Dual action of ketamine confines addiction liability

Linda D. Simmler, Yue Li, Lotfi C. Hadjas, Agnès Hiver, Ruud Zessen and Christian Lüscher ()
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Linda D. Simmler: University of Geneva
Yue Li: University of Geneva
Lotfi C. Hadjas: University of Geneva
Agnès Hiver: University of Geneva
Ruud Zessen: University of Geneva
Christian Lüscher: University of Geneva

Nature, 2022, vol. 608, issue 7922, 368-373

Abstract: Abstract Ketamine is used clinically as an anaesthetic and a fast-acting antidepressant, and recreationally for its dissociative properties, raising concerns of addiction as a possible side effect. Addictive drugs such as cocaine increase the levels of dopamine in the nucleus accumbens. This facilitates synaptic plasticity in the mesolimbic system, which causes behavioural adaptations and eventually drives the transition to compulsion1–4. The addiction liability of ketamine is a matter of much debate, in part because of its complex pharmacology that among several targets includes N-methyl-d-aspartic acid (NMDA) receptor (NMDAR) antagonism5,6. Here we show that ketamine does not induce the synaptic plasticity that is typically observed with addictive drugs in mice, despite eliciting robust dopamine transients in the nucleus accumbens. Ketamine nevertheless supported reinforcement through the disinhibition of dopamine neurons in the ventral tegmental area (VTA). This effect was mediated by NMDAR antagonism in GABA (γ-aminobutyric acid) neurons of the VTA, but was quickly terminated by type-2 dopamine receptors on dopamine neurons. The rapid off-kinetics of the dopamine transients along with the NMDAR antagonism precluded the induction of synaptic plasticity in the VTA and the nucleus accumbens, and did not elicit locomotor sensitization or uncontrolled self-administration. In summary, the dual action of ketamine leads to a unique constellation of dopamine-driven positive reinforcement, but low addiction liability.

Date: 2022
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DOI: 10.1038/s41586-022-04993-7

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