Consequences of chronic caffeine administration on ventilation and schedule-controlled behavior were studied in different people. In seated subjects trained with a head plethysmograph, ventilation was measured by the impact of air and elevated levels of CO2 in the mixed air (Richard J, pp 65-72). Marked acute administration of caffeine, a dose-dependent increase in ventilation provided normocapnia and hypercapnia. Nevertheless, in a daily dose of caffeine for consecutive days resulted in tolerance to its respiratory-stimulant effects, which were overcome at higher doses. Caffeine-tolerant subjects were also cross-tolerant to theophylline, an active metabolite of caffeine, as well as rolipram, selective inhibitors of phosphodiesterase. When chronic administration was terminated and was destined to acute effects of caffeine sensitivity returned to levels obtained before chronic administration for several days (Charles, pp 12-15). Acute administration of caffeine produced a significant increase in the rate impact on fixed interval measures, but chronic administration resulted in tolerance, which was irresistible, such that does not meet the dose increased control over the pace. Although the time course for development and the loss of resistance to the behavioral effects of caffeine corresponded closely with the breath, cross-tolerance does not extend to the behavioral effects of rolipram. Chronic administration of caffeine has little effect on caffeine metabolism or clearance, which indicated that caffeine tolerance, pharmacodynamic. Results indicate that different neurochemical mechanisms mediate the action of caffeine on respiration and behavior, and that inhibition of phosphodiesterase type IV plays an important role in caffeine-induced respiratory stimulation (Charles, pp 12-15).
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Caffeine is a methylxanthine alkaloid, which can be found naturally or artificially in a wide range of food products such as coffee, tea, chocolate and cola drinks. As a rule, are recognized for different bitter taste and for its properties as a stimulant of the central nervous system, heart and respiration. In America, 240mg of caffeine consumed per person per day from all sources (Charles, pp 12-15). Caffeine in its pure form it has no smell, but very bitter white powder. Medically it is simply recognized trimethylxanthine. Caffeine is sometimes called Theine (found in green tea), as is almost identical to the caffeine in coffee.
In connection with the widespread use of caffeine and related xanthines as components of food and beverages and as a medicine, the definition of the mechanisms that mediate its pharmacological effects has considerable relevance to the development of drugs and treatments. Numerous studies have shown that caffeine can have a significant influence on various behavioral measures, including the schedule-controlled behavior, drug self-delayed match to sample, and repeated acquisition (Sumner J, pp 456-465). In the range of doses, xanthines have significant behavioral-stimulant effects suggests central nervous system stimulation, whereas higher doses can suppress behavioral activity and behavioral performance related to disrupt learning and memory. Xanthines also expressed the respiratory stimulant effects, which were used for the treatment of respiratory diseases and experimental data indicate that the xanthines may act by affecting the central mechanisms controlling breathing. Both caffeine and theophylline increased minute volume and sensitivity to elevated levels of inspired CO2 (Laurel, pp 31-36). These effects were attributed to lower the threshold of the central chemo receptors sensitive to CO2, but not in the peripheral effects in the lung (Samantha J, pp 654-666).
Study of pharmacological tolerance during chronic drug administration has been effective approach to characterize the drug mechanism of action. A direct comparison between the pace of development and loss of tolerance, and altered sensitivity to drugs with selective action of neurochemical, can serve as a basis for comparing the mechanisms that mediate respiratory and behavioral effects of caffeine. Human and animal studies have reported the development of tolerance to CNS effects of caffeine, which include behavioral effects, and shoulder and cardiovascular effects (Laurel, pp 31-36). However, the mechanisms involved in caffeine tolerance poorly understood, and specific neurochemical substrates were not identified. Thus, the study established primate model of caffeine tolerance to investigate neurochemical mechanisms that mediate caffeine-induced changes in respiration and behavior. Effects of caffeine, compared with those of theophylline, xanthine with nonselective PDE inhibitory effects and the primary metabolites of caffeine in different people (Laurel, pp 31-36). In addition, caffeine pharmacokinetics was assessed before and after chronic administration of caffeine.
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Five adult male and seven adult female were considered. Between investigational gathering, subjects lived in individual home and were presented every day access to food and unrestricted access to water. Weight restrictions were not imposed. Subjects had been researched earlier under the common measures defined below and had established medicines.
Apparatus Respiration experiments
During the study collection, the subjects sat in a chair and primates, concluded in ventilated, sound-attenuating chamber. Ventilation was observed at constant pressure plethysmograph head movement, as described above. Sealed, Rectangular helmet is made of 1/16-inch Lexan with a gap for the collar was positioned over his head, and served as a force dislodgment plethysmograph. Continuous flow of gas is controlled by the flow meter, came into the helmet through the port in the face of the subject and was removed by a vacuum pump through the port for the head of the subject. Second flow meter monitoring the flow of gas produced by the pump. Modifications in the plethysmograph due to variations in ventilation considered stress sensor are connected to a polygraph. Polygraph integrator is converted to a flow signal that measure. Microcomputer involves a polygraph integrator and a polygraph examined and accumulated information. Respiratory rate (F) was resulted straight through including the modifications of the optimistic course of pessimistic courses (Laurel, pp 31-36). Minute ventilation (VE) is firmed through integrating the force compensated plethysmograph sign after calibration preconception for bias flow, and tidal volume (VT) was calculated as the quotient of the VE, M, T = VE / F. Continuous exhaust fan and white noise masked inappropriate sounds throughout every session.
Under experimental gatherings, subjects sat in a chair and primates, concluded in ventilated, sound-attenuating chamber. A bar is mounted on the front of the chair was equipped with a response lever and a couple of 5-W AC red and white light. The tail of the topic was held in the still small cuffs, and two brass plates resting on a shaved part near the end. Electrode paste a minimum of changes in resistance from the tail and brass plates at 10 mA electrical stimulus 200 ms duration was delivered (Laurel, pp 31-36). The microcomputer controlled experimental events and recording and storing data on diskettes. Continuous exhaust fan masked and white noise inappropriate sounds throughout every session.
Drug plasma levels were analyzed by a reverse-phase HPLC analytical system with a variable wavelength UV absorption detector and C-18, Spherisorb ODS-2 analytical column. Chemresearch microcomputer and system management software packages commanded HPLC system, monitoring brace for the absorption and determined the peak area (Robertson, pp 132-136).
Procedure Respiration experiments
Patients were adapted to the conditions of the experiment and the stable models of ventilation systems were installed prior to this study. Ventilation was recorded in isolated, undisturbed subjects breathing air for the initial 25 to 30 minutes. Subsequently, subjects were subjected to hypercapnia conditions under which the saline and drug injections were given to them in the thigh or calf muscles 30 minutes of each other, with the following sequence of Exposure Time: 10 minutes of air, 5 min 3% of CO2 in the air 5 minutes of 4% CO2 in the air 5 min of 5% CO2 in the air, and 5 min of air. The injection was given at the beginning of 10-min in the air, so that for the absorption and distribution of the drug before subjects were exposed to elevated CO2 concentration in the mixed air. Typically, two doses of the drug was studied during daily sessions lasting 2 to 3 hours, and drug experiments were conducted no more frequently than twice a week for each subject.
Patients were trained to press a response lever under the FI 300 sec schedule of stimulus termination with 10-sec limited hold. A red light illuminated the experimental chamber during the interval and the limited hold. If a question is answered in a limited to 300 seconds after the interval has expired, the white light illuminated for 2 seconds, followed by a 60-sec timeout during which the House was overshadowed by the responses and was not scheduled consequences. If no response within a limited Hold, electrical stimulation was delivered, and then 60 seconds timeout. Daily experimental session consisted of five successive components of the graph FI, and each component is included extended waiting period, after which three consecutive FIS. The total time session is approximately 140 minutes, and meetings are held 5 days a week. The effects of drugs on behavior were determined by the cumulative-dosing procedure similar to that described by researchers. Full dose-effect curve was established in the course of one session for each injecting drug sequential high-dose in the thigh or calf muscle. Saline and drug injections were administered at the beginning of the extended time-out periods. Typically, drugs, experiments were conducted on Tuesdays and Fridays, and saline (control) were administered on Thursdays. The impact of the full range of doses of each drug was determined at least twice in each subject. To prevent excessive presentation of stimulus presentation in connection with drug-induced violation of the answer, 10 mA source stimuli was turned off in the days when they were used cumulative-dosing procedures. Subjects received a rare presentation of a stimulus when connecting incentive units and responses were maintained when the stimulus was turned off the unit.
Subjects were trained to extend a leg through the front of the home for repeated blood withdrawals. After administration of 10.0 mg/kg caffeine, 1.0 ml of blood was withdrawn from the saphenous vein at 0.5, 1.0, 2.0, 6.0 and 24.0 hr post injection. Caffeine and two primary metabolites, theophylline and paraxanthine, were extracted and assayed by a procedure described previously (Ayala, pp 27-33). Whole blood was collected in vacutainer tubes and centrifuged at 3,000 rpm for 10 min. Serum was then aspirated into collection tubes, and 40 Î¼l of distilled water and 10 Î¼l of 60% per choleric acid were added to the sample. After the sample was vortexed and placed in the freezer for 10 min, an additional 350 Î¼l of distilled water was added, and the sample was centrifuged again. The supernatant was transferred to micro filtration tubes containing 0.45 Î¼m membranes and centrifuged a third time. The filtered product was then injected into the HPLC system with a mobile phase comprising 65% 50 mM sodium phosphate buffer and 35% methanol at a flow rate of 1.0 ml/min. The eluate was monitored for absorbance at 280 nm, and the limit of detection for caffeine and its metabolites was 200 ng/ml serums (Ayala, pp 27-33). Drug-free samples of blood were spiked with known quantities of drug and carried through the extraction procedure to calibrate the process and to determine the percentage yield of recovery.
On multiple occasions, caffeine was administered i.m. on a chronic, daily basis with each occasion separated by at least 4 weeks of drug abstinence. During the conduct of experiments, the daily dose of caffeine was administered 10 min pre session. To assess caffeine tolerance and drug cross-tolerance, the acute effects of caffeine and several other drugs were determined before and during chronic caffeine administration. When the acute effects of a drug were determined in caffeine-tolerant subjects, the daily dose of caffeine was not administered on that day. In respiration studies, the first series of experiments characterized the development and time course of caffeine tolerance. The second and third series of experiments determined whether caffeine tolerance was surmountable and investigated cross-tolerance to rolipram, respectively. The fourth series of experiments investigated cross-tolerance to theophylline during the second and third weeks of chronic caffeine administration, respectively. The last series of experiments investigated potential changes in base-line sensitivity to CO2 during chronic administration of caffeine. The daily dose of caffeine was administered post session in the latter experiments to preclude acute drug effects during CO2 determinations (Ayala, pp 27-33). Hence, subjects received chronic administration of caffeine on five separate occasions ranging from 8 to 21 days each (Ayala, pp 27-33).
In behavioral studies, the first series of experiments characterized the development and time course of caffeine tolerance, and the second series determined whether caffeine tolerance was surmountable. The third series of experiments investigated cross-tolerance to theophylline during the second week of chronic caffeine administration. The fourth series of experiments investigated cross-tolerance to rolipram and cocaine during the second and third weeks of chronic caffeine administration, respectively. In all cross-tolerance studies, the acute effects of each drug were determined immediately before chronic administration of caffeine to control for the influence of drug history. Hence, subjects received chronic administration of caffeine on four separate occasions ranging from 14 to 21 days each.
Results were calculated for individual subjects and combined to derive the mean for the group. In respiration studies, the last 3 min of each 5-min exposure to CO2 were used for information examine to permit time for ventilation to reach a steady position. In behavioral experiments, response rates were computed separately for each component by dividing the total number of responses in a component by the total time the red light was present. Mean control rates were determined for each person by averaging response rates for all saline control sessions. The effects of drugs on responding were expressed as a percent of control rate obtained when saline was administered. In pharmacokinetic experiments, caffeine half-life was calculated by least-squares linear-regression analysis of ln as a function of time where Ct = concentration at time t, Cpeak = peak concentration and ln. In some figures, the S.E.M. or 95% confidence limits were presented only for the control data to avoid figures that appeared cluttered and difficult to interpret.
The drugs studied were caffeine and theophylline, cocaine hydrochloride, rolipram and Ro 20-1724. Caffeine and theophylline were dissolved in 0.9% saline containing sodium benzoate, and doses are expressed in terms of the free base of the drugs. Ro 20-1724 was dissolved in 45% aqueous 2-hydroxypropyl-Î²-cyclodextrin. Cocaine and rolipram were dissolved in 0.9% saline. Injection volumes were 0.5 to 3.0 ml.
During control conditions when subjects breathed air alone, f averaged 19.0 Â± 1.5 breaths/min, VT averaged 78.9 Â± 9.8 ml and VE averaged 1.5 Â± .2 l/min for the group of three persons. Exposure to elevated levels of CO2 in air produced marked increases in ventilation above levels recorded during exposure to air alone. There was a concentration-dependent increase in f, VT and VE as inspired CO2increased to a maximum of 5% (Tondo, pp 494-503). During the first 2 to 3 min of subsequent exposure to air, ventilation decreased and returned to prior values. Polygraph tracings also illustrate caffeine-induced changes in ventilation. On the first day of chronic, daily administration of 10.0 mg/kg caffeine, there was a marked increase in ventilation during exposure both to air alone and to elevated levels of CO2 in air (Tondo, pp 494-503). However, caffeine had little effect on ventilation by day 8 of chronic administration.
Responding during the FI 300-sec schedule was characteristic of performance maintained under FI schedules of stimulus termination. Little or no responding occurred early in the interval, and the response rate increased as the interval elapsed (Barry, pp 355-361). Mean response rates during control sessions were 0.89 Â± 0.34, 0.40 Â± 0.14 and 0.37 Â± 0.10 response/sec for subjects. Caffeine produced significant increases in response rate to more than 200% of control values for the group of three persons during the first day of chronic administration (Barry, pp 355-361). However, the behavioral-stimulant effects of caffeine gradually diminished during 5 consecutive days, and by day 5, caffeine had no significant effect on FI responding. When chronic administration of caffeine was terminated on day 20, there was no obvious behavioral disruption characteristic of drug withdrawal.
Standard curves for caffeine and its metabolites were linearly related to peak areas over a range of 1.0 to 50.0 Î¼g/ml (Calamaro, pp 1005-1010). Chromatograms were completed in less than 10 min with reliable separation of peak retention times for caffeine, theophylline and paraxanthine at approximately 7.9, 5.3 and 4.9 min, respectively. The percent yield obtained during extractions of standards varied little among xanthines and ranged from 86.9% to 95.6% with a mean value of 92.4% Â± 1.7%. Before chronic administration, 10.0 mg/kg caffeine resulted in a peak plasma concentration of 8.6 Â± 0.6 Î¼g/ml at 30 min post injection for the group of six persons (Calamaro, pp 1005-1010). The calculated half-life of caffeine was 10.8 Â± 0.6 hr, and as caffeine plasma levels decreased, there was a corresponding increase in theophylline levels. No significant amount of paraxanthine was detected. At 24 hr post injection, only small amounts of caffeine were detected, whereas significant amounts of theophylline were still present. When caffeine pharmacokinetics was redetermined during the second week of chronic, daily administration of 10.0 mg/kg caffeine, neither the peak plasma concentration nor the calculated half-life of caffeine differed significantly from pre chronic conditions. However, theophylline levels were significantly greater throughout the 24-hr post injection period because of accumulation of theophylline from prior daily injections of caffeine. The results indicate that chronic caffeine administration had little effect on caffeine metabolism or clearance (Curt von, pp 148-154).
Discussion and Conclusion
The present study established a human primate model of caffeine tolerance to investigate neurochemical mechanisms that mediate the physiological and behavioral effects of caffeine. Chronic daily administration of caffeine resulted in tolerance to its respiratory- and behavioral-stimulant effects that developed gradually over several days, and was reversible when chronic administration was terminated (Robertson, pp 132-136). Caffeine tolerance appeared to be pharmacodynamic because no significant changes in caffeine metabolism or clearance were evident in caffeine-tolerant subjects. Although the time course for the development and loss of tolerance was similar for the respiratory and behavioral effects of caffeine, important characteristics of caffeine tolerance differed for respiration and behavior. Tolerance to the respiratory-stimulant effects of caffeine was surmountable and extended to the type IV PDE inhibitors, rolipram and Ro 20-1724. A high dose of caffeine produced significant increases in ventilation in caffeine-tolerant subjects, and the acute effects of rolipram and Ro 20-1724 were less pronounced during chronic caffeine administration (Hagen, pp 153-159). In contrast, tolerance to the behavioral-stimulant effects of caffeine was insurmountable and did not extend to rolipram. No dose of caffeine increased responding above control rates in caffeine-tolerant subjects, and the acute effects of rolipram were unchanged during chronic caffeine administration. The results indicate that different neurochemical mechanisms mediate the effects of caffeine on respiration and behavior, and that inhibition of type IV PDE plays a prominent role in caffeine-induced respiratory stimulation (Calamaro, pp 1005-1010).
Caffeine had pronounced effects on ventilation during conditions of normocapnia, and produced dose-dependent increases in f and VE during exposure to elevated levels of CO2 mixed in air such that the CO2 response curve was shifted upward in a parallel manner (Hagen, pp 153-159). The effects observed during hypercapnia are consistent with previous studies reporting that xanthines act by affecting central mechanisms controlling respiration. For example, caffeine increases the ventilatory response to CO2 in cats at levels of CO2 equal to or below the range, and theophylline increases the ventilatory response to CO2 in dogs during hypercapnia. Accordingly, a series of experiments investigated potential changes in baseline sensitivity to CO2 during chronic administration of caffeine to determine whether physiological adaptation resulted from repeated exposure to hypercapnia. When the chronic daily dose of caffeine was administered post session to preclude acute drug effects during CO2 determinations, caffeine-tolerant subjects exhibited CO2-induced increases in ventilation that were similar to those obtained in no tolerant subjects. The latter results indicate that caffeine tolerance was pharmacological and did not result from changes in baseline responsiveness to CO2.
In contrast to the respiratory-stimulant effects of caffeine and related xanthines, the behavioral-stimulant effects have been linked more closely to adenosine receptor antagonism than to PDE inhibition. In previous studies conducted in nonhuman primates, only xanthines with prominent adenosine-antagonist actions had significant behavioral-stimulant effects, and there was a close correspondence between the drug potencies for increasing response rate and for antagonizing the behavioral-suppressant effects of the adenosine receptor agonist, NECA. Selective PDE inhibitors that lacked adenosine-antagonist effects either suppressed behavior or had no behavioral effect. Consistent with these findings, rolipram only decreased response rate in the present study, and subjects tolerant to the behavioral-stimulant effects of caffeine were not cross-tolerant to rolipram. The pharmacological specificity of caffeine tolerance was exemplified further by the lack of cross-tolerance to the nonxanthine psychomotor stimulant, cocaine (Estevez, pp 164-173). In contrast to rolipram, acute administration of theophylline, a xanthine with adenosine-antagonist effects, had modest behavioral-stimulant effects similar to those of caffeine. Although there was no significant main effect of chronic caffeine treatment on the acute effects of theophylline, no dose of theophylline increased responding above control rates during chronic caffeine administration. Hence, there was some indication of cross-tolerance to theophylline in caffeine-tolerant subjects. However, the role of adenosine antagonism as a mechanism underlying tolerance to caffeine-induced stimulation of behavior remains undefined (Estevez, pp 164-173). Some investigators have reported an increase in the number of adenosine binding sites in brain during chronic administration of caffeine, whereas others have found no appreciable changes in the potency of caffeine as an adenosine antagonist in caffeine-tolerant animals.
In summary, chronic administration of caffeine resulted in tolerance to its respiratory- and behavioral-stimulant effects which developed gradually and was reversible. Caffeine pharmacokinetics was unchanged during chronic administration, which indicated that caffeine tolerance was pharmacodynamic. Tolerance to the respiratory-stimulant effects of caffeine was surmountable and extended to the type IV PDE inhibitors and rolipram, whereas tolerance to the behavioral-stimulant effects was insurmountable and did not extend to rolipram. The outcomes describe that various neurochemical mechanisms mediate the results of caffeine on behavior and respiration and that inhibition of type IV PDE plays a main role in caffeine-induced respiratory stimulation.
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Sumner J, Yaffe; 2005 pp 456-465; Neonatal and pediatric pharmacology: therapeutic principles in practice; Publisher Lippincott Williams & Wilkins; ISBN 0781741858, 9780781741859. (article from book)
Richard J, Wurtman; 2008 pp 65-72; Physiological and behavioral effects of food constituents; Publisher Raven Press; Original from the University of Michigan; ISBN 0890047332, 9780890047330. (old)
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Robertson, Cushny; 2007 pp 132-136; A text-book of pharmacology and therapeutics; Publisher Lea & Febiger; Original from Harvard University. (1918)
Charles, Edward; 2006 pp 12-15; Journal of bacteriology; Society of American Bacteriologists; Publisher American Society for Microbiology; Original from the University of Michigan.
Ayala, J; 2009; Quantitative determination of caffeine and alcohol in energy drinks and the potential to produce positive transdermal alcohol concentrations in human subjects. Journal of Analytical Toxicology 27-33. (article)
Tondo, L; 2009 pp 494-503; Coffee and cigarette use: Association with suicidal acts in 352 Sardinian bipolar disorder patients; Bipolar Disorders. (article)
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Estevez, E; 2009 pp 164-173; Caffeine during exercise in the heat: Thermoregulation and fluid-electrolyte balance; Medicine and Science in Sports and Exercise 41. (article)
Hagen, K; 2009 pp 153-159; High dietary caffeine consumption is associated with a modest increase in headache prevalence; results from the Head-HUNT Study; Journal of Headache and Pain . (article)
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