Enhancement of the rewarding effects of 3,4-methylenedioxymethamphetamine in orexin knockout mice.
Tomohisa Mori, Naoki Uzawa, Daiki Masukawa, Shigeto Hirayama, Yoshiyuki Iwase, Mayuna Hokazono, Yuya Udagawa, Tsutomu Suzuki
Behavioural Brain Research July 9, 2020 DOI: 10.1016/j.bbr.2020.112802 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical behavioral and neurochemical study in mice Peer reviewed |
|---|---|
| Population | Orexin knockout mice and wild-type mice |
| Interventions | Methamphetamine Methylphenidate MDMA 5-HT1A receptor agonist |
| Measures | conditioned place preference, drug discrimination procedure, substitution tests, 5-HT and dopamine release in the nucleus accumbens, G protein activation |
| Topics | MDMA |
| Key points | Methamphetamine and methylphenidate conditioned place preference was not altered in orexin knockout mice, but MDMA produced conditioned place preference and methylphenidate/methamphetamine-like discriminative stimulus effects only in orexin knockout mice. The authors suggest that orexin deficiency may enhance the abuse liability of MDMA, possibly through changes in postsynaptic signal transduction. |
Abstract
Orexinergic neurons, which are closely associated with narcolepsy, regulate arousal and reward circuits through the activation of monoaminergic neurons. Psychostimulants as well as 5-HT-related compounds have potential in the treatment of human narcolepsy. Previous studies have demonstrated that orexin receptor antagonists as well as orexin deficiencies affect the pharmacological effects of psychostimulants. However, little information is available on the consequences of psychostimulant use under orexin deficiency. Therefore, the present study was designed to investigate the abuse liability of psychostimulants in orexin knockout (KO) mice. In the present study, conditioned place preferences induced by methamphetamine and methylphenidate were not altered in orexin KO mice. Interestingly, we found that MDMA induced a conditioned place preference in orexin KO mice, but not in wild type (WT) mice. In addition, MDMA produced methylphenidate/methamphetamine-like discriminative stimulus effects in orexin KO mice, but not WT mice. Increases in 5-HT and dopamine release in the nucleus accumbens induced by MDMA were not altered by knockout of orexin; the steady-state level of G protein activation was higher in the limbic forebrain of orexin KO mice. In substitution tests using a drug discrimination procedure, substitution of 5-HT1A receptor agonist for the discriminative stimulus effects of methylphenidate was enhanced in orexin KO mice. These findings indicate that the orexinergic system is involved the rewarding effects of psychostimulants. However, there is a risk of establishing rewarding effects of psychostimulants even under orexin deficiency. On the other hand, deficiencies in orexin may enhance the abuse liability of MDMA by changing a postsynaptic signal transduction accompanied by changes in discriminative stimulus effects themselves.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 1
Cites 3
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