Caffeine is the most widely consumed behaviorally active substance in the world. Almost all caffeine comes from dietary sources (beverages and food), most of it from coffee and tea. Acute and, especially, chronic caffeine intake appear to have only minor negative consequences on health. For this

Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use

Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects.

SUMMARY Cadmium (Cd) is a heavy metal found as an environmental contaminant, both through natural occurrence and from industrial and agricultural sources. Foodstuffs are the main source of cadmium exposure for the non-smoking general population. Cadmium absorption after dietary exposure in humans is relatively low (3–5 %) but cadmium is efficiently retained in the kidney and liver in the human body, with a very long biological half-life ranging from 10 to 30 years. Cadmium is primarily toxic to the kidney, especially to the proximal tubular cells where it accumulates over time and may cause renal dysfunction. Cadmium can also cause bone demineralisation, either through direct bone damage or indirectly as a result of renal dysfunction. After prolonged and/or high exposure the tubular damage may progress to decreased glomerular filtration rate, and eventually to renal failure. The International Agency for Research on Cancer has classified cadmium as a human carcinogen (Group 1) on the basis of occupational studies. Newer data on human exposure to cadmium in the general population have been statistically associated with increased risk of cancer such as in the lung, endometrium, bladder, and breast. Cadmium bioavailability, retention and consequently toxicity are affected by several factors such as nutritional status (low body iron stores) and multiple pregnancies, preexisting health conditions or diseases. A health based guidance value for cadmium of 7 μg/kg body weight (b.w.) per week (Provisional Tolerable Weekly Intake (PTWI)) was established previously by the Joint 1 For citation purposes: Scientific Opinion of the Panel on Contaminants in the Food Chain on a request from the European

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Scientific Opinion of the Panel on Contaminants in the Food Chain

Methylxanthines are a group of phytochemicals derived from the purine base xanthine and obtained from plant secondary metabolism. They are unobtrusively included in daily diet in common products as coffee, tea, energetic drinks, or chocolate. Caffeine is by far the most studied methylxanthine either in animal or epidemiologic studies. Theophylline and theobromine are other relevant methylxanthines also commonly available in the aforementioned sources. There are many disseminated myths about methylxanthines but there is increased scientific knowledge to discuss all the controversy and promise shown by these intriguing phytochemicals. In fact, many beneficial physiologic outcomes have been suggested for methylxanthines in areas as important and diverse as neurodegenerative and respiratory diseases, diabetes or cancer. However, there have always been toxicity concerns with methylxanthine (over)consumption and pharmacologic applications. Herein, we explore the structure-bioactivity relationships to bring light those enumerated effects. The potential shown by methylxanthines in such a wide range of conditions should substantiate many other scientific endeavors that may highlight their adequacy as adjuvant therapy agents and may contribute to the advent of functional foods. Newly designed targeted molecules based on methylxanthine structure may originate more specific and effective outcomes.

https://www.mdpi.com/1420-3049/21/8/974/pdf/1

Structure-Bioactivity Relationships of Methylxanthines: Trying to Make Sense of All the Promises and the Drawbacks

The effects of diazepam (DZ) (0, 10, and 20 mg) and caffeine (CAF) (0, 200, 400, and 600 mg) alone and in combination were examined in nine healthy male subjects using a within-subject experimental design in which all subjects received all twelve possible dose combinations. Drug effects were assessed using various psychomotor and cognitive performance tasks, staff (observer) ratings of subject behavior, and subject ratings of mood and drug effect. DZ treatment alone impaired performance on all tasks and produced staff and subject ratings indicative of sedative drug effects. CAF treatment alone facilitated performance on two psychomotor tasks requiring rapid reaction speed and increased staff ratings of subject restlessness and subject ratings of tension, alertness, arousal, and CAF symptoms. CAF generally antagonized the DZ-induced ratings of sedation and impairment of psychomotor performance; however, CAF did not consistently antagonize the DZ impairment of immediate recall or delayed recognition memory performance. DZ antagonized the CAF-induced staff-rated restlessness, and subject-ratings of tension, alertness, arousal and CAF symptoms. The results generally support the hypothesis that DZ and CAF produce antagonistic effects through functionally opposing mechanisms, however, the observed effects of drug combinations are dependent on the specific doses being tested and on the measures of drug effect being examined.

Interactions of diazepam and caffeine: behavioral and subjective dose effects in humans.

Discriminative stimulus properties of methylxanthines and their metabolites in rats.

Rats were trained to discriminate either caffeine or theophylline from saline using a two-lever discrimination paradigm. Since methylxanthines have been found to interfere with agonist binding at both adenosine and benzodiazepine (BDZ) receptors, chlordiazepoxide (CDP) and L-PIA (an adenosine analog) were tested for generalization to and blockade of both xanthine cues. Neither L-PIA nor CDP generalized to either xanthine cue, although both produced dose-related decreases in response rate. CDP, but not L-PIA, produced dose-related decreases in drug-lever responses when combined with training doses of caffeine or theophylline. Response rates indicated a complex interaction between the xanthines and both L-PIA and CDP. When combined with the caffeine training dose, pentobarbital also produced a dose-dependent decrease in response rate but not in drug lever choices. Finally, papaverine generalized to the caffeine cue in a dose-dependent fashion. In a second experiment, rats trained to discriminate CDP from saline showed no generalization in L-PIA tests. CDP-appropriate responding was not significantly affected when the CDP training dose was combined with caffeine. These data indicate that: (a) methylxanthine interactions with L-PIA and CDP on response rate likely involve blockade of adenosine mechanisms; (b) the xanthine cue does not appear to depend on interactions with adenosine receptors; and (c) the xanthine cue may involve effects on cyclic AMP activity and/or interaction with the BDZ/GABA receptor complex.

Methylxanthine discrimination in the rat: possible benzodiazepine and adenosine mechanisms.

Twenty-one rats were trained to discriminate 32 mg/kg caffeine from saline in a two-lever drug discrimination task (variable ratio) while another ten rats were trained to discriminate 56 mg/kg theophylline from saline. For each group, dose-effect curves (% drug-lever responses and overall response rate) were obtained for both caffeine and theophylline. Significant dose-related generalization of each training drug was found for both the caffeine- and theophylline-trained rats. Concomitant dose-related decreases in overall response rate also were apparent. Similar dose-related effects were seen with cross-generalization tests for various doses of the other xanthine. The nature of the training session preceding the test session was found to have an effect on discrimination performance at intermediate test doses. Drug appropriate responding was higher and overall response rate was lower after saline- than after drug-training days. Such data may suggest the possibility of short-term tolerance to caffeine's cue. That the discriminative cue was specific to the xanthines was shown by the lack of generalization seen after either amphetamine or metrazol.

Drug discrimination and cross generalization between two methylxanthines.

Rats, trained to discriminate 32 mg/kg caffeine from saline in a two-lever operant task, were tested for the presence of caffeine-appropriate lever responding at various intervals after the intraperitoneal injection of 32 mg/kg caffeine. Following completion of all behavioral tests, caffeine plasma levels were determined in the same animals at the same intervals after caffeine administration. After injection, both caffeine levels and caffeine-appropriate responding showed rapid increases followed by a differential decline.

Harold E. Modrow

Papers

Discriminative stimulus properties of methylxanthines and their metabolites in rats.

Methylxanthine discrimination in the rat: possible benzodiazepine and adenosine mechanisms.

Drug discrimination and cross generalization between two methylxanthines.

Relationship between caffeine discrimination and caffeine plasma levels.