SEARCH

SEARCH BY CITATION

Keywords:

  • Status epilepticus;
  • Xanthines;
  • Adenosine;
  • Anticonvulsant;
  • Spontaneous seizures;
  • Coffee

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Summary: Purpose: To investigate the consequences of caffeine consumption on epileptic seizures, we used the pilocarpine and the kainate models of epilepsy. We hypothesized that prolonged caffeine consumption or its withdrawal would alter adenosine levels and hence alter seizure susceptibility.

Methods: We administered a 0.1% caffeine solution in the drinking water of adult male Wistar rats over a 2-week period. We challenged another group of animals with the same doses of pilocarpine or kainate 12 h after the withdrawal of the same caffeine-administration protocol.

Results: This did not alter the threshold for the induction of seizures by a subconvulsant dose of pilocarpine (200 mg/kg, i.p.) or kainic acid (8 mg/kg, i.p.). Similarly, challenging another group of animals with the same doses of pilocarpine or kainate 12 h after the withdrawal of the same caffeine-administration protocol did not lead to any significant changes in seizures.

Conclusions: With the pilocarpine model of epilepsy, we were not able to find any significant difference in seizure profile that could stem from either caffeine administration or its withdrawal. Despite the extensive laboratory evidence on the convulsant properties of xanthine derivatives in animal models of epilepsy, such strong evidence is lacking in clinical settings. Our current findings with the administration of caffeine at doses similar to those of daily life both support and confirm the clinical experience.

Caffeine is one of the central nervous system (CNS) stimulants most widely present in human diet (1). This methylxanthine is found in appreciable concentrations in our common beverages such as coffee, tea, and soft drinks (2). It has proconvulsant effects on seizures in rats induced by kainic acid or pilocarpine (3–5), induces seizures in genetically epilepsy-prone rats (1), and prolongs kindled seizures in rats (6,7). In humans, scarce evidence of the convulsive effects of caffeine exists, with only two case reports indicating a clear association between excessive caffeine ingestion and increased seizure frequency (8) and caffeine withdrawal and the occurrence of a tonic–clonic seizure (9).

Several studies demonstrated that the CNS effects of methylxanthines might be linked to their ability to antagonize the actions of endogenous adenosine by blocking its receptors (10–12). The population of receptors involved on adenosine activities is heterogeneous, but the main mechanism of action of caffeine is represented by the antagonism of adenosine A1 and A2a receptors (13). A1 receptors are plentiful in the hippocampal complex, especially at CA1 and CA3 sectors and molecular layer of dentate gyrus, sites related to spontaneous recurrent seizures in pilocarpine models (14–16). Evidence exists that adenosine causes an inhibition of the release of different types of excitatory transmitters, such as glutamate and aspartate (17), and it has been suggested that adenosine is released during seizures, providing an inhibitory tone in the mammalian nervous system (18). Thus adenosine may function as an endogenous anticonvulsant (18–23).

Caffeine consumption is extremely common, yet surprisingly little attention has been paid to the brain biochemical effects of its administration and mainly its withdrawal. Caffeine intake varies worldwide according to the population studied. Overall, caffeine consumption can be estimated at ∼70–76 mg/person/day [i.e., 1–2 cups of coffee per day (24)], but reaches 210 to 238 mg/day (3–4 mg/kg/day) in the United States and >400 mg/person/day in Sweden and Finland (25–27).

Prolonged dietary consumption for 2 weeks of 0.1% caffeine ad libitum increased the plasma adenosine concentration in rats compared with that in control animals drinking tap water. Caffeine discontinuation had the opposite effect, that is, when the caffeinated solution was discontinued and replaced with tap water on the evening before the measurement, the plasma adenosine concentration declined compared with that in a second control group consuming tap water. Intravenously administered caffeine also increased plasma adenosine concentration in a dose-related and saturable manner, but long-term caffeine administration was of greater magnitude than that after acute intravenous administration: 10-fold as opposed to twofold (28). These data show that adenosine antagonists such as caffeine influence plasma adenosine concentrations, by an unknown mechanism, at doses similar to those in the range of medium to heavy coffee drinkers. Thus sudden changes in methylxanthine consumption could alter plasma adenosine concentrations and could be involved to the genesis of seizures in epilepsy patients.

Because long-term consumption of caffeine increases plasma adenosine levels in rats and its abrupt discontinuation results in a decrease of this purine nucleoside (28), and adenosine may act as an endogenous anticonvulsant (18–23), we expected a proconvulsant effect on seizures after caffeine discontinuation. Therefore the purpose of the present study was to evaluate the convulsive effects of long-term exposure to doses of caffeine, similar to the regular daily human intake, and after its abrupt discontinuation, in three groups of animals: (a) rats subjected to acute subconvulsant doses of pilocarpine; (b) rats subjected to acute subconvulsant doses of kainic acid; and (c) rats subjected to status epilepticus (SE), induced by systemic administration of cholinergic agonist pilocarpine, that underwent a latent period and subsequently developed a state of “chronic” epilepsy, characterized by the emergence of spontaneous recurrent seizures (SRSs).

These findings may have implications for individuals who cavalierly increase or withdraw from consumption of caffeine, a compound generally considered to be a useful but innocuous stimulant (28).

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

General

Adult male Wistar rats, weighing 180–300 g at the beginning of the studies, were used. For ∼1 week before the experiments, the animals were housed in groups and maintained on a standard light–dark cycle with rat chow pellets and tap water ad libitum. All of the experiments were conducted under the approval of the Animal Care and Use Committee of the University.

Experiment 1

Sixty rats were divided into two groups: pilocarpine group and kainic acid group. Each group was separated into three subgroups, with at least eight animals each: Caffeine (I), Withdrawal (II) and Control (III).

Subgroup I were allowed ad libitum access to 0.1% caffeine (caffeine anhydrous; Sigma-Aldrich, St. Louis, MO, U.S.A.) in drinking water for 2 weeks and were injected with pilocarpine or kainic acid on the 15th day, while still consuming caffeine. Subgroup II received the same solution of caffeine as subgroup I during the same time but was injected with pilocarpine or kainic acid 12 h after caffeine discontinuation. Subgroup III consumed tap water and was injected while under the same drinking conditions.

Based on our hypothesis that caffeine discontinuation would have proconvulsant effects, pilocarpine was injected at the subconvulsant dose of 200 mg/kg (i.p.). Methylscopolamine nitrate was injected subcutaneously (1 mg/kg) 30 min before pilocarpine to reduce the peripheral cholinergic effects. Rats were observed for ≥2 h for the occurrence of seizure activity. Based on the same reported hypothesis, kainic acid was injected at the subconvulsant dose of 8 mg/kg (i.p.), and the rats were observed for 3–4 h for the occurrence of seizure activity.

The criterion used to indicate convulsive response to pilocarpine or kainic acid was the occurrence of a seizure similar to or greater than a stage III of Racine's scale (29). Therefore as we did not perform EEG recording, only seizures involving forelimb clonus were considered, easily recognized by direct eye observation.

Experiment 2

In another set of animals, sustained seizures were induced by intraperitoneal administration of pilocarpine at a dose of 350 mg/kg. Methylscopolamine nitrate was injected subcutaneously (1 mg/kg) 30 min before pilocarpine to reduce the peripheral cholinergic effects. Approximately 30 min after pilocarpine injection, most of the animals had entered SE (30). To reduce the otherwise high mortality rate, thionembutal (25 mg/kg) was injected 1.5 h after SE onset. Animals were carefully intubated every time a toraxic fremitus was observed for the removal of bronchial secretions for the first 4–6 h after thionembutal injections. Every animal that underwent SE was given oral saline and sucrose for the next 2–3 days, to avoid dehydration. Rats injected with pilocarpine that did not show SE were excluded from the study. For easy identification, we marked the animals' fur with a saturated picric acid solution on different parts of the body. Animals were monitored for the occurrence of spontaneous recurrent seizures with the help of a video camera in a 3 × 3-m well-lit room with the animals lodged in clear Plexiglas cages, each containing four animals. Video recording of seizures was performed from 8:00 am to 2:00 pm for a total of 6 h on each recording day, during weekdays (Monday to Friday).

Baseline seizure frequency was established during two periods of 5 days (weekdays) over 2 consecutive weeks, starting 2 weeks after the animals were injected with pilocarpine. The allocation of the animals to each of the two different groups (control and caffeine) took into account the frequency of SRSs recorded during the baseline period. Therefore both the mean SRS frequency and the range of SRSs in each group were defined for the groups to be initially no different from each other. The mean latency for the first SRS to be video-recorded was 17.9 ± 2.3 days after SE induction for the animals in the caffeine group and 18.3 ± 2.6 days for the animals in the control group (p = 0.67). Exactly on the 15th day after the initial video recording (4 weeks after pilocarpine injection), rats in the experimental group (n = 6) were allowed ad libitum access to 0.1% caffeine (caffeine anhydrous; Sigma-Aldrich) in drinking water for 2 weeks (treatment period). During the treatment period, the animals did not have their seizures recorded. At the end of this 2-week period, the caffeinated solution was withdrawn and replaced with tap water. In the immediate 24 h at the end of this 2-week caffeine-administration period, thus immediate- experimental group (n = 6) were allowed ad libitum access to 0.1% caffeine (Caffeine anhydrous, Sigma-Aldrich, USA) in drinking water for 2 weeks (treatment period). During the treatment period, the animals did not have their seizures recorded. At the end of this 2 weeks period the caffeinated solution was withdrawn and replaced by tap water. In the immediate 24 h at the end of this 2 weeks caffeine-administration period, thus immediate discontinuation period, animals were continuously video-recorded for the occurrence of SRSs. In the subsequent 2 weeks (weekdays) immediately after caffeine withdrawal, video recording was performed as already described (6 h/day). Control animals, consuming tap water (n = 6), were subjected to the same protocol of seizure recording in the same days and hours as the caffeine group.

For another group (n = 6) of animals, we repeated this protocol, except that we also assessed the frequency of spontaneous recurrent seizures during the period of caffeine administration. These animals were also subjected to video recording of their SRSs in a manner similar to that previously described. Here the criterion used to indicate convulsive response was the occurrence of a spontaneous seizure similar to or greater than a stage III seizure of Racine's scale (29). Therefore for the current study, only seizures involving forelimb clonus were considered. In most seizures, clonic episodes rapidly developed onto one or more episodes of rearing and falling. Statistical significance levels were obtained by Student's t test, with significance level set at p < 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

General

During the 2-week period, the mean daily intake of liquid was almost identical whether or not the 0.1% caffeine was present in drinking water. The fluid intake reached values of 41.9 ± 3.4 ml/day for rats receiving plain tap water (mean ± SD) and 39.5 ± 4 ml/day for the rats receiving tap water containing 0.1% caffeine.

Experiment 1

To investigate whether caffeine would be able to influence acutely induced seizures, we injected animals that had received long-term treatment with caffeine with subconvulsant doses of either pilocarpine or kainic acid and observed them for the occurrence of seizures. Administration of caffeine for 2 weeks, or for 2 weeks followed by a 12-h withdrawal period, as compared with control, saline-treated animals, did not influence the later development of seizures in rats subjected to a subconvulsant dose of pilocarpine (Table 1).

Table 1. Incidence of seizures after subconvulsant doses of pilocarpine or kainic acid
 CaffeineWithdrawalTap water
Pilocarpine2/11 (18%)  2/10 (20%)1/10 (10%)
Kainate 1/8 (12.5%)0/11 (0%) 1/10 (10%)

In the same way, a subconvulsant dose of kainic acid did not alter the number of animals developing seizures in another group of animals subjected to the same regimens of caffeine administration as compared with controls (see Table 1). All animals that developed pilocarpine-induced seizures, irrespective of the treatment, showed similar signs of cholinergic activation such as mild tremors, facial automatisms, salivation, and jaw movements, as well as of subsequent convulsive phenomena, described as a seizure similar to or greater than a stage III of Racine's scale (29). Similarly, all animals that developed kainate-induced seizures initially became immobile with staring gaze and progressively developed bursts of wet-dog shakes, which later evolved to more obvious convulsive phenomena characterized by clonic movements of the head and long-lasting clonus of forelimbs, followed by generalized tonic–clonic seizures.

Latency for the onset of these behaviors and their duration was not different between caffeine and saline-treated animals undergoing seizure activity. None of the animals died after pilocarpine or kainic acid injection. Forelimb clonus, rearing, and falling were the hallmarks of such seizures. We did not encounter differences in terms of latency to different convulsive phenomena (e.g., time to reach stage III seizures) or duration of convulsive events.

Experiment 2

In another experiment, naïve animals that were initially subjected to pilocarpine-induced SE had their frequency of SRSs recorded for the purpose of setting a baseline against which to assess the effects of caffeine and its withdrawal. As already reported (31–33), the baseline frequency of SRSs varied extensively across the different animals. Our currently reported frequency of SRSs of 0.41 SRS/animal over a 60-h observation period (range, 0–15 SRSs/animal) is within the range recently reported for SRSs triggered by the electrical stimulation of the amygdala (34), even though much lower than that reported after lithium-pilocarpine SE (35).

Prolonged administration of caffeine for a period of 2 weeks for pilocarpine-epileptic animals and its abrupt withdrawal did not change the frequency of spontaneous recurrent seizures (Fig. 1). Even when only the frequency of SRSs occurring during the first 24 h immediately after caffeine withdrawal was considered, no significant consequences of caffeine administration (or withdrawal) could be seen. The main frequency of spontaneous recurrent seizures for the 2 days immediately before caffeine administration was 0.036 seizures/animal/6 h, whereas the mean frequency of SRSs in the first 24 h immediately after caffeine withdrawal was a similar 0.041 seizures/animal/6 h.

image

Figure 1. Frequency of spontaneous recurrent seizures in two groups of pilocarpine epileptic animals (controls, ctr; n = 6; caffeine, cfe; n = 6) either before (pre) or after (post) a 2-week treatment with 0.1% caffeine. No significant differences were encountered between any of the conditions.

Download figure to PowerPoint

Analysis of an additional animal group for the assessment of SRSs frequency not only before and after, but also during caffeine administration, once again did not reveal any significant changes between any of the periods (before, during, and after) considered, as shown in Fig. 2 (p = 0.8234).

image

Figure 2. Frequency of spontaneous recurrent seizures in a group of pilocarpine epileptic animals (n = 6) either before (pre), during (dur), or after (post) a 2-week treatment with 0.1% caffeine. No significant differences were encountered between any of the treatment periods.

Download figure to PowerPoint

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Our study was based on the hypothesis of Conlay and colleagues (28) that sudden changes in caffeine consumption—and thus in plasma adenosine concentrations—could influence seizure thresholds. Unexpectedly, given that adenosine receptors are known to be involved in seizure threshold in humans and laboratory animals (36,37), we showed that prolonged administration of 0.1% caffeine in drinking water for a period of 2 weeks and its abrupt withdrawal did not influence the later development of seizures in rats subjected to an acute subconvulsant dose of pilocarpine or kainic acid (experiment 1) and did not change the frequency of SRSs in the pilocarpine model epilepsy (experiment 2).

How can we reconcile the data and hypothesis forwarded by Conlay and colleagues (28) and our current findings? In addition, how can we reconcile the discrepancy regarding the convulsive effects of caffeine over animal models of epilepsy and the scarcity of human clinical observations on the convulsive effects of caffeine?

To extrapolate information derived from animal experiments to humans is not a trivial task, particularly regarding frequency (short term and long term) and dose (low and high) of caffeine consumption in relation to physiologic and toxic effects. The only known biochemical mechanism that is significantly affected by clinically relevant doses of caffeine, similar to those attained during normal human consumption, is the blockade of adenosine A1 and A2 receptors without any selectivity (38).

A brief exposure to methylxanthines decreases the threshold to various convulsants (1,4–7,39), whereas prolonged exposure to low doses of caffeine leads to decreased susceptibility to seizures induced by γ-aminobutyric acid (GABA)A-receptor antagonists such as bicuculline and pentylenetetrazol (40), or by the glutamatergic agonist N-methyl-d-aspartate (NMDA) (41,42). These data indicate that the effects of prolonged caffeine use are not related to any specific form of seizure model but are rather more general and occur in the complete absence of any change in the number of adenosine A1 receptors (41,43) or GABAA/benzodiazepine receptors (40). In contrast, Boulenger and colleagues (44) reported an increase in the number of central adenosine receptors and also a transitory increase in the number of benzodiazepine receptors in the mouse brain as a result of the prolonged blockade of adenosine receptors by long-term caffeine consumption in high doses. Dose size might be the critical issue underlying some of these discrepancies. Indeed, seizures and altered seizure susceptibility by means of caffeine or methylxanthine are possible only by means of unrealistic very high doses of these compounds (1,2).

Studies investigating the effects of prolonged caffeine administration at doses similar or equal to that used in the current study report either decreased seizure susceptibility in mice (40,41) or unaltered frequency of spontaneous seizures in rats (45). Similarly, we did not find any evidence for an effect of long-term caffeine administration in the pilocarpine and kainate models of epilepsy. In addition, our data indicate that at the currently used doses, abrupt withdrawal of caffeine also did not increase seizure susceptibility and did not alter the frequency of spontaneous seizures. In this sense, not even the abrupt biochemical changes likely be associated to caffeine withdrawal seem to interfere with seizure susceptibility in these models of epilepsy.

The main hypothesis underlying the current experiments was that altered adenosine levels associated with abrupt caffeine withdrawal (28) would be able to affect seizure susceptibility. Evidence exists that the release of excitatory transmitters is more strongly inhibited by adenosine than is that of inhibitory transmitters (46). In addition, when the effect of endogenous adenosine on potassium channels via A1 receptors on glutamatergic neurons is blocked by caffeine, it leads to epileptiform activity (19,20). However, recent evidence suggests that field potentials in CA3 pyramidal cells evoked by mossy fiber stimulation increase by only 20–30%, even when A1 adenosine receptors are fully blocked (47).

Although caffeine acts at the level of adenosine receptors and caffeine consumption and/or cessation influence adenosine concentrations, it clearly appears that this does not seem to change brain excitability enough to trigger seizures or increase their occurrence in an epileptic brain. It is known that long-term caffeine also alters the coupling of receptors to G proteins and the phosphorylation of DARPP-32 (48). Thus, first, whether or not the serum concentrations of adenosine reflect its central level and/or action must be proven, and second, the molecular cascade involved in caffeine action is far from being entirely clear, which most likely explains the paradoxical results observed in the present study.

It is surprising that the available evidence about the effects of caffeine on seizure susceptibility on animal models is not matched by clinical evidence over different forms of epilepsy in humans. Indeed, none of the major textbooks and clinical information databases on human epilepsy devotes more than a few sentences, if any, to describing an association of caffeine consumption and seizure threshold. A survey made to compare the distribution of seizures precipitants among epilepsy syndromes showed that caffeine was infrequently noted by patients as a precipitant (49). The only two reports of an association between caffeine consumption and seizures are the description of a single patient who often ingested a high volume (>2 L) of a caffeinated beverage over a short period (8) and a 45-year-old woman who had a tonic–clonic seizure after caffeine withdrawal (9).

In conclusion, these data suggest that caffeine administration and withdrawal, even though affecting plasma adenosine levels, are also associated with additional compensatory changes and had no influence on seizures in two different models of temporal lobe epilepsy in rats. Despite the extensive laboratory evidence on the convulsant properties of xanthine derivatives in animal models of epilepsy, such strong evidence is lacking in clinical settings. Our current finding with the administration of caffeine at doses similar to those in the range of medium to heavy coffee drinkers (28) supports and confirms the clinical experience. It is possible that long-term treatment with caffeine, at doses similar to those provided to humans, induces important adaptive changes in the brain (50), which may be beneficial rather than detrimental.

Acknowledgments

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Acknowledgment:  We thank the anonymous referees who greatly contributed for the current version of the manuscript. FAPESP-CEPID, CNPq-Institutos do Milênio, PRONEX; P.S.R. was a FAPESP fellow.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES
  • 1
    De Sarro A, Grasso S, Zappala M, et al. Convulsant effects of some xanthine derivatives in genetically epilepsy-prone rats. Naunyn Schmiedebergs Arch Pharmacol 1997;356: 4855.
  • 2
    Chu NS. Caffeine- and aminophylline-induced seizures. Epilepsia 1981;22: 8594.
  • 3
    Turski WA, Cavalheiro E, Ikonomidou C, et al. Effects of aminophylline and 2-chloroadenosine on seizures produced by pilocarpine in rats: morphological and electroencephalographic correlates. Brain Res 1985;361: 30923.
  • 4
    Ault B, Olney MA, Joyner JL, et al. Proconvulsant actions of theophylline and caffeine in the hippocampus: implications for the management of temporal lobe epilepsy. Brain Res 1987;426: 93102.
  • 5
    Cutrufo C, Bortot L, Giachetti A, et al. Differential effects of various xanthines on pentylenetetrazole-induced seizures in rats: an EEG and behavioral study. Eur J Pharmacol 1992;222: 16.
  • 6
    Albertson TE, Joy RM, Stark KG. Caffeine modification of kindled amygdaloid seizures. Pharmacol Biochem Behav 1983;19: 33944.
  • 7
    Dragunow M. Adenosine receptor antagonism accounts for the seizure-prolonging effects of aminophylline. Pharmacol Biochem Behav 1990;36: 7515.
  • 8
    Kaufman KR, Sachdeo RC. Caffeinated beverages and decreased seizure control. Seizure 2003;12(suppl 7):51921.
  • 9
    Antonaci F, Sances G, Manni R, et al. Epileptic seizure during aspirin and caffeine withdrawal in a drug induced headache. Funct Neurol 1996;11: 3337.
  • 10
    Scholfield CN. Depression of evoked potentials in brain slices by adenosine compounds. Br J Pharmacol 1978;63: 23944.
  • 11
    Smellie FW, Davis CW, Daly JW, et al. Alkylxanthines: inhibition of adenosine-elicited accumulation of cyclic AMP in brain slices and of phosphodiesterase activity. Life Sci 1979;24: 247582.
  • 12
    Katims JJ, Murphy KMM, Snyder SH. Xanthine stimulants and adenosine. In: CreeseI, eds. Stimulants: neurochemical, behavioral and clinical perspectives. New York : Raven Press, 1983: 6379.
  • 13
    Fredholm BB, Battig K, Holmen J, et al. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 1999;51: 83133.
  • 14
    Fastbom J, Pazos A, Palacios JM. The distribution of adenosine Al receptors and 5′-nucleotidase in the brain of some commonly used experimental animals. Neuroscience 1987;22: 81326.
  • 15
    Jarvis MF, Jacobson KA, Williams M. Autoradiographic localization of adenosine A1 receptors in rat brain using [3H]XCC, a functionalized congener of 1,3-dipropyhanthine. Neurosci Lett 1987;81: 6974.
  • 16
    Weber RG, Jones CR, Lohse MJ, et al. Autoradiographic visualization of A1 adenosine receptors in rat brain with [3H] 8-cyclopentyl-1,3-dipropylxanthine. J Neurochem 1990;54: 134453.
  • 17
    Fredholm BB, Hedqvist P. Modulation of neurotransmission by purine nucleotides and nucleosides. Biochem Pharmacol 1980;29: 163545.
  • 18
    Dragunow M, Goddard GV, Laverty R. Is adenosine an endogenous anticonvulsant? Epilepsia 1985;26: 4807.
  • 19
    Dunwiddie TV. Endogenously released adenosine regulates excitability in the in vitro hippocampus. Epilepsia 1980;21: 5418.
  • 20
    Dunwiddie TV, Hoffer BJ, Fredholm BB. Alkylxanthines elevate hippocampal excitability: evidence for a role of endogenous adenosine. Naunyn Schmiedebergs Arch Pharmacol 1981;316: 32630.
  • 21
    Snyder SH, Katims JJ, Annau Z, et al. Adenosine receptors and behavioral actions of methylxanthines. Proc Natl Acad Sci U S A 1981;78: 32604.
  • 22
    Stone TW. Physiological roles for adenosine and adenosine 5′-triphosphate in the nervous system. Neuroscience 1981;6: 52355.
  • 23
    Lee KS, Schubert P, Heinemann U. The anticonvulsive action of adenosine: a postsynaptic, dendritic action by a possible endogenous anticonvulsant. Brain Res 1984;321: 1604.
  • 24
    Gilbert RM. Caffeine consumption. In: SpillerGA, ed. The methylxanthine beverages and foods: chemistry, consumption, and health effects. New York : Alan R. Liss, 1984: 185213.
  • 25
    Debry G. Coffee and health. Paris : John Libbey, 1994: 1538.
  • 26
    Barone JJ, Roberts HR. Caffeine consumption. Found Chem Toxicol 1996;34: 11929.
  • 27
    Viani R. Caffeine consumption. Proc Caffeine Workshop. Bangkok : Thai FDA and ILSI, 1996.
  • 28
    Conlay LA, Conant JA, DeBros F, et al. Caffeine alters plasma adenosine levels. Nature 1997;389: 136.
  • 29
    Racine RJ. Modification of seizure activity by electrical stimulation, II: motor seizure. Electroencephalogr Clin Neurophysiol 1972;32: 28194.
  • 30
    Turski WA, Czuczwar SJ, Kleinrok Z, et al. Cholinomimetics produce seizures and brain damage in rats. Experientia 1983;39: 140811.
  • 31
    Arida RM, Scorza FA, Peres CA, et al. The course of untreated seizures in the pilocarpine model of epilepsy. Epilepsy Res 1999;34: 99107.
  • 32
    Leite JP, Bortolotto ZA, Turski L, et al. Spontaneous recurrent seizures in rats: an experimental model of partial epilepsy in rats. Neurosci Biobehav Rev 1990;14: 5117.
  • 33
    Mello LEAM, Cavalheiro EA, Babb TL, et al. Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: cell loss and mossy fiber sprouting. Epilepsia 1993;34: 98595.
  • 34
    Brandt C, Glien M, Potschka H, et al. Epileptogenesis and neuropathology after different types of status epilepticus induced by prolonged electrical stimulation of the basolateral amygdala in rats. Epilepsy Res 2003;55: 83103.
  • 35
    Rigoulot MA, Koning E, Ferrandon A, et al. Neuroprotective properties of topiramate in the lithium-pilocarpine model of epilepsy. J Pharmacol Exp Ther 2004;308: 78795.
  • 36
    Dragunow M. Purinergic mechanisms in epilepsy. Prog Neurobiol 1988;31: 85108.
  • 37
    Eldridge FL, Paydarfar D, Scott SC, et al. Role of endogenous adenosine in recurrent generalized seizures. Exp Neurol 1989;103: 17985.
  • 38
    Freedholm BB, Lindström K. Autoradiographic comparison of the potency of several structurally unrelated adenosine receptor antagonists at adenosine A1 and A2A receptors. Eur J Pharmacol 1999;380: 197202.
  • 39
    Coffey CE, Figiel GS, Weiner RD, et al. Caffeine augmentation of ECT. Am J Psychiatry 1990;147: 57985.
  • 40
    Johansson B, Kuosmanen T, Fredholm BB. Long-term treatment with some methylxanthines decreases the susceptibility to bicuculline- and pentylenetetrazol-induced seizures in mice: relationship to c-fos expression and receptor binding. Eur J Neurosci 1996;295: 14754.
  • 41
    Georgiev V, Johansson B, Fredholm BB. Long-term caffeine treatment leads to a decreased susceptibility to NMDA-induced clonic seizures in mice without changes in adenosine A1 receptor number. Brain Res 1993;612: 2717.
  • 42
    Von Lubitz DK, Paul IA, Carter M, et al. Effects of N6-cyclopentyl adenosine and 8-cyclopentyl-1,3-dipropylxanthine on N-methyl-d-aspartate induced seizures in mice. Eur J Pharmacol 1993;249: 26570.
  • 43
    Bona E, Aden U, Fredholm BB, et al. The effect of long term caffeine treatment on hypoxic-ischemic brain damage in the neonate. Pediatr Res 1995;38: 3128.
  • 44
    Boulenger JP, Patel J, Post RM, et al. Chronic caffeine consumption increases the number of brain adenosine receptors. Life Sci 1983;32: 113542.
  • 45
    Rigoulot MA, Leroy C, Koning E, et al. Prolonged low-dose caffeine exposure protects against hippocampal damage but not against the occurrence of epilepsy in the lithium-pilocarpine model in the rat. Epilepsia 2003;44: 52935.
  • 46
    Fredholm BB, Dunwiddie TV. How does adenosine inhibit transmitter release? Trends Pharmacol Sci 1988;9: 1304.
  • 47
    Kukley M, Schwan M, Fredholm BB, et al. The role of extracellular adenosine in regulating mossy fiber synaptic plasticity. J Neurosci 2005;25: 283237.
  • 48
    Fastbom J, Fredholm BB. Effects of long-term theophylline treatment on adenosine-A1 receptors in rat-brain: autoradiographic evidence for increased receptor number and altered coupling to G-proteins. Brain Res 1990;507: 1959.
  • 49
    Frucht MM, Quigg M, Schwaner C, et al. Distribution of seizure among epilepsy syndromes. Epilepsia 2000;41(suppl 12):15349.
  • 50
    Jacobson KA, Von Lubitz DK, Daly JW, et al. Adenosine receptor ligands: differences with acute versus chronic treatment. Trends Pharmacol Sci 1996;17: 10813.