Caffeine is widely consumed for its psychoactive effects worldwide. No pre-clinical study has established reliable caffeine self-administration, but we found that caffeine can enhance the reinforcing effects of non-drug rewards. The goal of the present studies was to determine if this effect of caffeine could result in reliable caffeine self-administration. In 2 experiments rats could make an operant response for caffeine delivered in conjunction with an oral ‘vehicle’ including saccharin (0.2% w/v) as a primary reinforcer. In Experiment 1, intravenous (IV) caffeine infusions were delivered in conjunction with oral saccharin for meeting the schedule of reinforcement. In control conditions, oral saccharin alone or presentations of IV caffeine alone served as the reinforcer. In Experiment 2, access to caffeine was provided in an oral vehicle containing water, decaffeinated instant coffee (0.5% w/v), or decaffeinated coffee and saccharin (0.2%). The concentration of oral caffeine was then manipulated across testing sessions. Oral and IV caffeine robustly increased responding for saccharin in a manner that was repeatable, reliable, and systematically related to unit IV dose. However, the relationship between oral caffeine dose and operant behavior was less systematic; the rats appeared to titrate their caffeine intake by reducing the consummatory response (drinking) rather than the appetitive response (lever pressing). These studies establish reliable volitional caffeine self-administration in rats. The reinforcement enhancing effects of caffeine may help to explain widespread caffeine use by humans, who ingest caffeine in complex vehicles with reinforcing properties.

Indiana University-Purdue University Indianapolis (IUPUI) / Recently, the co-consumption of highly caffeinated energy drinks and alcohol has become a public health concern. Consumption of these beverages has been linked to a wide variety negative consequences including alcohol poisoning, driving under the influence, physical harm, and sexual violence. The more protracted consequences of caffeinated alcohol consumption have received very little attention, however. Some evidence suggests that individuals that frequently consume energy drinks mixed with alcohol are more likely to develop an alcohol use disorder. Interestingly, both caffeine and alcohol use alone have been linked to polydrug abuse. It is therefore of interest whether combined caffeine and alcohol consumption may pose an additive risk for substance abuse. Given that both compounds can positively influence dopamine signaling in mesolimbocortical reward circuitry via different mechanisms, this is an important question to address. Psychostimulants, such as cocaine, are of particular interest considering the significant involvement of dopamine in their effects. The current project explored this possibility employing an established mouse model of binge caffeine and alcohol co-consumption. Male C57BL/6J mice underwent 14 days of daily, 2hr limited access to water, alcohol, caffeine, or combined caffeine and alcohol. Water was freely available after these sessions. In Experiment 1, mice underwent an 11-day locomotor sensitization protocol for cocaine initiating on day 15. Locomotor sensitization has been associated with a greater propensity to self-administer psychostimulants in rodents. Mice were subjected to injections of cocaine (5 or 10 mg/kg; i.p.) or saline every other day, with 15 minute activity monitoring until day 25. In Experiment 2, a separate group of mice underwent an identical drinking procedure. A conditioned place preference (CPP) protocol commenced on day 15. CPP assesses the conditioned rewarding effects of cues associated with drugs of abuse. On day 15, mice received saline injections and were immediately placed onto a neutral floor texture (paper) in the place conditioning box for 15 minutes in order to habituate the animals to the apparatus and injection procedure. Starting on day 16, mice received daily alternating systemic injections of cocaine (1 or 5 mg/kg; i.p.) and saline or saline throughout (naïve controls) and were placed onto one of two particular tactile floor cues: a metal floor with holes punched out or a grid floor made of metal rods. Mice were exposed to the other injection/floor pairing on the alternate days. Mice were placed into these activity monitors for 15 minute conditioning sessions. These sessions alternated drug and vehicle over the course of 8 days so that a total of 4 drug and 4 saline injections were given. The first place preference test occurred on day 24 wherein all mice were injected with saline and offered access to both floor textures. On day 25, mice were returned to the conditioning protocol for another 8 days and a second CPP test on day 33. The results of Experiment 1 suggested that prior caffeine consumption, irrespective of the presence of ethanol, enhanced the initial psychomotor stimulating effect of 10 mg/kg cocaine. However, prior fluid consumption history did not influence the capacity to develop locomotor sensitization. The results of Experiment 2 indicate that prior caffeine and/or ethanol consumption had no influence on the development or expression of CPP for 1 mg/kg or 5 mg/kg cocaine. Collectively, these results suggest that a history of caffeine consumption may increase the stimulant response to a moderate dose of cocaine, perhaps indicating cross-sensitization. Although the conditioned rewarding effects of cocaine were not altered by prior caffeine and/or ethanol consumption, an enhanced stimulant response may be indicative of enhanced cocaine abuse potential. This study demonstrates that moderate caffeine consumption may influence an individual’s early interactions with cocaine which may eventually influence the likelihood of later problematic use.

The improvement of physical performance has long been a problem of great importance to athletes, coaches, and physical educators. Many different methods and techniques of coaching, conditioning, and motivation have been utilized in an effort to push the participant to his top or ultimate performance. There is much conjecture as to whether this optimum or top level of performance can be raised by artificial stimulation after peak condition has been reached and the skills involved in the performance have been mastered. According to Boke, stimulants are widely used today by athletes in all types of competition. He groups the substances used into four classes: (a Food preparations, including the sugars, vitamins, phosphates, and salts; (b) Oxygen; (c) Artificial sunshine; and (d) Pharmaceutical substances, including the ‘dopes’ which influence the nervous system, heart, and circulation.

This cross-sectional study aims to evaluate the association of caffeine intake with renal function among adults between ages 18-55. Participants of the National Health and Nutritional Examination Survey (NHANES) survey for the three consecutive years (2013-2014, 2015-2016, and 2017-2018) were used. A weighted multivariable linear regression analysis of the caffeine concentration was conducted. Greater intake was associated with lowered renal function. This association persisted when limiting the daily caffeine intake to 2000 mg/day or less. Among younger adults, ages 18 to 39 the beta coefficient was about 50 percent larger than the beta coefficient for individuals ages 40 to 55. This suggests that caffeine intake may have a greater impact on renal function among younger adults. While greater caffeine intake was associated with reduced renal function in this cross-sectional study, further investigation such as an experimental study should be performed to confirm the findings of this thesis. / Epidemiology

Cutaneous melanoma accounts for less than 5% of all skin cancers but over 75% of skin cancer related deaths. Prior biologic research suggests caffeine may arrest cancer cell formation and metastasis in vivo. Additionally, certain tea components exhibit anti-inflammatory, anti-oxidant, and other anti-carcinogenic effects. Prior epidemiologic studies show possible protective effect of both coffee and tea on risk of melanoma, but results remain inconsistent. We examined the association between coffee and tea intake and risk of cutaneous melanoma using the Women’s Health Initiative Observational Study. Coffee and tea intake were measured through self-administered questionnaires. Melanomas were self-reported and physician adjudicated. Cox proportional hazards models were used to evaluate associations. Of the 66,484 white post-menopausal women with no prior history of cancer (average follow up=7.8 years), 73% reported daily intake of coffee, 26% reported daily tea intake, and 398 cases of melanoma were adjudicated. Daily coffee intake (HR=0.84 95% CI=0.66-1.08) and daily tea intake (HR=1.00, 95% CI=0.78-1.29) were not significantly associated with increased risk of cutaneous melanoma compared to non-daily intake. No significant trend was observed with increased daily coffee (p-trend=0.22) or tea intake (p-trend=0.28). In conclusion, we observed insignificant inverse associations between coffee intake and cutaneous melanoma among post-menopausal Caucasian women.

No description available.

Caffeine is the most consumed psychoactive substance in the world, and most caffeine consumption in coffee and energy drinks is intended to produce a psychoactive effect. However, caffeine is not a primary reinforcer in preclinical paradigms – non-human species do not reliably take the drug to produce a psychoactive effect. However, caffeine is a ‘reinforcement enhancer’ in preclinical models; the effects of caffeine increase the motivation to obtain other non-drug reinforcers. The overall goal of this project was to determine if these reinforcement enhancing effects of caffeine could promote caffeine self-administration and to subsequently investigate the behavioral and neurochemical underpinnings of this effect. We hypothesized reliable caffeine self-administration would occur by adventitious pairing of caffeine with saccharin, a primary reinforcer. Second, we hypothesized that caffeine enhances reinforcement by increasing the salience of incentive stimuli, which are stimuli that come to evoke approach behaviors through associative learning (e.g., Pavlovian conditioning). Finally, incentive salience is moderated by dopamine release in the nucleus accumbens (NAc), an area highly involved in reward-learning and substance dependence. Therefore, we hypothesized that if caffeine enhanced control of approach behavior by incentives, then it would increase the ability of incentive stimuli to evoke dopamine in the NAc. These studies show that intravenous delivery of caffeine with oral saccharin increases operant relative to control groups responding for intravenous caffeine or oral saccharin. The effect was also dose-dependent, confirming that the psychoactive effects of caffeine increased behavior. We also extended this effect to an oral model of caffeine self-administration, which included a simple sweetener (saccharin) or a complex oral vehicle (saccharin with decaffeinated coffee) to mask the bitter taste of caffeine. Presenting caffeine with oral saccharin promoted self-administration, relative to saccharin alone and did not depend on the nature of the complexity of the vehicle. Caffeine also dose-dependently increased approach to an incentive stimulus and this effect was associated with increased extracellular dopamine in the NAc. These findings suggest caffeine enhances incentive motivation and that this effect may result from increases in CS-evoked striatal dopamine.

Skeletal muscle has the ability to increase in size (hypertrophy) after resistance is placed upon it. This hypertrophy is marked by significant upregulation of the mammalian target of rapamycin (mTOR) and its downstream targets. The upstream kinases, protein kinase B (also known as Akt) and AMP-activated protein kinase (AMPK), are two of the many regulators of the mTOR pathway. Recent studies suggest that the widely consumed neuroactive compound caffeine could potentially inhibit mTOR by acting through Akt and/or AMPK. The purpose of this thesis was to: 1) determine if caffeine can inhibit the mTOR pathway and ultimately attenuate skeletal muscle hypertrophy and 2) determine if this inhibition is through LKB1, an upstream regulator of AMPK. First, 3 month old male rats underwent unilateral tenotomy of the gastrocnemius, resulting in overloading (OVLD) of the synergistic plantaris muscle. The contralateral limb was sham-operated (SHAM) on. Rats were given ad libitum access to tap water or tap water + caffeine (1 g/L). The OVLD procedure resulted in significant hypertrophy of the plantaris which was attenuated after 1 wk of caffeine treatment. However, after two wks this effect was not observed. mTOR targets were examined in both the SHAM and OVLD plantaris muscle which showed significant upregulation with OVLD but no impact with caffeine treatment. Akt and AMPK was also assessed in the plantaris muscle which showed diminished Akt phosphorylation in 1 wk treated rats while the phosphorylation of AMPK remained relatively unaffected. Notably, caffeine caused decreased atrophy of the tenotomized gastrocnemius after 1 wk along with decreased body weight gains, food consumption, and retroperitoneal fat pad weight in both 1 and 2 wk treated rats. Second, to elucidate how caffeine could be impacting the mTOR pathway and how LKB1/AMPK might be involved, skeletal muscle specific LKB1 knockout (skmLKB1-KO) mice were subjected to high-frequency electrical stimulation (HFES) of the sciatic nerve resulting in contraction of the tibialis anterior (TA) and extensor digitorum longus (EDL) muscles against the larger gastrocnemius. All mice were given an intraperitoneal injection of saline or saline + caffeine (20 mg/kg BW at 1 g/L). HFES resulted in marked upregulation of mTOR targets in the TA/EDL of mice 0, 3, and 8 h post HFES. mTOR targets remained relatively unchanged with caffeine treatment. We also observed that these markers were consistently upregulated in our skmLKB1-KO mice with or without HFES. Our findings indicate that caffeine, at physiological concentrations, does not impact anabolic signaling. Furthermore, diminished LKB1 levels resulted in increased levels and activation of markers of protein synthesis.

Individuals with schizophrenia consume nearly three times more caffeine than the general population. In healthy controls, caffeine intake has been linked to better cognitive performance on several of the cognitive domains typically impaired in patients with schizophrenia. Despite this, only one prior study examined the association between caffeine intake and cognitive functioning in patients with a psychotic disorder. The current cross-sectional study compared moderate (0-250 mg/day) and high caffeine users (251 mg or more/day) on measures of cognitive functioning and symptomatology in 19 outpatients diagnosed with either schizophrenia or schizoaffective disorder. Participants were divided into one of the two caffeine groups based on their self-reported daily caffeine intake. Primary analysis was to compare moderate and high caffeine users on measures of cognitive functioning, namely working memory, sustained attention/vigilance, processing speed, verbal learning, and visual learning. Secondary analysis compared moderate caffeine users to high caffeine users on measures of symptomatology, namely positive symptoms, negative symptoms, and cognitive symptoms. Measures included the Cogstate battery and the Positive and Negative Syndrome Scale (PANSS). Independent samples t-test was used to examine potential differences between the two caffeine groups on measures of demographic and illness-related variables, cognitive functioning, and symptomatology. The results showed that, when assessing demographic and illness-related variables, participants with high caffeine consumption were prescribed higher antipsychotic doses and were more dependent on nicotine compared to participants with moderate caffeine consumption. With respect to cognitive functioning, participants with moderate caffeine consumption demonstrated better performance on a task measuring executive function (e.g., the Groton Maze Learning Test) compared to participants with high caffeine consumption. Finally, with respect to symptomatology, participants with high caffeine consumption demonstrated fewer negative symptoms compared to participants with moderate caffeine consumption. No other differences were discovered. In conclusion, the results from this study appear to suggest that moderate caffeine consumption, rather than high caffeine consumption, is associated with better cognitive functioning in patients with schizophrenia, while high caffeine consumption, rather than moderate caffeine consumption, is associated with fewer negative symptoms without necessarily exacerbating positive symptoms. The small sample size in this study limits the generalizability of its findings. More research is warranted.

Pollution is an increasing threat to health and biodiversity, especially chemical pollution in the air, land, and water. One such example is caffeine, which is a main active ingredient in coffee and is ingested by humans worldwide for its stimulant effects and cultural significance. This widespread caffeine ingestion coupled with incomplete removal during wastewater treatment results in high concentrations of caffeine in the environment. Aquatic organisms living in waterways receiving wastewater effluent are often exposed to caffeine continuously. Given this long-term and widespread exposure, caffeine is an emerging contaminant of concern. However, most research investigating the effects of caffeine on aquatic organisms use caffeine doses that are much higher and caffeine exposure durations that are much shorter than those found in the environment. Also, most caffeine exposure studies also rely on relatively simple behavioural endpoints and make use of neotropical species. In contrast, I exposed fathead minnow (Pimephales promelas), a common freshwater fish in North America, to environmentally relevant concentrations of caffeine (0 ng/L; 1,000 ng/L; 10,000 ng/l) for 35 days. Caffeine exposure did not affect morphology (e.g., length, mass, growth) or metabolism (maximum metabolic rate, resting metabolic rate, and aerobic scope), but decreased their hepatosomatic index (liver investment). While caffeine did not affect the number of trials taken to associative or reversal learn, or the latency of fish to avoid an aversive trawl, three weeks of exposure to low caffeine concentrations may have decreased anxiety. Taken together our results suggest that future studies perhaps with different endpoints are needed clarify our understanding of how caffeine influences metabolism, anxiety, and learning. Overall, our results provide evidence that complex behavioural endpoints such as aversive learning can be used in ecotoxicological studies. / Thesis / Master of Science (MSc) / Aquatic pollution has adverse effects on human and wildlife health, biodiversity and ecosystem function. One way aquatic pollution occurs is when the substances we consume, like caffeine, are not fully removed by wastewater treatment and enter water bodies. Concentrations of caffeine in the environment are high and yet caffeine’s effects on exposed organisms are seldom studied. To redress this, we investigated how environmentally relevant caffeine concentrations affected fathead minnow (Pimephales promelas), a common North American baitfish. Caffeine did not affect the growth rates, length, or mass of exposed fish, but exposure to low caffeine concentrations decreased liver investment. Caffeine did not influence fish metabolism or their ability to learn to avoid a negative stimulus (a trawl), but, at low concentrations, caffeine appeared to decrease anxiety. Our results show further research is needed to better understand caffeine’s effects on aquatic organisms.