. fellowship from grant 31377-N. We greatly appreciate the helpful comments of Drs R. García-Miss and E. Dumonteil.

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