Plant defence compounds occur in floral nectar, but their ecological role is not well-understood. We provide the first evidence that plant compounds pharmacologically alter pollinator behaviour by enhancing their memory of reward. Honeybees rewarded with caffeine, which occurs naturally in nectar of Coffea and Citrus species, were three times more likely to remember a learned floral scent than those rewarded with sucrose alone. Caffeine potentiated responses of mushroom body neurons involved in olfactory learning and memory by acting as an adenosine receptor antagonist. Caffeine concentrations in nectar never exceeded the bees' bitter taste threshold, implying that pollinators impose selection for nectar that is pharmacologically active but not repellent. By using a drug to enhance memories of reward, plants secure pollinator fidelity and improve reproductive success.Many drugs commonly consumed by humans are produced by plants as a form of toxic defence against herbivores (1, 2). While plant-derived drugs like caffeine or nicotine are lethal in high doses (3-5), they have pharmacological effects at low doses that affect mammalian behaviour. For example, low doses of caffeine are mildly rewarding and enhance cognitive performance and memory retention (6). Interestingly, caffeine has been detected in low doses in the floral nectar and pollen of Citrus (7), but whether it has an ecological function is unknown.Two caffeine-producing plant genera, Citrus and Coffea, have large floral displays with strong scents and produce more fruits and seeds when pollinated by bees (8, 9). If caffeine confers a selective advantage when these plants interact with pollinators, we might expect it to be commonly encountered in nectar. We measured caffeine in the nectar of 3 species of Coffea (C. canephora, C. arabica, and C. liberica) and 4 species of Citrus (C. paradisi, C. maxima, C. sinesis, C. reticulata) using liquid chromatography-mass spectrometry (10, Fig. Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts S1A). When caffeine was present, its concentration ranged from 0.003 -0.253 mM. The median caffeine concentration in both genera was not significantly different (Fig. 1A, MannWhitney, Z = −1.09, P = 0.272). Caffeine was more common in the nectar of C. canephora than in C. arabica or C. liberica (Coffea: logistic regression χ 2 2 = 11.1, P = 0.004); it was always present in Citrus nectar. The mean total nectar sugar concentration ranged from 0.338-0.843 M (Fig. 1B, see Fig S1B for individual sugars). Caffeine concentration in nectar did not correlate with total sugar concentration (Pearson's r = 0.063, P = 0.596).We hypothesized that caffeine could affect the learning and memory of foraging pollinators.To test this, we trained individual honeybees to associate floral scent with 0.7 M sucrose and 7 different concentrations of caffeine and tested their olfactory memory. Using a method for classical conditioning of feeding responses (proboscis extension reflex, 11), bees...

In summary we believe sudden onset chest wall rigidity may be a significant and previously unreported factor leading to an increased mortality, from illicit IV fentanyl use. Fentanyl and norfentanyl ratios and concentrations suggest a more rapid onset of death given the finding of fentanyl without norfentanyl in many of the fatalities. Chest wall rigidity may help explain the cause of death in these instances, in contrast to the typical opioid-related overdose deaths. Intravenous heroin users should be educated regarding this potentially fatal complication given the increasingly common substitution and combination with heroin of fentanyl.

The decline of honeybees and other pollinating insects is a current cause for concern. A major factor implicated in their decline is exposure to agricultural chemicals, in particular the neonicotinoid insecticides such as imidacloprid. Honeybees are also subjected to additional chemical exposure when beekeepers treat hives with acaricides to combat the mite Varroa destructor. Here, we assess the effects of acute sublethal doses of the neonicotinoid imidacloprid, and the organophosphate acaricide coumaphos, on honey bee learning and memory. Imidacloprid had little effect on performance in a six-trial olfactory conditioning assay, while coumaphos caused a modest impairment. We report a surprising lack of additive adverse effects when both compounds were administered simultaneously, which instead produced a modest improvement in learning and memory.

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Increases in methadone and oxycodone related deaths have been recently documented in the United States. In response to these reports, the authors investigated cases over a six-year period in which postmortem toxicological analyses revealed the presence of methadone, hydrocodone, and oxycodone. The study was designed to determine whether regional methadone-associated mortality in Cuyahoga County reflected national trends and more specifically, to distinguish methadone mortality from other commonly used opioid analgesics. All records of decedents that were found to be positive for methadone, hydrocodone, and/or oxycodone in 1998-2003 were reviewed. The cause and manner of death and demographic information was compiled. The cases were divided into lethal intoxications and cases where a positive result was determined to be an incidental finding. Lethal intoxications as a result of only methadone, hydrocodone, or oxycodone were separated from polydrug intoxications. Thoroughout the study, an increase was observed in the number of positive cases. In contrast to recent national data, although the number of methadone-positive cases increased from 4 in 1998 to 18 in 2003, this did not result in an increase in methadone overdoses [1 death in 1998 (25%) to 4 deaths in 2003 (22%)]. Although the pharmacokinetic profiles differ, methadone, hydrocodone, and oxycodone lethal intoxications equally comprised 28-29% of cases in which these drugs were detected. There was an overlap in the range of blood concentrations observed for the drug-related death groups and the incidental finding groups. However, mean and median concentrations in oxycodone and hydrocodone related deaths were more than two times greater than those in non-drug-related deaths.