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PubMed2006

Transgenic tobacco plants producing caffeine: a potential new strategy for insect pest control.

Caffeine (1,3,7-trimethylxanthine) is one of the most widely used plant secondary metabolites, primarily as a stimulant and an ingredient in drugs. In nature, caffeine is believed to function in chemical defense, acting as an antiherbivory and allelopathic agent, and therefore it might be employed to protect agriculturally important crop plants. In coffee plants, caffeine is synthesized from the precursor xanthosine in four steps, three N-methylations and removal of ribose. We had previously isolated genes encoding three distinct N-methyltransferases, and we demonstrated production of recombinant enzymes that yielded caffeine in in vitro reconstitution experiments. When these caffeine biosynthetic pathway genes were simultaneously expressed in tobacco plants (Nicotiana tabacum), caffeine was successfully produced up to 5 microg/g fresh weight in leaves. The leaves were unpalatable to tobacco cutworms (Spodoptera litura). This repellent action appeared to be more widely applicable to lepidopteran caterpillars as observed with small white (Pieris rapae) fed on Chinese cabbages that had been top-treated with caffeine. Our recent results suggest a novel approach to strengthen anti-herbivore traits by producing caffeine in crop plants.

Animals↗
PubMed1984

Caffeine and hypertension.

The effect of prolonged caffeine administration on blood pressure in hypertensive subjects was assessed in a double-blind placebo-controlled study. Eighteen hypertensive subjects participated, nine of whom received placebo throughout the study and nine of whom received placebo during the first three days, caffeine during the subsequent seven days, and placebo during the final four days of the two-week study. Those who received caffeine were given 250 mg with meals three times daily. There were no untoward reactions in the course of the study, but one subject with unacceptably high blood pressures while receiving placebo had to be discharged from the study to resume antihypertensive therapy. Systolic blood pressure was immediately increased (9.2 +/- 3.4 mm Hg) within 15 minutes after the first dose of 250 mg of caffeine. On the first day of caffeine, systolic pressure was increased a mean of 7.3 +/- 4.0 mm Hg, but this was no longer significant after the initial day of caffeine administration. Diastolic pressure showed a trend toward increasing, but this never reached significance. The minor increases in plasma catecholamine levels and plasma renin activity were not significant on either a short- or long-term basis. After discontinuation of caffeine, no overshoot phenomena were observed. It is concluded that prolonged administration of caffeine is not associated with significant elevation in blood pressure, plasma catecholamine levels, or plasma renin activity in patients with borderline hypertension.

Adult↗
PubMed1986

Caffeine consumption during pregnancy and association with late spontaneous abortion.

In a prospective cohort study, 3135 pregnant women were followed to evaluate the association of caffeine consumption during pregnancy with late first- and second-trimester spontaneous abortion. Almost 80% of pregnant women used some caffeine; among users the average daily intake was 99.3 mg from all sources. Sources of caffeine were nonherbal tea (used by 49.4% of women), coffee (41.2%), colas (35.0%), and drugs (6.6%). In all, 28% of pregnant women consumed greater than or equal to 151 mg of caffeine daily, and these "moderate-to-heavy" caffeine users were significantly more likely to experience late first- or second-trimester spontaneous abortion when compared with nonusers and light users (0 to 150 mg). Demographic characteristics, reproductive and medical history, contraceptive use, and smoking and drinking habits were taken into consideration. The adjusted relative risk of miscarriage after moderate-to-heavy caffeine consumption was 1.73 (p = 0.03). Light caffeine use (1 to 150 mg daily) was associated with increased risk for spontaneous abortion only among women who aborted in their last pregnancy (RR = 4.18, p = 0.04). Replicative studies are necessary before the association of caffeine with spontaneous abortion can be confirmed.

Abortion, Spontaneous↗
PubMed1988

Preferential effects of caffeine on limbic and cortical dopamine systems.

In this study, we investigated the effects of acute caffeine administration on the activity of midbrain dopamine neurons. Caffeine significantly depressed the firing rates of dopamine neurons in the ventral tegmental area (A10 group), but had no significant effect on the firing rates of dopamine neurons in the substantia nigra zona compacta (A9 group). The action of caffeine in A10 was completely blocked by pretreatment with the adenosine agonist L-phenyl-isopropyl-adenosine (L-PIA), confirming numerous lines of evidence that caffeine and other xanthines act as competitive antagonists at adenosine receptors. The dopamine antagonist haloperidol also antagonized the effects of caffeine. This finding is consistent with a mechanism of caffeine-induced depression of dopamine neuron activity involving dopamine release, similar to that observed during amphetamine administration. Finally, the benzodiazepine diazepam also antagonized the dopaminergic effects of caffeine. It appears that, in the rat, caffeine administration inhibits mesolimbic and mesocortical projecting dopamine neurons, but has no effect on dopamine neurons that project to the striatum.

Animals↗
PubMed1987

Effects of caffeine and cyclic adenosine 3',5'-monophosphate on adenosine triphosphate-dependent calcium uptake by lysed brain synaptosomes.

The adenosine triphosphate-dependent calcium uptake by endoplasmic reticulum elements of lysed synaptosomes from rat brain cortex was studied. Caffeine exhibited a biphasic effect on this calcium uptake activity: concentrations of 1, 2, 5, 10 or 30 mM caffeine stimulated calcium uptake by 62, 111, 73, 88 and 60% respectively, whereas calcium uptake was inhibited by 55% at a 60-mM concentration of caffeine. Calcium release from endoplasmic reticulum elements of lysed brain synaptosomes was stimulated by 10 mM caffeine. Cyclic adenosine 3',5'-monophosphate stimulated calcium uptake in the lysed synaptosome preparation: exogenous concentrations of 0.05, 0.5, 5, 50, or 500 microM stimulated uptake by 67, 67, 95, 38 or 67% respectively. To explore the possibility that caffeine stimulated calcium uptake through inhibition of phosphodiesterase and consequent preservation of cyclic adenosine 3',5'-monophosphate, we have tested whether caffeine retained its ability to stimulate calcium uptake under conditions of maximal stimulation by cyclic adenosine 3',5'-monophosphate. The combined presence of 10 mM caffeine and 5 microM cyclic adenosine 3',5'-monophosphate resulted in an approximate doubling of the calcium uptake as compared to the uptake in the presence of the cyclic nucleotide alone, indicating that the stimulation due to caffeine does not occur via cyclic adenosine 3',5'-monophosphate.

Adenosine Triphosphate↗
PubMed1987

Caffeine inhibits post-tetanic potentiation but does not alter long-term potentiation in the rat hippocampal slice.

The effects of caffeine were investigated on the extracellular excitatory postsynaptic potentials (EPSPs) recorded in the stratum radiatum of CA1 of the rat hippocampal slice in response to stimulation of the Schaffer collaterals. Caffeine in concentrations from 500 microM to 10 mM caused an increase in the amplitude of the EPSP, which reached a peak after 5-10 min perfusion. This increase was antagonized by pretreatment with 20 microM trifluoperazine. Paired-pulse facilitation, augmentation and potentiation were strongly inhibited by caffeine. Augmentation was most sensitive to caffeine, being abolished by 500 microM caffeine. Long-term potentiation (LTP) induced by high-frequency stimulation was not significantly inhibited by caffeine either by 5-10 min or by 60 min perfusion with 10 mM caffeine. Moreover, the caffeine-induced increase in the low-frequency EPSP could be reversed by 30 min washout, demonstrating that it was not an LTP type increase.

Afferent Pathways↗
PubMed1993

Long-term caffeine treatment leads to a decreased susceptibility to NMDA-induced clonic seizures in mice without changes in adenosine A1 receptor number.

The effects of long-term caffeine treatment on N-methyl-D-aspartate (NMDA)-induced seizures in mice were studied. Caffeine was added (0.3 g/l) to drinking water for 14 days and the mice ingested 60-70 mg/kg/day. During the treatment, the plasma concentrations of methylxanthines (caffeine, theophylline and/or paraxanthine, theobromine) were measured. NMDA (150 mg/kg i.p.) was administered to control mice and to mice during and after the caffeine administration. A1 adenosine receptor density in the gyrus dentatus of hippocampus, measured by quantitative receptor autoradiography with [3H]cyclohexyl adenosine as the ligand, was not significantly altered after long-term caffeine treatment. NMDA-induced clonic seizures, wet dog shakes and mortality were significantly reduced at the end of long-term caffeine treatment but returned towards control at 1 and 2 days after withdrawal. At the end of caffeine treatment, tonic seizures were also absent. These results show that long-term treatment with caffeine in a dose that gives plasma levels of 6-10 microM decreases the effects of NMDA on e.g. seizure susceptibility, and that this effect cannot be ascribed to changes of A1 adenosine receptor density.

Animals↗
PubMed1980

Caffeine inhibition of postreplication repair of UV-damaged DNA in mouse epidermal cells.

The effect of caffeine (0.25-1.5 mM) on UV-irradiated (5 and 10 J/m2) primary cultures of mouse epidermal cells (EPD) and an in vitro transformed cell line (PDV) was studied at the cellular and molecular levels. A synergistic reduction in cell survival induced by caffeine with UV-irradiation was found in the PDV cells at 10 J/m2 but not at 5 J/m2. When conversion of low molecular weight newly-synthetized DNA to high molecular weight DNA was studied in both cell types, caffeine at 2.5 mM had no effect on this conversion in unirradiated cultures. At 5 J/m2, caffeine had a transitory inhibitory effect on this conversion. However, at 10 J/m2 caffeine had a strong permanent inhibitory effect on this conversion at doses higher than 0.5 mM in PDV cells and higher than 0.25 mM in EPD cells. This apparent inhibition of elongation by caffeine in irradiated cells could not be accounted for by an effect on the rate of DNA synthesis. In PDV cells there was a direct correlation in terms of effective caffeine dose level between synergistic reduction in cell survival after UV and the effect on DNA elongation. Irradiated EPD cells were more sensitive to the inhibitory effect of caffeine on DNA elongation.

Animals↗
PubMed1985

Effects of (-)-N6-(R-phenylisopropyl)-adenosine (PIA) and caffeine on nociception and morphine-induced analgesia, tolerance and dependence in mice.

(-)-N6-(R-phenylisopropyl)-adenosine (PIA) was shown to possess analgesic activity in both the tail flick and acetic acid writhing assays. The analgesic actions of PIA were antagonized by caffeine in a dose-dependent manner. An apparent pA2 analysis in vivo suggested that the antagonism by caffeine was not competitive. Subanalgesic doses of PIA potentiated morphine-induced analgesia, tolerance and dependence. Caffeine antagonized these effects of morphine. PIA attenuated while caffeine exacerbated opiate withdrawal. While a low dose of caffeine antagonized PIA effects on withdrawal, a low dose of PIA did not antagonize the effects of caffeine. These results indicate that PIA can facilitate, and caffeine can antagonize the actions of morphine and that caffeine may be exerting some of its actions independent of adenosine receptor antagonism.

Adenosine↗
PubMed1986

Comparative effects of acute and chronic administration of caffeine on local cerebral glucose utilization in the conscious rat.

The quantitative 2-[14C]deoxyglucose autoradiographic method was used to compare the effects of acute and chronic administration of caffeine on rat brain energy metabolism. The acute intravenous administration of caffeine (10 mg/kg) to naive rats induced widespread increases in glucose utilization in 20 of 62 structures, mainly in striatal and related areas as well as in the 2 raphe nuclei and the locus coeruleus. After 2 weeks' chronic intraperitoneal injection of caffeine (10 mg/kg), increases in glucose utilization were seen in 6 of 62 structures: the substantia nigra, pars compacta, dorsal raphe, locus coeruleus and the 3 parts of the caudate nucleus. An acute caffeine injection (10 mg/kg) to these chronically caffeine-treated rats induced a further increase in glucose utilization in 9 additional structures but there was no significant difference in the effects of an acute administration of caffeine whether the rats had been chronically pretreated with caffeine or saline. The results of the present study show that brain energy metabolism seems to be subject to only partial tolerance to central stimulation by caffeine.

Animals↗
PubMed1992

Opioid receptor mediation of the hypothermic response to caffeine.

Caffeine and other methylxanthines induce a dose-dependent reduction in core body temperature in mice. These experiments investigated the effects of neurotransmitter and neuromodulator antagonists on caffeine-induced hypothermia. Pretreatment with the alpha 2-adrenoceptor antagonist, atipamezole; the beta-adrenoceptor antagonist, propranolol; the dopamine antagonist, haloperidol; or the benzodiazepine receptor antagonist, flumazenil had no intrinsic effects on core body temperature nor did they interact significantly with the hypothermic effects of caffeine. The alpha 1-adrenoceptor antagonist, prazosin and the 5-HT receptor antagonist, metergoline significantly enhanced the hypothermic effects of caffeine, probably involving a combined effect with their intrinsic hypothermic actions. Pretreatment with the opiate receptor antagonist, naloxone (3 mg/kg i.p.), had no intrinsic effect on core body temperature but attenuated the hypothermic effect of caffeine reflected in a parallel shift to the right in the caffeine dose-effect curve. The naloxone-induced attenuation of the hypothermic effects of caffeine was also seen to be dose-dependent. The results reveal that opiate receptors (but not adrenoceptors, 5-HT, dopamine or benzodiazepine receptors) may play a role in modulating the hypothermic action of caffeine and possibly other methylxanthines.

Animals↗
PubMed1989

A G-protein of sarcoplasmic reticulum of skeletal muscle is activated by caffeine or inositol trisphosphate.

Here we show the activation of G-protein by inositol trisphosphate (IP3) or caffeine in sarcoplasmic reticulum (SR) of skeletal muscle and the consequent existence of a common mechanism of Ca2+ release from SR induced by caffeine and by IP3. (i) Indomethacin inhibits Ca2+ release induced by IP3 or caffeine. (ii) PGE1 does not induce Ca2+ release itself, but does stimulate Ca2+ release induced by IP3, or caffeine, from SR. (iii) Forskolin stimulates both types of Ca2+ release. The inhibitory effect of indomethacin on both forms of Ca2+ release, and the stimulatory effect of PGE1 and forskolin on either Ca2+ release suggest that there exists a common mechanism between IP3- and caffeine-induced Ca2+ release. (iv) Caffeine or IP3 activates G-protein via inhibition of a GTPase activity. (v) Indomethacin itself inactivates this G-protein by stimulation of a GTPase activity and reverses the activation of G-protein induced by IP3 or caffeine. (vi) PGE1 competes with the inhibitory effect of indomethacin on GTPase activity and PGE1 itself activates G-protein through inhibition of GTPase activity. From these results, it could be suggested that caffeine or IP3 induces Ca2+ release from the SR via activation of G-protein, which affects the Ca2+ channel and cAMP which seems to affect G-protein via A-kinase.

Alprostadil↗
PubMed1991

Caffeine rapid cooling contractures and negative force staircase in rat papillary muscle.

In rat papillary muscle, rapid cooling causes membrane depolarization which initiates action potentials that lead to a contraction. This rapid cooling contraction (RCC) can be blocked by TTX, Mn2+, Ni2+ or high K+ superfusion. In the presence of caffeine (0.5-1 mM), the rapid cooling contracture (caffeine-RCC) has an amplitude similar to that of a twitch elicited by field stimulation at 37 degrees C, but is not inhibited by these agents. As the caffeine-RCC appears to be independent of membrane depolarization and Ca influx but can be inhibited by increasing the bathing caffeine concentration to 20 mM, we consider that the amplitude of this contracture gives a good indication of the calcium content of the sarcoplasmic reticulum (SR). In Tyrode containing 1.8 mM Ca an increased stimulus frequency leads to a negative force staircase which is paralleled by a similar decrease in the amplitude of the caffeine-RCC. These effects are lost if the bathing Ca is reduced (0.18-0.45 mM) in a way which can be reversed by isoproterenol (100 nM). In verapamil (2 microM), however whilst the twitch responses may show a steeper dependence upon stimulus frequency, the negative frequency dependence of the caffeine-RCC is also lost. Low external Na+ also inhibits the frequency dependent reduction of the caffeine-RCC. The results suggest that if the amplitude of the caffeine-RCC is a good indication of the SR calcium content, then this Ca store is related reciprocally to membrane Ca current where activation of the Ca channels leads to a depletion of the store whereas inhibition of membrane Ca channels leads to a filling of the Ca store. We propose that on stimulation the size of the Ca influx determines the fraction of Ca released from the SR. This released Ca may be partially extruded from the cell by way of the Na/Ca exchange which acts in competition with the re-uptake mechanism of the SR to control SR Ca content.

Action Potentials↗
PubMed1982

Blood-brain barrier transport of caffeine: dose-related restriction of adenine transport.

We studied the transport of 14C-caffeine across the blood-brain barrier (BBB) by measuring brain 14C:3H ratios five seconds after rats received the caffeine, with 3H2O, by intracarotid injection. Caffeine was found to enter the brain by both simple diffusion and saturable, carrier-mediated transport. This latter observation suggested to us that caffeine's transport might involve macromolecules that are structurally similar to caffeine. Hence, we examined caffeine's ability to inhibit the BBB transports of 14C-adenosine and 14C-adenine. Caffeine caused a dose-dependent inhibition of 14C-adenine transport but no clear change in that of 14C-adenosine. At very high blood levels (Ki = 9.8 mM), caffeine may restrict the availability of circulating purines to the brain. This effect may be important neonatally, when carrier-mediated adenine transport apparently is maximal.

Adenine↗
PubMed1984

Effects of chronic caffeine on brain adenosine receptors: regional and ontogenetic studies.

The effect of chronic caffeine treatment on three different binding sites in five brain areas of mice is characterized. The sites studied were the adenosine receptor, using [3H] diethylphenylxanthine, the benzodiazepine receptor, using [3H] diazepam and the adenosine uptake site, using [3H] nitrobenzylthioinosine. Significant increases were only observed in adenosine receptors with the greatest degree of change seen in the cerebellum and brain stem at both 16 and 23 days of caffeine treatment. The lack of significant effects of chronic caffeine on benzodiazepine receptors and adenosine uptake sites indicates that the caffeine effect is specific. The effect of chronic caffeine treatment on the ontogeny of adenosine receptors was also studied with the result showing a significantly accelerated development of the receptor in the caffeine treated animals. The adult adenosine receptor levels were 20-30% higher than those observed in control animals. The observed alterations in adenosine receptor number which occur as a consequence of caffeine consumption may underlie some of the behavioral effects of this cortical stimulant as well as provide insights concerning the mechanisms of tolerance to and dependence on caffeine.

Adenosine↗
PubMed1989

Caffeine and regional brain monoamine utilization in mice.

Caffeine (100 and 200 mg/kg, 30 min., i.p.) selectively altered the regional utilization of monoamines in the brains of mice. This depended upon the specific neurotransmitter and metabolite studied. Caffeine increased serotonin (5HT) utilization a dramatic ten-fold in the OB but decreased 5HT utilization in the HT. No 5HT changes were seen in other brain regions. Caffeine markedly increased norepinephrine (NE) utilization in the olfactory bulbs (OB), olfactory tubercles (OT), prefrontal cortex (PC), amygdala (AMY), hypothalamus (HT) and hippocampus (HC). Caffeine increased dopamine (DA) utilization in the OB, OT, PC, septum (SP), HT and thalamus (TH) but by various metabolic routes. The selective regional alterations in monoamine utilization produced by caffeine may be relevant to caffeine's central stimulatory effects. Limbic structures are predominantly involved. These changes may have important clinical and research implications. For example, the profound effect of caffeine on OB monoamines indicates that it may serve as a meaningful tool in olfactory research, including the bulbectomy model. Caffeine may also be useful in other limbic system behavioral models.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Effects of caffeine on social behavior, exploration and locomotor activity: interactions with ethanol.

The effects of caffeine and its interaction with ethanol were examined in a test of social behavior and a holeboard test of exploration and locomotion. Male mice were injected i.p. with 15, 30 or 60 mg/kg caffeine alone or in combination with 2 g/kg ethanol. The animals were then put in pairs into a familiar arena, or examined individually in the holeboard. Only the highest dose of caffeine (60 mg/kg) had a significant effect on the time spent in social interaction and motor activity in the social behavior test: both measures were reduced. The duration and frequency of avoidance-irritability behavior was dose-dependently increased by caffeine. In the holeboard, caffeine caused a dose-dependent increase in locomotor activity. 30 mg/kg caffeine reversed the ethanol-induced reduction of time spent in social interaction, and 60 mg/kg caffeine antagonized the ethanol-induced increase in locomotor activity in both the social behavior and holeboard tests. Caffeine's effects on ethanol-induced behavioral changes are compared with those of other drugs.

Aggression↗
PubMed1983

Synergism between caffeine and gamma-radiation in the induction of dominant lethal mutations in oocytes and spermatozoa of Musca domestica.

Caffeine was studied with regard to its synergism with gamma-radiation in the induction of dominant lethal mutations in S14 oocytes and mature spermatozoa of M. domestica. In S14 oocytes an increase in the frequency of such a type of mutation was observed only when the exposure to gamma-radiation followed a pretreatment with a diet containing 0.2% of caffeine. Negative results were obtained with (a) post-treatment with the same kind of diet, (b) pretreatment with diets containing 0.1 and 0.02% of caffeine and (c) exposure to the radiation 6 h after interruption of the feeding treatment with the diet containing 0.2% of caffeine. Such influence of the conditions under which the treatment is performed and the synergistic effects is probably related to the food intake pattern and the rapid metabolism of the caffeine. When the 0.2% caffeine pretreatment was combined with an exposure of the oocytes to variable doses of gamma-radiation, the increments in the mutations observed seemed to be negatively correlated to the radiation doses used. Also, under such conditions, the dose/survival relationship fits well an exponential curve expressed by 1n y = -0.866x. With mature spermatozoa, synergism by caffeine was found only when the females, after having been mated with the irradiated males, were fed for 24 h on a diet supplemented with 0.2% of caffeine.

Animals↗