However, the data use agreement is designed to maximize transparency in the science, by requiring those who use the data resource to reference a versioned release of the data so that other investigators can repeat, expand, and challenge the results—particularly important in this era of renewed focus on scientific rigor and reproducibility. New standards for responsible use of large shared databases are emerging and are likely to guide editorial practices in the future, but the benefits of such databases for increasing transparency, enabling rapid replication, and generally accelerating scientific progress should outweigh the challenges. Finally, the ABCD Study may set new records for the number and disciplinary reach of scientists engaged by a single study. Over 200 investigators are actively engaged to date, and as the study evolves and the data emerge, a large number of additional scientists are expected to participate in the evolving design, data collection, analysis and interpretation, and many novel uses of the data. Furthermore, the availability of the data may draw scientists from wide-ranging disciplinary back grounds to the cause of understanding development of the human brain and finding innovative approaches for preventing adverse health and mental health outcomes and thus improving life trajectories.Chemotherapy-induced nausea and vomiting can be classified into three categories: acute onset, occurring within 24 h of the initial chemotherapy administration; delayed onset, occurring 24 h to several days after the initial treatment; and anticipatory nausea and vomiting . Anticipatory nausea develops in response to chemotherapy treatments,vertical cannabis farming in which cytotoxic drugs are delivered in the presence of a novel context . Developing in approximately 30% of patients by their fourth treatment , AN has traditionally been understood in terms of classical conditioning.
After one or more treatment sessions, a conditional association develops between the distinctive contextual cues of the treatment environment and the unconditioned stimulus of chemotherapy treatment that results in the unconditioned response of post-treatment illness experienced by the patient. Subsequent exposure to the treatment environment results in the patient experiencing a conditioned response of nausea and/ or vomiting before initiation of chemotherapy treatment. Once it develops, AN has been reported to be especially refractive to anti-emetic treatment . The evaluation of potential treatments for AN would be accelerated by the establishment of a reliable rodent model of nausea. Although rats are incapable of vomiting, they display characteristic gaping reactions when exposed to a flavoured solution previously paired with lithium induced nausea. In fact, this gaping reaction in the rat requires the same orofacial musculature as that required for vomiting in other species . Only drugs that produce emesis in species capable of vomiting produce conditioned gaping in rats, although many non emetic drugs produce conditioned taste avoidance . Furthermore, anti-emetic drugs interfere with the establishment of conditioned gaping reactions elicited by a nausea-paired flavor, presumably by interfering with the nausea .Not only are flavor cues capable of eliciting conditioned gaping reactions when paired with lithium chloride – induced nausea in rats, but recently Limebeer et al. have demonstrated that re-exposure to LiCl-paired contextual cues also elicit conditioned gaping reactions in rats. This paradigm more closely resembles that reported to produce AN in chemotherapy patients. Rats were injected with LiCl or saline before placement in a vanilla-odor laced chamber with lights and texture different than their home cage on each of four trials, separated by 72 h. To equate both groups for experience with illness, the rats in group unpaired were injected with LiCl and those in group paired were injected with saline 24 h after each conditioning trial but were then simply returned to their home cage. When the rats were returned to the conditioning context, 72 h after the final conditioning trial, rats in group paired showed the conditioned gaping reaction, as a measure of AN. Although classical anti-emetic treatments such as the 5- hydroxytryptamine-3 antagonist, Ondansetron , effectively reduce unconditioned nausea and vomiting, they are ineffective in the alleviation of conditioned nausea once it develops in humans . Indeed, OND also did not suppress the conditioned gaping reactions displayed during re-exposure to the LiCl-paired context .
Further more, using the emetic species, Suncus murinus as an animal model for AN, pre-treatment with a dose of OND that was shown to alleviate acute vomiting , did not reduce the display of conditioned retching reactions during re-exposure to a nausea-paired context . Thus, although OND has proven effective in the reduction of acute post-treatment nausea and vomiting, it does not appear to relieve conditioned nausea when it does develop. The endocannabinoid system has been implicated in control of nausea and vomiting . The psychoactive component in marijuana— delta-9-tetrahydrocannabinol —has been shown to interfere with the expression of vomiting in shrews and ferrets and conditioned gaping reactions elicited by a lithium-paired flavor in rats . The Δ9 -THC-induced suppression of conditioned nausea could be reversed by a CB1 receptor antagonist/reverse agonist , implicating the CB1 receptor in this effect . Limebeer et al. demonstrated that, unlike OND, Δ9 -THC also interfered with the expression of conditioned gaping elicited by the LiCl paired contextual cues in rats. This finding was consistent with the demonstration that Δ9 -THC, unlike OND, also suppressed the expression of conditioned retching in shrews when returned to a LiCl-paired context . The primary non-psychoactive compound found in marijuana, cannabidiol , has also been shown to suppress nausea and vomiting. In shrews, vomiting elicited by LiCl is suppressed by low doses of CBD, while higher doses were found to facilitate vomiting, rather than reducing its expression . Additionally, CBD reduced conditioned retching in shrews elicited by a lithium-paired context . In rats, a dose of 5 mg/kg CBD interfered with the establishment of conditioned gaping elicited by a LiCl paired flavor, as well as its expression . Because CBD has not been shown to bind with known CB receptors, this suppression of nausea and vomiting does not appear to be linked to activity of the CB1 or CB2 receptors . These results suggest that the primary nonpsychoac tive compound found in marijuana may be a useful treatment for conditioned nausea.
Arachidonylethanolamide or anandamide is an endogenous agonist for cannabinoid receptors which is rapidly degraded by the fatty acid amide hydrolase that is distributed throughout the brain and periphery . The action of AEA can be prolonged by inhibiting its degradation, through the use of URB597 , an FAAH enzyme inhibitor, that can increase basal levels of AEA in the rat brain . URB administration has been shown to reduce the establishment of conditioned gaping elicited by LiCl-paired saccharin solution in rats . Thus, prolonging the action of AEA with the FAAH inhibitor URB has been shown to suppress the establishment of conditioned nausea in rats. The experiments described below evaluated the potential of the non-psychoactive component of marijuana, CBD, and the FAAH inhibitor, URB, to interfere with conditioned gaping elicited by a LiCl-paired chamber in rats. On each of four conditioning trials,vertical farm company rats were injected with LiCl-paired immediately before placement in a distinctive context laced with the odor of vanilla extract. After the conditioning trials, the rats were injected with CBD or URB before placement in the distinctive CS context. Additionally, experiment 2 evaluated the potential of the CB1 antagonist/ inverse agonist, SR141716A , to reverse the suppression of conditioned gaping produced by URB. Finally, in experiment 3, the ability of URB to interfere with the establishment of conditioned gaping was also assessed. In each experiment, to ensure that the suppression of conditioned gaping was not merely an artefact of drug-induced suppression of general activity, the number of seconds that the rats remained immobile was recorded as a measure of activity. The doses of CBD were selected on the basis of our previous work demonstrating that these lower doses suppressed lithium induced vomiting in the shrew, but higher doses potentiated vomiting. Furthermore, a dose of 5 mg/kg of CBD interfered with the establishment and the expression of conditioned gaping elicited by a lithium paired flavour . The doses of URB were chosen based upon results showing that in vivo FAAH activity is blocked with a half-maximal inhibitory dose of 0.15 mg/kg ip with concurrent increase in brain AEA . Additionally, a dose of 0.3 mg/kg has been shown to attenuate the establishment of conditioned gaping elicited by a flavored stimulus .The subjects were male Sprague-Dawley rats and Long-Evans rats .
The change in strain across experiments coincided with a change in laboratory locations. There were no strain differences in baseline measures. The animals were group-housed in Plexiglas cages in the colony room at an ambient temperature of 21°C with a 12/12 light dark schedule and were maintained on an ad libitum schedule of food and water. All procedures adhered to the guidelines of the Canadian Council of Animal Care and were approved by the Animal Care Committee of University of Guelph.The distinctive context utilized for conditioning varied the dimensions of location, visual, tactile and olfactory cues from the home cage environment. The room was dark with two 50-Watt red lights on either side of the conditioning chamber. The conditioning chamber was made of opaque Plexiglas sides with an opaque lid. The chamber was placed on a table with a clear Plexiglas top. A mirror beneath the chamber on a 45° angle facilitated viewing of the ventral surface of the rat. Four plastic containers were permanently attached to holes on each side of the chamber in which a cotton dental roll saturated with vanilla flavour extract was placed to create the olfactory cue in the chamber. The cotton roll was inaccessible to the rat, with a newly saturated cotton roll used for each rat placed in the context.The rats received four conditioning trials, during which the contextual chamber was paired with 127 mg/kg LiCl. On each conditioning trial, each rat was injected with LiCl and immediately placed in the distinctive context for a 30-min period. This procedure was followed for a total of four conditioning trials, with 72 h between each trial.When re-introduced to a context previously paired with LiCl, rats display conditioned gaping ,a measure of conditioned nausea. The expression of this gaping reaction is not reduced by pre-treatment with a classic anti-emetic agent, OND, as has been reported by human chemotherapy patients; however, the psychoactive component in marijuana, Δ9 -THC, did suppress conditioned gaping elicited by a LiCl-paired chamber . In agreement with the gaping data with rats, Parker et al. reported that shrews display a conditioned retching reaction when re-introduced to a chamber previously paired with LiCl and this conditioned retching reaction was sup pressed by pre-treatment with Δ9 -THC or CBD, but not OND. The present findings provide additional support for the potential of cannabinoid treatments to suppress AN on the basis of results with the rat gaping model. Experiment 1 demonstrated that low doses of CBD that suppressed LiCl-induced vomiting and conditioned retching in the shrew as well as the establishment and the expression of gaping elicited by a LiCl-paired flavor in the rat , also suppressed the expression of gaping elicited by LiCl-paired context in the rat. A low dose of 5 mg/kg CBD has also been reported to serve as an effective anti-inflammatory agent , as well as a neuroprotective antioxidant . As CBD is a non-psychoactive component in marijuana, the ability of CBD to suppress conditioned gaping is promising for its use in the suppression of AN. The effective anti-nausea range of CBD appears to be narrow because at the highest dose tested , CBD did not suppress the expression of gaping elicited by a LiCl-paired context. Our previous work with the Suncus murinus revealed that although doses of 1–10 mg/kg CBD reversed LiCl-induced vomiting, higher doses potentiated LiCl-induced vomiting. It is possible, that CBD also produces a biphasic effect on the expression of conditioned gaping with lower doses reducing the expression of conditioned gaping, but higher doses enhancing the expression of gaping elicited by a LiCl-paired context. Experiments 2 and 3 demonstrated that the FAAH inhibitor, URB, also suppressed the display of AN as measured by gaping in rats. Presumably, prolonging the action of endogenous AEA produced an anti-nausea effect when rats were re-exposed to the LiCl-paired context. The effect of URB on the expression of conditioned gaping was dose-dependent, with 0.3 mg/kg serving as the effective dose.