Caffeine and muscarinic antagonists act in synergy to inhibit haloperidol-induced catalepsy
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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2015, Behavioural Brain ResearchCitation Excerpt :Catalepsy was evaluated in the bar test immediately before surgery and on 7 consecutive days after surgery, i.e. testing on days 0–7. The apparatus (23 cm long × 10.5 cm wide × 9 cm high), with a horizontal bar (0.4 cm diameter × 23 cm long) suspended 9 cm above the floor, was similar to others reported in the literature [26,36]. Catalepsy was evaluated by measuring the mean time taken by a rat to climb over the bar after being laid across it with its hind limbs on the floor [9,24,26,27,29].
The potency and efficacy of anticholinergics to inhibit haloperidol-induced catalepsy in rats correlates with their rank order of affinities for the muscarinic receptor subtypes
2014, NeuropharmacologyCitation Excerpt :Data analysis only included results from animals in which the dye stained the cavity of the lateral cerebral ventricle, as shown in Fig. 1. The variables measured were: (1) descent time, defined as the time elapsed until the animal released both forepaws from the bar, up to a maximum of 300 s; (2) cumulative descent time (CDT[5h]), defined as the sum of the descent time values measured every 15 min during 5 h after haloperidol administration; (3) catalepsy latency, defined as the time elapsed between haloperidol injection and the first testing interval when the descent time was ≥150 s (Moo-Puc et al., 2003). The percent inhibition of catalepsy intensity caused by anticholinergics was calculated with the formula: 100 – (CDT[5h]/3906 × 100), where the value 3906 represents the average CDT[5h] recorded in control rats, pretreated with vehicle followed by haloperidol (n = 14).