title: Phentermine induces conditioned rewarding effects via activation of the PI3K/Akt signaling pathway in the nucleus accumbens.
abstract: BACKGROUND
  Phentermine is structurally similar to methamphetamine and is widely used as an anti-obesity drug in the USA and many other countries. The potential for reward of phentermine has been noted; however, the mechanisms of phentermine dependence have not been established.
  
  
  OBJECTIVE
  Here, we investigated the rewarding and dopaminergic behavioral responses to phentermine in mice and found that phentermine produced conditioned rewarding effects through the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in the nucleus accumbens (NAc).
  
  
  METHODS
  The impact of phentermine was assessed using conditioned place preference (CPP) test, climbing behavior test, and western blot analysis.
  
  
  RESULTS
  Phentermine 1 and 3 mg/kg (i.p.) significantly increased CPP. Phentermine, a known dopamine releaser, boosted apomorphine-induced climbing behavior in mice, and methamphetamine (i.p.) also increased apomorphine-induced dopaminergic behavior. Phentermine and methamphetamine increased the level of expression of the dopamine transporter (DAT) and phospho-Akt proteins to a similar degree in the NAc of CPP mice. To determine whether the conditioned rewarding effects of phentermine were mediated through the PI3K/Akt pathway, we assessed the effects of the Akt inhibitor LY294002 on phentermine-induced place preference and climbing behavior. LY294002 (1 and 3 μg/site, i.c.v.) reduced phentermine-induced CPP and phentermine-increased climbing behavior. However, LY294002 did not change CPP and climbing behavior itself and also did not decrease apomorphine-induced climbing behavior in mice. Further, LY294002 decreased the phentermine-increased levels of DAT protein and phosphorylation of Akt in the NAc of CPP mice.
  
  
  CONCLUSIONS
  Thus, these findings suggest that phentermine induces conditioned rewarding effects via activation of the PI3K/Akt signaling pathway in the NAc.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 440-746, Republic of Korea.
authors.forename: Sa-Ik
authors.initials: SI
authors.lastname: Hong
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 440-746, Republic of Korea.
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 440-746, Republic of Korea.
authors.forename: In-Jee
authors.initials: IJ
authors.lastname: You
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 440-746, Republic of Korea.
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Kwon
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 440-746, Republic of Korea.
authors.forename: Shi-Xun
authors.initials: SX
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 440-746, Republic of Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Hwang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 440-746, Republic of Korea.
authors.forename: Jee-Yeon
authors.initials: JY
authors.lastname: Seo
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 440-746, Republic of Korea.
authors.forename: Yong-Hyun
authors.initials: YH
authors.lastname: Ko
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 440-746, Republic of Korea.
authors.forename: Bo Ram
authors.initials: BR
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 440-746, Republic of Korea.
authors.forename: Seok-Yong
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 440-746, Republic of Korea. jang@skku.edu.
authors.forename: Choon-Gon
authors.initials: CG
authors.lastname: Jang
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D001058:Apomorphine / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010645:Phentermine / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D019440:Anti-Obesity Agents; D001058:Apomorphine; D004298:Dopamine; D008694:Methamphetamine; D051058:Oncogene Protein v-akt; D010645:Phentermine; D019869:Phosphatidylinositol 3-Kinases
keywords: Accumbens; Dopamine transporter; Reward