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57-444: While the phrase gateway drug was first popularized by anti-drug activists such as Robert DuPont in the 1980s, the underlying ideas had already been discussed since the 1930s by using the phrases stepping-stone theory , escalation hypothesis , or progression hypothesis . The scientific and political discussion has intensified since 1975 after the publications of several longitudinal studies by Denise Kandel and others. In 2019,

114-586: A clinical professor of psychiatry at the Georgetown University School of Medicine , and founded the Anxiety Disorders Association of America . In 1981 he served as a paid consultant for Straight, Incorporated , one of the few drug treatment programs at that time that enrolled adolescents, which was criticized by some as a "controversial non-profit drug rehabilitation program", was the subject of numerous allegations of abuse, and which

171-453: A domesticated pet during the Edo period and in the 18th century guidebooks on keeping domestic rats were published by Youso Tamanokakehashi (1775) and Chingan Sodategusa (1787). Genetic analysis of 117 albino rat strains collected from all parts of the world carried out by a team led by Takashi Kuramoto at Kyoto University in 2012 showed that the albinos descended from hooded rats and all

228-451: A high (and very variable) rate, the study was considered flawed in design and its findings unsubstantiated. The biobreeding rat (a.k.a. the biobreeding diabetes-prone rat or BBDP rat) is an inbred strain that spontaneously develops autoimmune type 1 diabetes . Like NOD mice , biobreeding rats are used as an animal model for Type 1 diabetes. The strain re-capitulates many of the features of human type 1 diabetes and has contributed greatly to

285-626: A much higher rate compared to other strains, thus require less time for these behavioral studies. The Sprague Dawley is an outbred, multipurpose breed of albino rat used extensively in medical and nutritional research. Its main advantage is its calmness and ease of handling. This breed of rat was first produced by the Sprague Dawley farms (later to become the Sprague Dawley Animal Company ) in Madison, Wisconsin , in 1925. The name

342-542: A population with genetic variation is required, and these rats are usually referred to as "stocks" rather than "strains". The Wistar rat is an outbred albino rat. This breed was developed at the Wistar Institute in 1906 for use in biological and medical research, and is notably the first rat developed to serve as a model organism at a time when laboratories primarily used the house mouse ( Mus musculus ). More than half of all laboratory rat strains are descended from

399-426: A potential causal role of cannabis use, non shared environment factors could play a role in the association such as differing peer affiliations that preceded the cannabis use. Another twin study (of 510 same sex twin pairs) also examined the association of earlier cannabis use and later hard drug use. Like other studies it examined later drug use differences between siblings where one sibling had used cannabis early and

456-504: A research report by the National Institute on Drug Abuse determined that marijuana use is "likely to precede use of other licit and illicit substances", and cited a longitudinal study in which "adults who reported marijuana use during the first wave of the survey were more likely than adults who did not use marijuana to develop an alcohol use disorder within 3 years; people who used marijuana and already had an alcohol use disorder at

513-488: A sample of 6,624 people who had not used other illegal drugs before their cannabis consumption the overall probability of later use of other illegal drugs was estimated to be 44.7%. Subgroup analyses showed that personal and social conditions, such as gender, age, marital status, mental disorders, family history of substance use, overlapping illegal drug distribution channels, alcohol use disorder, nicotine dependence, ethnicity , urbanicity , and educational attainment influenced

570-453: Is coupled to a later increased risk of a transition from cocaine use to cocaine addiction. Controlled animal and human studies showed that caffeine ( energy drinks ) in combination with alcohol increased the craving for more alcohol more strongly than alcohol alone. These findings correspond to epidemiological data that people who consume energy drinks generally showed an increased tendency to take alcohol and other substances. According to

627-430: Is not random but shows trends . On the basis of established techniques of longitudinal studies such trends can be described precisely in terms of statistical probability . As to the interpretation of the observed trends, it is important to note the difference between sequence and causation. Both may – but need not – be coupled, a question which is subject of further research, e.g., by physiological experiments. From

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684-473: Is not unique to marijuana. Alcohol and nicotine also prime the brain for a heightened response to other drugs and are, like marijuana, also typically used before a person progresses to other, more harmful substances." On the other hand, the 2018 report issued by the National Institute of Justice states "that the current state of research on this issue is limited, and the studies that have been conducted suffer from difficulties in collecting information and applying

741-782: Is reflected by the amount of literature on it: roughly 50% more than that on laboratory mice . Laboratory rats are frequently subject to dissection or microdialysis to study internal effects on organs and the brain, such as for cancer or pharmacological research. Laboratory rats not sacrificed may be euthanized or, in some cases, become pets . Domestic rats differ from wild rats (various spp. of Rodentia ) in many ways: they are calmer and significantly less likely to bite, they can tolerate greater crowding, they breed earlier and produce more offspring, and their brains , livers , kidneys , adrenal glands , and hearts are smaller. Scientists have bred many strains or "lines" of rats specifically for experimentation. Most are derived from

798-483: Is the first known animal with inherited retinal degeneration. Although the genetic defect was not known for many years, it was identified in the year 2000 as a mutation in the gene MERTK. This mutation results in defective retinal pigment epithelium phagocytosis of photoreceptor outer segments. The shaking rat Kawasaki (SRK) is an autosomal recessive mutant that has a short deletion in the RELN (reelin) gene. This results in

855-615: Is uncommon, 83.2% of the people who used illicit substances did not use cannabis first. The concept received additional support from a large-scale genetic analysis that showed a genetic basis for the connection of the prevalence of cigarette smoking and cannabis use during the life of a person. The results of a twin study presented indications that familial genetic and familial environmental factors do not fully explain these associations, and are possibly only relevant for sequences of some drugs. In 219 same-sex Dutch identical and non-identical twin pairs, one co-twin had reported cannabis use before

912-425: The epidemiological observations in humans that nicotine consumption is coupled to an increased probability of later use of cannabis and cocaine, as well as other drugs. In rats, alcohol increased the probability of later addiction to cocaine and again relevant alterations in the reward system were identified. These observations thus correspond to the epidemiological findings that the consumption of alcohol in humans

969-621: The Hazelden Foundation . DuPont is a fellow of the American Society of Addiction Medicine and a life fellow of the American Psychiatric Association . He has described marijuana as "the most dangerous drug", a description contradicted by current scientific consensus. In 1958 DuPont earned his BA from Emory University and in 1963 earned his M.D. from Harvard Medical School . He completed training at Harvard and

1026-487: The Lewis are other well-known stocks developed from Wistars. The Long–Evans rat is an outbred rat developed by Long and Evans in 1915 by crossbreeding several Wistar females with a wild gray male. Long-Evans rats are white with a black hood, or occasionally white with a brown hood. They are utilized as a multipurpose model organism , frequently in behavioral research, especially in alcohol research. Long-Evans consume alcohol in

1083-757: The National Institutes of Health . He worked for the District of Columbia Department of Corrections and in 1970 for the DC Narcotics Treatment Administration. DuPont was the first Director of the National Institute on Drug Abuse from 1973 to 1978 and was the second White House Drug Czar from 1973 to 1977 under presidents Richard Nixon and Gerald Ford . In 1978 he founded the Institute for Behavior and Health, Inc. In 1980 he became

1140-439: The U.K. and New Zealand from 2015 and 2017 showed an association between cannabis use and an increased probability of later disorders in the use of other drugs. Students who regularly consume caffeinated energy drinks have a greater risk of alcohol use disorder, cocaine use and misuse of prescription stimulants. The elevated risk remains after accounting for prior substance use and other risk factors. A meta-analysis about

1197-409: The albino and hooded varieties. The first time one of these albino mutants was brought into a laboratory for a study was in 1828 for an experiment on fasting . Over the next 30 years, rats were used for several more experiments and eventually the laboratory rat became the first animal domesticated for purely scientific reasons. In Japan , there was a widespread practice of keeping rats as

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1254-404: The rat subspecies Rattus norvegicus domestica (Domestic Norwegian rat) which are bred and kept for scientific research . While less commonly used for research than laboratory mice , rats have served as an important animal model for research in psychology and biomedical science . In 18th-century Europe , wild brown rats ( Rattus norvegicus ) ran rampant and this infestation fueled

1311-690: The size and number of fat cells . Obesity in Zucker rats is primarily linked to their hyperphagic nature and excessive hunger; however, food intake does not fully explain the hyperlipidemia or overall body composition. A knockout rat (also spelled knock out or knock-out ) is a genetically engineered rat with a single gene turned off through a targeted mutation . Knockout rats can mimic human diseases, and are important tools for studying gene function and for drug discovery and development. The production of knockout rats became technically feasible in 2008, through work financed by $ 120 million in funding from

1368-622: The testicular tumors occurred in the rats from a single supplier. The researchers found that the incidence of tumors in Sprague Dawleys from different suppliers varied as much from each other as from the other strains of rats. The authors of the study "stressed the need for extreme caution in evaluation of carcinogenicity studies conducted at different laboratories and/or on rats from different sources." During food rationing due to World War II , British biologists had eaten laboratory rats, creamed. Scientists have also spent time studying

1425-427: The thermoregulation of the rat's tail in research. The rat's tail works as a variable heat exchanger. The tail's blood flow allows for thermoregulation to take place because it is under control of sympathetic vasoconstrictor nerves. Vasodilation occurs when the tail temperature increases, causing heat loss. Vasoconstriction occurs when the tail temperature decreases allowing heat to be conserved. Thermoregulation in

1482-418: The age of 18 whereas the other had not. In the cannabis group the lifetime prevalence of later reported use of party drugs was four times higher and the lifetime prevalence of later reported use of hard drugs was seven times higher than in the non-cannabis group. The authors concluded that at least family influences – both genetic and social ones – could not explain the differences. The study noted that, besides

1539-495: The albino Wistar rat , which is still widely used. Other common strains are the Sprague Dawley , Fischer 344 , Holtzman albino strains, Long–Evans , and Lister black hooded rats. Inbred strains are also available, but are not as commonly used as inbred mice. Much of the genome of Rattus norvegicus has been sequenced . In October 2003, researchers succeeded in cloning two laboratory rats by nuclear transfer . This

1596-553: The albinos descended from a single ancestor. As there is evidence that the hooded rat was known as the "Japanese rat" in the early 20th century, Kuramoto concluded that one or more Japanese hooded rats might have been brought to Europe or the Americas and an albino rat that emerged as a product of the breeding of these hooded rats was the common ancestor of all the albino laboratory rats in use today. The rat found early use in laboratory research in five areas: W. S. Small suggested that

1653-460: The concept of similar attitudes across different drugs ( common liability to addiction ), a number of personal, social, genetic and environmental factors can lead to a generally increased interest in various drugs. The sequence of first-time use would then depend on these factors. Violations of the typical sequence of first-time drug usage give credit to this theory. For example, in Japan, where cannabis use

1710-425: The development of genetic research techniques applicable to rats. A 1972 study compared neoplasms in Sprague Dawleys from six different commercial suppliers and found highly significant differences in the incidences of endocrine and mammary tumors. There were even significant variations in the incidences of adrenal medulla tumors among rats from the same source raised in different laboratories. All but one of

1767-474: The early 1950s. Characteristics include albino coloring, docile behavior, and low fertility. The Lewis rat suffers from several spontaneous pathologies: first, they can suffer from high incidences of neoplasms, with the rat's lifespan mainly determined by this. The most common are adenomas of the pituitary and adenomas/adenocarcinomas of the adrenal cortex in both sexes, mammary gland tumors and endometrial carcinomas in females, and C-cell adenomas/adenocarcinomas of

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1824-666: The field of substance abuse. He is president of the Institute for Behavior and Health, whose mission is "to reduce the use of illegal drugs". He has written books including Chemical Slavery: Understanding Addiction and Stopping the Drug Epidemic, The Selfish Brain: Learning from Addiction , as well as Drug Testing in Treatment Settings , Drug Testing in Schools , and Drug Testing in Correctional Settings , published by

1881-438: The findings to a larger population. The report further notes that although many of the reviewed studies found statistically significant associations between cannabis use and the users' later use of other illicit drugs, there is currently no conclusive evidence that cannabis use caused the later use of harder illicit drugs." The concept of gateway drug is based on observations that the sequence of first-time use of different drugs

1938-451: The height of probability. A study of drug use of 14,577 U.S. 12th graders showed that alcohol consumption was associated with an increased probability of later use of tobacco , cannabis , and other illegal drugs. Adolescents who smoked cigarettes before age 15 were up to 80 times more likely to use illegal drugs. Studies indicate vaping serves as a gateway to traditional cigarettes and cannabis use. Large-scale longitudinal studies in

1995-434: The importance of the findings from animal studies for the reward system in the human brain in relation to the liability to the use of further drugs has been pointed out in several reviews. In mice , nicotine increased the probability of later consumption of cocaine , and the experiments permitted concrete conclusions on the underlying molecular biological alteration in the brain. The biological changes in mice correspond to

2052-400: The industry of rat-catching. Rat-catchers would not only make money by trapping the rodents, but also by selling them for food or, more commonly, for rat-baiting . Rat-baiting was a popular sport, which involved filling a pit with rats and timing how long it took for a terrier to kill them all. Over time, breeding the rats for these contests may have produced variations in color, notably

2109-451: The likelihood of later hard drug usage. The study suggested that a causal role of cannabis use in later hard drug usage is minimal, if it exists at all, and that cannabis use and hard drug use share the same influencing factors such as genetics and environment. Robert DuPont Robert L. DuPont (born March 25, 1936, in Toledo, Ohio ) is an American psychiatrist, known for his advocacy in

2166-437: The litter of 17 drank and urinated excessively. Hairless laboratory rats provide researchers with valuable data regarding compromised immune systems and genetic kidney diseases. It is estimated that there are over 25 genes that cause recessive hairlessness in laboratory rats. The more common ones are denoted as rnu (Rowett nude), fz (fuzzy), and shn (shorn). The Lewis rat was developed by Margaret Lewis from Wistar stock in

2223-525: The lowered expression of reelin protein, essential for proper cortex lamination and cerebellum development. Its phenotype is similar to the widely researched reeler mouse. Shaking rat Kawasaki was first described in 1988. This and the Lewis rat are well-known stocks developed from Wistar rats. The Zucker rat was bred to be a genetic model for research on obesity and hypertension. They are named after Lois M. Zucker and Theodore F. Zucker, pioneer researchers in

2280-422: The observed trends were developed. The scientific discussion (state of 2016) is dominated by two concepts, which appear to cover almost all possible causal connections if appropriately combined. These are the theories of biological alterations in the brain due to an earlier drug use and the theory of similar attitudes across different drugs. Adolescent rats repeatedly injected with tetrahydrocannabinol increased

2337-422: The opposite. A 2016 review of 39 studies which examined the relation between cannabis use and alcohol use found that 16 studies support the idea that cannabis and alcohol are substitutes for each other, 10 studies found that they are complements, 12 found that they are neither complementary nor substitutes, and one found that they are both. A study involving self-reported data from a sample of 27,461 people examined

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2394-539: The original colony established by physiologist Henry Herbert Donaldson , scientific administrator Milton J. Greenman , and genetic researcher/embryologist Helen Dean King . The Wistar rat is currently one of the most popular rats used for laboratory research. It is characterized by its wide head, long ears, and a tail length that is always less than its body length. The Sprague Dawley and Long–Evans were developed from Wistars. Wistars are more active than others like Sprague Dawleys. The spontaneously hypertensive rat and

2451-412: The other had not. The study examined identical twins (who share approximately 100% of their genes) and non-identical twins (who share approximately 50% of their genes) separately and adjusted for additional confounders such as peer drug use. It found, after confounder adjustment, that the associations with later hard drug use existed only for non-identical twins. This suggests a significant genetic factor in

2508-435: The outset were at greater risk of their alcohol use disorder worsening." They further claimed that marijuana use "is also linked to other substance use disorders including nicotine addiction." While stating that their "findings are consistent with the idea of marijuana as a "gateway drug"", they conceded that "the majority of people who use marijuana do not go on to use other, "harder" substances", and that " cross-sensitization

2565-484: The rat tail has been used to study metabolism. A " strain ", in reference to rodents, is a group in which all members are, as nearly as possible, genetically identical. In rats, this is accomplished through inbreeding . By having this kind of population, it is possible to conduct experiments on the roles of genes, or conduct experiments that exclude variations in genetics as a factor. By contrast, " outbred " populations are used when identical genotypes are unnecessary or

2622-533: The rate of learning could be measured by rats in a maze ; a suggestion employed by John B. Watson for his Ph.D. dissertation in 1903. The first rat colony in America used for nutrition research was started in January 1908 by Elmer McCollum and then, nutritive requirements of rats were used by Thomas Burr Osborne and Lafayette Mendel to determine the details of protein nutrition . The reproductive function of rats

2679-638: The relationship of cannabis use and AUD. These respondents had no prior diagnosis of AUD. Of the 27,461 people, 160 had reported cannabis use within the past year. At the end of a three-year period, it found that those who had previously reported cannabis use were associated with a five times greater odds of being diagnosed with AUD than those who had not. After adjustment for select confounders (age, race, marital status, income, and education), these odds were reduced to two times greater risk. Another sample of self-reported data from 2,121 persons included only those who had already been diagnosed with AUD. In this sample, it

2736-537: The research of T1DM pathogenesis. The Brattleboro rat is a strain that was developed by Henry A. Schroeder and technician Tim Vinton in West Brattleboro , Vermont, beginning in 1961, for Dartmouth Medical School . It has a naturally occurring genetic mutation that makes specimens unable to produce the hormone vasopressin , which helps control kidney function. The rats were being raised for laboratory use by Henry Schroeder and technician Tim Vinton, who noticed that

2793-417: The self-administration of heroin (results based on 11 male rats and >50 male rats), morphine (study based on 12 male rats) and also nicotine (34 rats). There were direct indications that the alteration consisted of lasting anatomical changes in the reward system of the brain. Because the reward system is anatomically, physiologically , and functionally almost identical across the class of mammals ,

2850-591: The study of the genetics of obesity. There are two types of Zucker rat: a lean Zucker rat, denoted as the dominant trait (Fa/Fa) or (Fa/fa); and the characteristically obese (or fatty) Zucker rat or Zucker diabetic fatty rat (ZDF rat), which is actually a recessive trait (fa/fa) of the leptin receptor , capable of weighing up to 1 kilogram (2.2 lb) — more than twice the average weight. Obese Zucker rats have high levels of lipids and cholesterol in their bloodstream, are resistant to insulin without being hyperglycemic , and gain weight from an increase in both

2907-453: The thyroid gland and tumors of the hematopoietic system in males. Second, Lewis rats are prone to develop a spontaneous transplantable lymphatic leukaemia. Lastly, when in advanced age, they sometimes develop spontaneous glomerular sclerosis. Research applications include transplantation research, induced arthritis and inflammation, experimental allergic encephalitis, and STZ-induced diabetes. The Royal College of Surgeons rat (or RCS rat)

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2964-423: The use of e-cigarettes of 2018 said that "Because the term 'gateway' has historically been used in colloquial, non-scientific settings and lacks a clear definition, it is not used in this report". The role of cannabis use in regard to alcohol use and Alcohol Use Disorder (AUD) is still not fully understood. Some studies suggest better alcohol treatment completion for those who use cannabis, while other studies find

3021-399: Was found that those who had reported cannabis use in the past year (416 people) were associated with 1.7 greater odds of AUD persistence three years later. After adjustment for the same confounders as before, these odds were reduced to 1.3. Because a sequence of first-time use can only indicate the possibility – but not the fact – of an underlying causal relation, different theories concerning

3078-505: Was originally hyphenated, although the brand styling today (Sprague Dawley, the trademark used by Inotiv ) is not. The average litter size of the Sprague Dawley rat is 11.0. These rats typically have a longer tail in proportion to their body length than Wistars. They were used in the Séralini affair , where the herbicide RoundUp was claimed to increase the occurrence of tumor in these rats. However, since these rats are known to grow tumors at

3135-679: Was studied at the Institute for Experimental Biology at the University of California, Berkeley by Herbert McLean Evans and Joseph A. Long. The genetics of rats was studied by William Ernest Castle at the Bussey Institute of Harvard University until it closed in 1994. Rats have long been used in cancer research ; for instance at the Crocker Institute for Cancer Research . The historical importance of this species to scientific research

3192-711: Was successfully sued for false imprisonment and maltreatment. In 1982 he and Peter B. Bensinger founded Bensinger, DuPont & Associates, a national consulting firm. He maintains a psychiatric practice in Maryland specializing in addiction and anxiety disorders. His younger brother is Herbert L. DuPont , M.D. On July 14, 1962, in Hennepin County, Minnesota , Robert L. DuPont married Helen G. Spink, whose father Wesley W. Spink , M.D., mentored Herbert DuPont. Robert and Helen DuPont have two children. Laboratory rat Laboratory rats or lab rats are strains of

3249-477: Was the first in a series of developments that have begun to make rats tractable as genetic research subjects, although they still lag behind mice, which lend themselves better to the embryonic stem cell techniques typically used for genetic manipulation . Many investigators who wish to trace observations on behavior and physiology to underlying genes regard aspects of these in rats as more relevant to humans and easier to observe than in mice, giving impetus to

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