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Psychopharmacology (Berl). 2016 Apr;233(8):1405-13. doi: 10.1007/s00213-016-4231-z. Epub 2016 Feb 18.

Phentermine induces conditioned rewarding effects via activation of the PI3K/Akt signaling pathway in the nucleus accumbens.

Author information

1
Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 440-746, Republic of Korea.
2
Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 440-746, Republic of Korea. jang@skku.edu.

Abstract

RATIONALE:

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.

OBJECTIVES:

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.

KEYWORDS:

Accumbens; Dopamine transporter; Reward

PMID:
26887589
DOI:
10.1007/s00213-016-4231-z
[Indexed for MEDLINE]

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