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Biol. Psychiatry, 2023 Jan 12;S0006-3223(23)00006-9 | https://doi.org/10.1016/j.biopsych.2022.12.024 Rewiring of Prelimbic Inputs to the Nucleus Accumbens Core Underlies Cocaine-Induced Behavioral Sensitization

Jaehan Kwon ^a, Hyun Jin Kim ^b, Hyoung-Ro Lee ^a, Won-Kyung Ho ^a, Joung-Hun Kim ^b,c, Suk-Ho Lee ^a,d

^aCell Physiology Lab, Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea
^bDepartment of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
^cInstitute of Convergence Science, Yonsei University, Seoul, Republic of Korea
^dDepartment of Brain and Cognitive Science, Seoul National University College of Natural Sciences, Seoul, Republic of Korea

Address correspondence to Joung-Hun Kim, Ph.D, Suk-Ho Lee, M.D., Ph.D

Abstract

Background: Unbalanced activity of medium spiny neurons (MSNs) of the direct and indirect pathways mediates reward-related behaviors induced by addictive drugs. Prelimbic (PL) input to MSNs in the nucleus accumbens core (NAcC) plays a key role in cocaine-induced early locomotor sensitization (LS). However, the adaptive plastic changes at PL-to-NAcC synapses underlying early LS remain unclear.

Methods: Using transgenic mice and retrograde tracing, we identified NAcC-projecting pyramidal neurons (PNs) in the PL cortex based on the expression of dopamine receptor types (D1R or D2R). To examine cocaine-induced alterations in PL-to-NAcC synapses, we measured excitatory postsynaptic current amplitudes evoked by optostimulation of PL afferents to MSNs. Riluzole was chosen to test the effects of PL excitability on cocaine-induced changes of PL-to-NAcC synapses.

Results: NAcC-projecting PNs were segregated into D1R- and D2R-expressing PNs (D1- and D2-PNs, respectively), and their excitability was opposingly regulated by respective dopamine agonists. Both D1- and D2-PNs exhibited balanced innervation of direct MSNs and indirect MSNs in naïve animals. Repeated cocaine injections resulted in biased synaptic strength toward direct MSNs through presynaptic mechanisms in both D1- and D2-PNs, although D2R activation reduced the D2-PN excitability. Under group 1 metabotropic glutamate receptors coactivation, however, D2R activation enhanced the D2-PN excitability. The cocaine-induced rewiring accompanied LS, and both rewiring and LS were precluded by PL infusion of riluzole, which reduced the intrinsic excitability of PL neurons.

Conclusions: These findings indicate that cocaine-induced rewiring of PL-to-NAcC synapses correlates well with early behavioral sensitization and that rewiring and LS can be prevented by riluzole-induced reduction of excitability of PL neurons.

논문정보

형식Research article
게재일2023년 01월 (BRIC 등록일 2023-05-26)
연구진국내 연구진
분야 의약학 > 신경의학

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