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Metabolite may play a role in nicotine addiction

A substance that scientists identify to screen people for nicotine use may also play a role in smokers becoming addicted to tobacco, writes Christie Delfanian for South Dakota State University in the United States.

“When you smoke, nicotine is converted into a metabolite called cotinine,” explained South Dakota State University Psychology Professor Brady Phelps. Even those who inhale second hand smoke can test positive for cotinine. The metabolite is measured in urine, saliva and blood.

"Cotinine remains in the body much longer than nicotine," Phelps said. The half-life – the amount of time it takes for half of the substance to leave a person's system – is about 15 hours for cotinine, but approximately two hours for nicotine, according to Mayo Medical Laboratories.

Phelps and Associate Professor Tyler M Miller worked with Professor Shafiqur Rahman of the Department of Pharmaceutical Sciences to study how cotinine affects the behaviour of flat worms called planarians. Pharmacology Professor Scott M. Rawls of the Center for Substance Abuse Research at Temple University was also part of the research team.

"Preliminary evidence suggests that nicotine dependence may involve more than just nicotine," Phelps said. "Cotinine may be amplifying or contributing to the addictive properties of nicotine." Study results were published online in March and will appear in print in the June 2019 issue of Neuroscience Letters.

Six undergraduate students worked on the project, which was supported by the SDSU Research and Scholarship Support Fund.

"Planarians are commonly used as an animal model to study the effects of a drug with addiction potential," Phelps explained. "If given a choice, these aquatic worms prefer a dark environment – they display behavior described as being very light phobic or a negative phototaxis response."

To test the addictive nature of this nicotine metabolite, the researchers immersed the aquatic worms in solutions containing three levels of cotinine under light for 10 minutes. The concentration levels mirrored those used to assess the worms' responses to nicotine in a study which Rawls conducted.

Pairing light with drug exposure has the potential to change the planarian's behavior, a technique called conditioned place preference. If the light phobic behavior is reversed and the worms have acquired a preference for an environment paired with light, this is evidence of a conditioned place preference, Phelps explained.

The conditioned place preference has been used in many other animal species, including mammals, and is one way to assess a compound's rewarding or addictive properties. With very few exceptions, drugs that establish a conditioned place preference will also serve as a reward for drug-self-administration, another widely used technique to assess addiction potential.

The study showed planarians exposed to cotinine, regardless of the level, spent significantly more time in the light than those in the control group. "This is the first demonstration that cotinine will establish a conditioned place preference in planarians," Phelps said. "There may be more to nicotine dependence than just nicotine—cotinine may be a contributing factor." However, he cautioned, "These data are preliminary and must be followed up on with other studies."

Preliminary evidence from planarians that cotinine establishes a conditioned place preference

Neuroscience Letters


Brady J Phelps, Tyler M  Miller, Heath Arens, Tayler Hutchinson, Kaitlyn A.Lang, Linda M.Muckey, NicholasThompson, StevenStanage, ShafiqurRahmanand Scott M Rawls.


  • The metabolites ofnicotine have not been studied adequately, with cotinine being the primary nicotine metabolite.
  • Planarians have been used to study the effects of nicotine and were used in the present study to investigate cotinine’s effects.
  • Place learning orconditioned place preference is used to study the effects of drugs such as nicotine.
  • Nicotine will establish place learning and our data demonstrate for the first time that cotinine will establish place learning with planarians.
  • Our data suggest that cotinine may be contributing to nicotine’s effects.


While the psychoactive stimulant nicotine has been the subject of extensive research, considerably less attention has focused on other compounds found in either tobacco smoke or that are nicotine metabolites.

Recent papers have suggested that some of the compounds in question may either alter nicotine’s effects or have reinforcing properties themselves, although they would only be experienced after consumption of tobacco.

The potential for these compounds to function as reinforcers or to potentiate the reinforcing properties of nicotine merits investigation. To pursue this line of inquiry, we examined cotinine in a planarian model of environmental place preference. In the present study, planarians demonstrated that the compound cotinine, which is present in tobacco smoke, and is also the principal nicotine metabolite, establishes a conditioned place preference.

These data represent the first ever demonstration that cotinine will establish a conditioned place preference in planarians and possibly contribute to the addictive properties of nicotine.

[link url=""]Metabolite may play a role in nicotine addiction[/link]


[link url=""]Preliminary evidence from planarians that cotinine establishes a conditioned place preference[/link]


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