Caffeine potentiates the discriminative-stimulus effects of nicotine in rats

RATIONALE: Caffeine and nicotine are the main psychoactive ingredients of coffee and tobacco, respectively, with a high frequency of concurrent use in humans. OBJECTIVES: The aim of the present study was to examine the interaction of caffeine and nicotine in rats trained to discriminate nicotine from saline. METHODS: Two groups of male Sprague-Dawley rats ( n=8 per group) were trained to discriminate 0.4 mg/kg nicotine, SC, from saline under a fixed ratio schedule of food presentation. One group of rats was chronically exposed to caffeine (1.0 mg/ml) dissolved in their drinking water whereas the other group was exposed to tap water. Effects of IP injections of caffeine on nicotine-lever selection were subsequently examined. In separate groups of rats exposed to the same caffeine-drinking or water-drinking regimen, effects of caffeine pretreatment on nicotine plasma levels were evaluated. RESULTS: Although caffeine (1.0-30.0 mg/kg) did not generalize to nicotine when administered alone, it markedly potentiated discriminative-stimulus effects of the threshold dose of nicotine (0.05 mg/kg) in both water- and caffeine-drinking rats. Nicotine plasma levels were, however, not affected by acute or chronic caffeine exposure. CONCLUSIONS: Caffeine appears to enhance the discriminative-stimulus effects of the threshold dose of nicotine by a pharmacodynamic rather than a pharmacokinetic interaction. This suggests that caffeine consumption may be a contributing factor in the onset, maintenance of and relapse to tobacco dependence.     

Association of the Anxiogenic and Alerting Effects of Caffeine with ADORA2A and ADORA1 Polymorphisms and Habitual Level of Caffeine Consumption

Caffeine, a widely consumed adenosine A₁ and A_2A receptor antagonist, is valued as a psychostimulant, but it is also anxiogenic. An association between a variant within the ADORA2A gene (rs5751876) and caffeine-induced anxiety has been reported for individuals who habitually consume little caffeine. This study investigated whether this single nucleotide polymorphism (SNP) might also affect habitual caffeine intake, and whether habitual intake might moderate the anxiogenic effect of caffeine. Participants were 162 non-/low (NL) and 217 medium/high (MH) caffeine consumers. In a randomized, double-blind, parallel groups design they rated anxiety, alertness, and headache before and after 100 mg caffeine and again after another 150 mg caffeine given 90 min later, or after placebo on both occasions. Caffeine intake was prohibited for 16 h before the first dose of caffeine/placebo. Results showed greater susceptibility to caffeine-induced anxiety, but not lower habitual caffeine intake (indeed coffee intake was higher), in the rs5751876 TT genotype group, and a reduced anxiety response in MH vs NL participants irrespective of genotype. Apart from the almost completely linked ADORA2A SNP rs3761422, no other of eight ADORA2A and seven ADORA1 SNPs studied were found to be clearly associated with effects of caffeine on anxiety, alertness, or headache. Placebo administration in MH participants decreased alertness and increased headache. Caffeine did not increase alertness in NL participants. With frequent consumption, substantial tolerance develops to the anxiogenic effect of caffeine, even in genetically susceptible individuals, but no net benefit for alertness is gained, as caffeine abstinence reduces alertness and consumption merely returns it to baseline.     

Oxidative stress parameters in rats exposed to fluoride and caffeine

In our experiment, the 1-month effects of caffeine (Caff) and fluoride (F) administered separately and together on nitric oxide and total antioxidant status in serum, brain, liver and kidney of rats were investigated. Also, the influence of caffeine on fluoride excretion with urine was studied. Thirty adult male Wistar rats were divided into five equal groups of six each: (I) controls drinking tap water; (II) controls drinking tap water and receiving intragastrically 0.5 ml of tap water; (III) animals receiving 25 mg F/L in drinking water; (IV) animals receiving 4.7 mg Caff/kg bw/day; (V) animals receiving 25 mg F/L in drinking water and 4.7 mg Caff/kg bw/day. The applied fluoride caused increase of nitric oxide level (NO), intensified lipid peroxidation (TBARS) and decreased total antioxidant status in serum (TAS), brain, kidney and liver. Caffeine administered intragastrically, as an antioxidant, was relatively efficient in alleviating these adverse effects of F. In rats treated only with fluoride the F excretion in urine significantly increased in an exposure-time dependent-manner and did not change both in rats treated with Caff and co-exposed to Caff and F.     

Effect of long-term caffeine administration on depressive-like behavior in rats exposed to chronic unpredictable stress

Chronic unpredictable stress (CUS) was used to study the effects of a long-term treatment with either caffeine (8 mg/kg, orally) or desipramine (DMI) (10 mg/kg, intraperitoneally) in Wistar rats. The CUS procedure was applied for 6 weeks. Animals underwent a 2-week drug-free CUS procedure. Drugs were administered for 4 weeks alongside the stress and both drug and stress were continued throughout the behavioral testing period. CUS-exposed rats showed depressive-like behavior with reduced weight gain, reduced consumption of sucrose solution, increased immobility in the forced swimming test, and hypolocomotion in an open field. For the open field and elevated plus maze, calculation of an anxiety index confirmed that CUS increased anxiety, which was accompanied by an increase in the core temperature. DMI counteracted these physical and behavioral changes. Caffeine caused similar effects to DMI on weight gain, motor activity, anxiety level, and core temperature. In CUS-exposed rats, caffeine showed antidepressant and anxiolytic activity, accompanied by increased hippocampal dopamine and serotonin levels. However, no significant change in weight gain or core temperature was observed after caffeine treatment in CUS-exposed rats. These results suggest that, similar to the antidepressant DMI, long-term caffeine exposure exerts an antidepressant and anxiolytic effect in the CUS model. The involvement of the dopaminergic and serotonergic systems is discussed.     

Chronic caffeine prevents changes in inhibitory avoidance memory and hippocampal BDNF immunocontent in middle-aged rats

Beneficial effects of caffeine on memory processes have been observed in animal models relevant to neurodegenerative diseases and aging, although the underlying mechanisms remain unknown. Because brain-derived neurotrophic factor (BDNF) is associated with memory formation and BDNF's actions are modulated by adenosine receptors, the molecular targets for the psychostimulant actions of caffeine, we here compare the effects of chronic caffeine (1?mg/mL drinking solution for 30?days) on short- and long term memory and on levels of hippocampal proBDNF, mature BDNF, TrkB and CREB in young (3 month old) and middle-aged (12 month old) rats. Caffeine treatment substantially reduced i) age-related impairments in the two types of memory in an inhibitory avoidance paradigm, and ii) parallel increases in hippocampal BDNF levels. In addition, chronic caffeine increased proBDNF and CREB concentrations, and decreased TrkB levels, in hippocampus regardless of age. These data provide new evidence in favor of the hypothesis that modifications in BDNF and related proteins in the hippocampus contribute to the pro-cognitive effects of caffeine on age-associated losses in memory encoding. This article is part of a Special Issue entitled 'Cognitive Enhancers'.     

Effects of caffeine on alcohol-related changes in behavioural control and perceived intoxication in light caffeine consumers

Rationale

Caffeinated alcoholic beverages have been associated with increased risk of alcohol-related harms. However, few studies have examined these combined effects on behavioural control, which is believed to underlie many of the negative effects of alcohol consumption. In addition, studies have often omitted subjective measures, and none have directly assessed the role of caffeine consumer history.

Objectives

To examine the combined effects of alcohol and caffeine on measures of behavioural control and perceived intoxication in abstinent, light caffeine consumers.

Methods

Participants (n?=?28; 50% male) attended four sessions at which they consumed one of the following beverages in a randomised order: placebo, alcohol alone (0.6?g/kg), caffeine alone (2.0?mg/kg), and alcohol/caffeine. They completed measures of mood, intoxication, anxiety and alcohol craving before and after a task battery comprising measures of behavioural control and reaction time performance.

Results

Caffeine attenuated alcohol-related performance deficits on stop-signal accuracy, had no effect on go–no-go performance deficits, and worsened accuracy on the Stroop task. Caffeine did not influence absolute changes in perceived intoxication but there was suggestion that caffeine may have changed the nature of intoxication with increases in stimulation.

Conclusions

Caffeine appears to have mixed effects on alcohol intoxication that are task-dependent. We found increased stimulation in the alcohol/caffeine condition, supporting the contention that caffeinated alcoholic beverages enable an individual to drink for longer. Future research should model real world drinking behaviour by examining how these effects change across multiple drink administrations.     

Carcinogenicity and chronic toxicity of hydrazine monohydrate in rats and mice by two-year drinking water treatment

The carcinogenicity and chronic toxicity of hydrazine monohydrate was examined by administrating hydrazine monohydrate in drinking water to groups of 50 F344/DuCrj rats and 50 Crj:BDF₁ mice of both sexes for two years. The drinking water concentration of hydrazine monohydrate was 0, 20, 40 or 80 ppm (wt/wt) for male and female rats and male mice; and 0, 40, 80 or 160 ppm for female mice. Survival rates of each group of males and females rats and mice were similar to the respective controls, except female rats administered 80 ppm. Two-year administration of hydrazine monohydrate produced an increase in the incidences of hepatocellular adenomas and carcinomas in rats of both sexes along with hepatic foci. In mice, the incidences of hepatocellular adenomas and carcinomas were increased in females, and significantly increased incidences of hepatocellular adenomas in females administered 160 ppm were observed. Thus, hydrazine monohydrate is carcinogenic in two species, rats and mice. Additionally, non-neoplastic renal lesions in rats and mice and non-neoplastic nasal lesions in mice were observed.     

Oral caffeine consumption by rats: the role of flavor history, concentration, concurrent food, and an adenosine agonist.

Some determinants of caffeine consumption by rats were examined using the two-bottle choice test. To describe the role of flavor history, groups of eight rats each received one of three fluids as their only source of fluid beginning at 29 days of age and continuing throughout the experiments. One group ("water") received tapwater, a second group ("caffeine") received 0.5 mg/ml caffeine in tapwater, and a third group ("quinine") received 0.01 mg/ml quinine in tapwater. Two-bottle choice tests began when rats were 40 days old. In the initial tests, caffeine rats drank more caffeinated water than water rats. Quinine rats were midway between these two groups. On a second block of tests, quinine and water rats' caffeine consumption increased so that the three groups were indistinguishable. When 0.5 mg/ml caffeine was available for 24 h, about one third of the total fluid consumption was of caffeinated water for all three groups. The presence of food greatly increased both caffeine and water consumption across a range of caffeine concentrations spanning 0.125-4.0 mg/ml. Increasing caffeine concentration generally increased consumption of plain water and decreased that of caffeinated water (but not total caffeine consumed) for water rats. Caffeine rats generally drank more caffeine than water rats, largely due to a tendency toward increased consumption of the 0.5-mg/ml concentration. Consumption of caffeinated water peaked at 0.5 mg/ml and showed graded decreases at higher and lower concentrations. Caffeine consumption showed dose-related increases with presession administration of l-phenylisopropyl adenosine. The serines of experiments characterize some of the determinants of caffeine consumption in rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Development of an alternative non-obese non-genetic rat model of type 2 diabetes using caffeine and streptozotocin

BackgroundThe aim of the present study was to develop an alternative non-obese non-genetic rat model of type 2 diabetes (T2D).MethodsSix-week-old male SD rats were randomly divided into six groups, namely: Normal Control (NC), Diabetic Control (DBC), Caffeine 5 mg/kg BW + STZ (CAF5), Caffeine 10 mg/kg BW + STZ (CAF10), Caffeine 20 mg/kg BW + STZ (CAF20) and Caffeine 40 mg/kg BW + STZ (CAF40) and were fed a normal rat pellet diet and drinking water ad libitum throughout the experimental period. After a one week acclimatization period, diabetes was induced in the animals in DBC and all CAF groups with an injection (i.p.) of the respective dosages of caffeine (mg/kg BW) 15 min before the injection of STZ (65 mg/kg BW) when normal saline was injected to the DBC group instead of caffeine. The NC group received normal saline and buffer instead of caffeine and STZ, respectively. One week after the STZ injection, animals with non-fasting blood glucose > 300 mg/dl were considered as diabetic. Three weeks after the STZ injection, the animals in the CAF5 and CAF10 groups were eliminated from the study due to the severity of diabetes and the experiment was continued with the remainder groups for a 13 weeks period.Results and conclusionThe data of food and fluid intake, body weight, blood glucose, glucose tolerance test, HOMA-IR, HOMA-beta, serum insulin, fructosamine, lipid profile and organ specific enzymes, anti-diabetic drug response tests, and pancreatic histopathology suggest that CAF20 group can be a better alternative non-genetic model of non-obese T2D.     

Chronic icv oxytocin attenuates the pathological high anxiety state of selectively bred Wistar rats

Central oxytocin (OXT) has been shown to promote numerous social behaviours, to attenuate hormonal stress responsiveness of the HPA axis and to decrease anxiety. Wistar rats selectively bred for high (HAB) and low (LAB) anxiety-related behaviour, respectively, have been shown to represent a suitable animal model to study the underlying aetiology of psychopathologies like anxiety- and depression-related disorders. The goal of the present studies was to assess the effects of central OXT on anxiety- and depression-related behaviour in male and female HAB and LAB rats. Acute icv OXT (1 μg) or OXT receptor antagonist (OXT-A; 0.75 μg) administration did not affect anxiety-related behaviour in male or female HAB and LAB rats as assessed in the light-dark box. In contrast, chronic icv OXT infusion (10 ng/h; 6 d) attenuated the high level of anxiety-related behaviour in female, but not male, HAB rats, whereas chronic OXT-A infusion (7.5 ng/h; 6 d) increased anxiety-related behaviour in female, but not male, LAB rats. Neither acute nor chronic manipulation of the OXT system altered depression-related behaviour as assessed by the forced swim test. Combined, these results suggest that pharmacological manipulation of the brain OXT system is effective to attenuate extremes in trait anxiety in an animal model of psychopathological anxiety. Moreover, the data indicate that differences in the activity of the brain OXT systems between HAB and LAB rats may, at least partially, contribute to the opposing anxiety but not depression-related behaviour.     

Why are caffeinated alcoholic beverages especially risky?

PurposeEvidence suggests that people drink more alcohol and experience more adverse alcohol-related consequences (ARCs) on occasions when they also consume caffeine. The current study examined whether this increase in risk is a result of caffeine attenuating the subjective effects of alcohol intoxication (i.e., the masking hypothesis).MethodsUndergraduate students (n = 148) reported their drinking patterns using a modified Timeline Followback approach. For each recalled drinking occasion, alcohol consumption, caffeine consumption, perceived blood alcohol concentration, and ARCs were assessed. Generalized linear mixed models were used to examine the influence that alcohol and caffeine consumption had on perceived intoxication and the experience of ARCs.ResultsAt the occasion level, greater caffeine consumption was associated with increased consumption of alcohol and increased ARCs. There was also a significant curvilinear relationship between the amount of alcohol consumed and perceived intoxication, such that the more alcohol was consumed on each occasion the less each additional drink increased perceived intoxication. Increased caffeine consumption weakened the association between alcohol consumption and perceived intoxication and it also weakened the association between alcohol consumption and ARCs. Specifically, the weakest relationship between ARCs and alcohol consumption existed at the highest level of caffeine consumption (240+ mg). Caffeine increased subjective intoxication.ConclusionsThese findings do not support the masking hypothesis. Caffeine was strongly associated with ARCs when consumed at high doses and this effect does not appear to be the result of drinking more alcohol or underestimating one's blood alcohol content. Efforts to reduce caffeinated alcohol beverage use are greatly needed.     

Effects of Adolescent Caffeine Consumption on Cocaine Sensitivity

Caffeine is the most commonly used psychoactive substance, and consumption by adolescents has risen markedly in recent years. We identified the effects of adolescent caffeine consumption on cocaine sensitivity and determined neurobiological changes within the nucleus accumbens (NAc) that may underlie caffeine-induced hypersensitivity to cocaine. Male Sprague-Dawley rats consumed caffeine (0.3 g/l) or water for 28 days during adolescence (postnatal day 28–55; P28–P55) or adulthood (P67–P94). Testing occurred in the absence of caffeine during adulthood (P62–82 or P101–121). Cocaine-induced and quinpirole (D₂ receptor agonist)-induced locomotion was enhanced in rats that consumed caffeine during adolescence. Adolescent consumption of caffeine also enhanced the development of a conditioned place preference at a sub-threshold dose of cocaine (7.5 mg/kg, i.p.). These behavioral changes were not observed in adults consuming caffeine for an equivalent period of time. Sucrose preferences were not altered in rats that consumed caffeine during adolescence, suggesting there are no differences in natural reward. Caffeine consumption during adolescence reduced basal dopamine levels and augmented dopamine release in the NAc in response to cocaine (5 mg/kg, i.p.). Caffeine consumption during adolescence also increased the expression of the dopamine D₂ receptor, dopamine transporter, and adenosine A₁ receptor and decreased adenosine A_2A receptor expression in the NAc. Consumption of caffeine during adulthood increased adenosine A₁ receptor expression in the NAc, but no other protein expression changes were observed. Together these findings suggest that caffeine consumption during adolescence produced changes in the NAc that are evident in adulthood and may contribute to increases in cocaine-mediated behaviors.     

The combined effects of developmental lead and ethanol exposure on hippocampus dependent spatial learning and memory in rats: Role of oxidative stress

Either developmental lead or ethanol exposure can impair learning and memory via induction of oxidative stress, which results in neuronal damage. we examined the effect of combined exposure with lead and ethanol on spatial learning and memory in offspring and oxidative stress in hippocampus. Rats were exposed to lead (0.2% in drinking water) or ethanol (4 g/kg) either individually or in combination in 5th day gestation through weaning. On postnatal days (PD) 30, rats were trained with six trials per day for 6 consecutive days in the water maze. On day 37, a probe test was done. Also, oxidative stress markers in the hippocampus were also evaluated. Results demonstrated that lead + ethanol co-exposed rats exhibited higher escape latency during training trials and reduced time spent in target quadrant, higher escape location latency and average proximity in probe trial test. There was significant decrease in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities and increase of malondialdehyde (MDA) levels in hippocampus of animals co-exposed to lead and ethanol compared with their individual exposures. We suggest that maternal consumption of ethanol during lead exposure has pronounced detrimental effects on memory, which may be mediated by oxidative stress.     

Improvement of mitochondrial NAD+/FAD+-linked state-3 respiration by caffeine attenuates quinolinic acid induced motor impairment in rats: Implications in Huntington's disease

BackgroundChronic quinolinic acid (QA) lesions in rats closely resemble Huntington's disease like conditions. Oxidative stress and mitochondrial dysfunction have long been implicated in the neurotoxic effects of QA acting through N-methyl-d-aspartate (NMDA) receptors. Reports suggest that inhibition of adenosine A2A receptor function elicits neuroprotective effect in QA induced neurotoxicity in rats. Caffeine, a preferential A2A receptor antagonist imitates antioxidant like actions and exerts neuroprotective effects in various neurodegenerative conditions. Thus, the present study was designed to evaluate the neuroprotective effects of caffeine against QA induced neurotoxicity in rats.MethodsIn the present study, QA (200 nmol/2 μl saline) has been administered bilaterally to the striatum of rats followed by chronic caffeine (10, 20 and 40 mg/kg) administration for 21 days. Motor performance of the animals was evaluated in weekly intervals and subsequently after 21 days, the animals were sacrificed and measurement of mitochondrial complexes activity, respiration rate and endogenous antioxidant levels were carried out in the striatal region.ResultsSingle intrastriatal QA administration resulted in drastic reduction in body weight, marked motor impairment (decreased total locomotor activity in actophotometer and impaired grip strength in rotarod), increased oxidative stress, impaired mitochondrial complexes activities and decreased state 3 respiration (NAD⁺/FAD⁺-linked) in rats. However, chronic treatment of caffeine for 21 days significantly attenuated the QA induced behavioural, biochemical and mitochondrial alterations displaying neuroprotective efficacy.ConclusionThe study highlights the possible involvement of A2A receptor antagonism in the neuroprotective effect of caffeine against QA induced mitochondrial dysfunction and oxidative stress in rats.     

Chronic caffeine exposure potentiates nicotine self-administration in rats

The prevalence of tobacco smoking and coffee drinking place nicotine and caffeine among the most used licit drugs in many societies and their consumption is often characterised by concurrent use. The pharmacological basis for any putative interaction between these drugs remains unclear. Epidemiological reports support anecdotal evidence, which suggests that smokers consume caffeine to enhance the euphoric effects of nicotine. The aim of the present experiment was to examine effects of chronic exposure to caffeine on responding maintained by nicotine. Sprague-Dawley rats consuming caffeine (approximately 150–180 mg/kg per day) in their drinking water for 7 days prior to the beginning and throughout behavioural testing acquired intravenous nicotine self-administration (0.03 mg/kg per infusion) more rapidly than did controls. In a cross-over design, exclusion of caffeine brought levels of nicotine self-administration back to baseline, while adding caffeine to the drinking water of control rats increased responding maintained by nicotine over 90%. These findings strongly suggest that caffeine can potentiate the reinforcing properties of nicotine, thus highlighting the importance of environmental factors in shaping and maintaining tobacco smoking. Received: 11 November 1997/Final version: 28 September 1998     

N-acetylcysteine in high-sucrose diet-induced obesity: Energy expenditure and metabolic shifting for cardiac health

To study the effects of N-acetylcysteine (NAC, C₅H₉–NO₃S) on high-sucrose diet-induced obesity and its effects on energy metabolism and cardiac oxidative stress, male Wistar 24 rats were divided into four groups (n = 6): (C) given standard chow and water; (N) receiving standard chow and 2 g/l N-acetylcysteine in its drinking water; (HS) given standard chow and 30% sucrose in its drinking water, and (HS-N) receiving standard chow, 30% sucrose and N-acetylcysteine in its drinking water.After 30 days of the treatment, obesity was evidenced in HS rats from enhanced body weight, respiratory quotient, hypertriglyceridemia. As well depressed resting metabolic rate, and oxygen consumption per surface area. HS rats had triacylglycerol accumulation, oxidative stress and metabolic shifting in cardiac tissue. NAC enhanced fat oxidation and energy expenditure, normalizing these adverse effects, comparing HS-N and HS rats. The beta-hydroxyacyl coenzymne-A dehydrogenase activity was higher in HS-N animals, indicating higher heart fatty acid degradation than in HS. NAC normalized myocardial glycogen and lactate dehydrogenase activity, comparing HS-N and HS rats, but had no effects on calorimetric and biochemical parameters in standard-fed rats, comparing N and C groups.In conclusion, N-acetylcysteine offers promising therapeutic value in prevention of high-sucrose induced-obesity and its effect on cardiac tissue. N-acetylcysteine reduced the oxidative stress and prevented the metabolic shifting in cardiac tissue, enhancing fatty acid oxidation and reducing anaerobic metabolism in high-sucrose-fed conditions. The application of this agent in food system via exogenous addition may be feasible and beneficial for antioxidant protection and energy metabolism in cardiac tissue.     

Effects of hot tea, coffee and water ingestion on physiological responses and mood: the role of caffeine, water and beverage type

Psychopharmacological studies using caffeinated beverages or caffeine have rarely considered temporal effects on psychological and physiological function or the specific contribution of caffeine, hot water, or beverage type to the observed effects. The effect of 400 ml hot tea, coffee, and water consumption on systolic and diastolic blood pressure (SBP and DBP), heart rate, skin conductance (a measure of sympathetic nervous system activation), skin temperature, salivary cortisol, and mood were monitored in 16 healthy caffeine-withdrawn (14 h) subjects in a complete crossover design. Beverages were ingested with/without 100 mg caffeine and milk (tea/coffee only). Hot beverage ingestion rapidly increased skin conductance and temperature (+1.7°C) with peak effects observed only 10–30 min post-consumption. Caffeine in the beverage rapidly augmented skin conductance responses but, in contrast to the effect of hot water, reduced the skin temperature response and increased SBP (+2.8 mmHg) and DBP (+2.1 mmHg) 30–60 min post-consumption. Both caffeine and milk addition to beverages independently improved mood and reduced anxiety 30 and 60 min post-consumption. Milk addition had no other effects apart from attenuating the transient increase in physiological responses associated with the drinking phase. There were no effects of beverage consumption on salivary cortisol or of beverage vehicle on salivary caffeine levels, the latter indicating that caffeine pharmacokinetics was similar in both tea and coffee, and not different from caffeinated water. In keeping with this, the responses to tea and coffee ingestion were similar and largely accounted for by the effects of hot water and caffeine. However, tea potentiated the increase in skin temperature compared to coffee and water indicative of a greater vasodilatory response plausibly related to the presence of flavonoids in tea. We conclude that ingestion of hot caffeinated beverages stimulates physiological processes faster than hitherto described, primarily via the effects of hot water and caffeine, but with beverage type and milk playing important modulatory roles. Received: 15 March 1997/Final version: 23 May 1997     

Caffeine as an intensifier of stress-induced hormonal and pathophysiologic changes in mice

Psychosocially stressed male mice competing in a Henry-Stephens complex population cage develop hypertension, cardiovascular damage, and chronic interstitial nephritis. Their plasma renin, noradrenaline, corticosterone, and adrenal-catecholamine synthetic enzymes are increased and they die prematurely. Adding 3.3 mg of caffeine a day per kilogram of mouse body weight (the equivalent of 20 μg/ml decaffeinated coffee) to their drinking water significantly intensifies most of these changes. A dose of 90 mg/kg of caffeine (the equivalent of 560 μg/ml, i.e., brewed tea or coffee) further increases the effects. The drug-induced enhancement of competitive social stimulation of the neuroendocrine system resulted in a further increase of plasma renin and corticosterone levels as well as blood pressure and adrenal weight. These effects together with accelerated mortality and increased pathology indicate that chronic consumption of caffeinated liquids adds to the risks of psychosocial stress.     

Faster but not smarter: effects of caffeine and caffeine withdrawal on alertness and performance

Rationale

Despite 100 years of psychopharmacological research, the extent to which caffeine consumption benefits human functioning remains unclear.

Objectives

To measure the effects of overnight caffeine abstinence and caffeine administration as a function of level of habitual caffeine consumption.

Methods

Medium-high (n?=?212) and non-low (n?=?157) caffeine consumers completed self-report measures and computer-based tasks before (starting at 10:30 AM) and after double-blind treatment with either caffeine (100 mg, then 150 mg) or placebo. The first treatment was given at 11:15 AM and the second at 12:45 PM, with post-treatment measures repeated twice between 1:45 PM and 3:30 PM.

Results

Caffeine withdrawal was associated with some detrimental effects at 10:30 AM, and more severe effects, including greater sleepiness, lower mental alertness, and poorer performance on simple reaction time, choice reaction time and recognition memory tasks, later in the afternoon. Caffeine improved these measures in medium-high consumers but, apart from decreasing sleepiness, had little effect on them in non-low consumers. The failure of caffeine to increase mental alertness and improve mental performance in non-low consumers was related to a substantial caffeine-induced increase in anxiety/jitteriness that offset the benefit of decreased sleepiness. Caffeine enhanced physical performance (faster tapping speed and faster simple and choice reaction times) in both medium-high and non-low consumers.

Conclusions

While caffeine benefits motor performance and tolerance develops to its tendency to increase anxiety/jitteriness, tolerance to its effects on sleepiness means that frequent consumption fails to enhance mental alertness and mental performance.     

Effects of long-term caffeine consumption on renal function in spontaneously hypertensive heart failure prone rats

Our previous studies supported the hypothesis that prolonged administration of caffeine to animals with high-renin hypertension causes progressive deterioration of renal function. However, thus far this hypothesis has been tested with only a few animal models of hypertension. The aim of this study was to test this hypothesis further by investigating the effects of long-term caffeine consumption on renal function in adult spontaneously hypertensive heart failure (SHHF/Mcc-fa(cp)) rats, another model of high-renin hypertension. Lean, male, 9-month-old SHHF/Mcc-fa(cp) rats were randomized to receive either normal drinking water (control group) or drinking water containing 0.1% caffeine (caffeine group) for 20 weeks. No changes in body weight, food and fluid intake, urine volume, and sodium and potassium excretion were found in conscious SHHF/Mcc-fa(cp) rats after 10 or 20 weeks of caffeine treatment. However, caffeine treatment accelerated the time-related decline in renal function and augmented urinary protein excretion. Ten weeks into the protocol, creatinine clearance was 3.6+/-0.4 and 5.7+/-0.9 L/kg/day in the caffeine group and control group, respectively (p<0.02), whereas 20 weeks into the study, creatinine clearance was similarly diminished in both groups. Proteinuria was greater in the caffeine group compared with the control group at both 10 (928+/-131 vs. 439+/-21 mg/kg/day, respectively; p<0.02) and 20 weeks (1,202+/-196 vs. 603+/-30 mg/kg/day, respectively; p<0.01) into the protocol. After 20 weeks, all animals were anesthetized and instrumented. Caffeine treatment for 20 weeks had no effects on blood pressure, heart rate, or vascular resistance in four examined vascular beds (abdominal aorta and renal, carotid, and mesenteric arteries). No changes in renal hemodynamics and electrolyte excretion were found, whereas significantly lower glomerular filtration rate (GFR; inulin clearance) and creatinine clearance (p<0.05) were observed in caffeine-treated animals. These data support our hypothesis that prolonged consumption of caffeine has adverse effects on renal function, in high-renin hypertension.