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A Conditioned Place Preference Protocol for Measuring Incubation of Craving in Rats
Published on: November 6, 2018
Circuit and molecular mechanisms underlying incubation of methamphetamine craving in the prelimbic cortex
Sai Shi1, Yi-Wen Sun1, Jin-Jun Ding1
1Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine and School of Psychology, Shanghai 200030, China.
Abstract:
Methamphetamine (METH) use disorder (MUD) is characterized by high relapse rates driven by craving, yet the underlying neural mechanisms remain unclear. Here, we reveal the temporal and circuit-specific contributions of somatostatin (SST) and parvalbumin (PV) interneurons (INs) in the prelimbic cortex (PL) in the incubation of METH craving. SST INs mediated drug seeking during early withdrawal (day 1) via lateral hypothalamus (LH) GABAergic inputs, while PV INs drove seeking following prolonged withdrawal (day 15) via anteromedial thalamus (AM) glutamatergic inputs. Single-cell RNA sequencing (scRNA-seq) revealed upregulated KCNC2 (encoding the Kv3.2 potassium channel) in both subtypes, with specific protein modifications. Selective KCNC2 knockdown in SST or PV INs significantly suppressed drug seeking during early or prolonged withdrawal, respectively. These findings uncover the distinct contributions of PL IN subtypes to the incubation of craving and identify KCNC2 as a potential phase-specific therapeutic target in MUD.
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