EFFECTS OF CHRONIC METHAMPHETAMINE ADMINISTRATION ON RESTING-STATE FUNCTIONAL CONNECTIVITY IN CYNOMOLGUS MONKEYS

Abstract Background Maladaptive decision-making by methamphetamine users may reflect circuit-level dysfunction underlying deficits in neural activity. In a previous study, it was reported that heightened resting-state connectivity within the mesocorticolimbic system, coupled with reduced prefrontal cortical connectivity, created a bias toward reward-driven behavior over cognitive control in methamphetamine users. Aim & Objectives The primary aim of this study was to investigate the effect of chronic methamphetamine administration on resting-state functional connectivity in cynomolgus monkeys. Additionally, the study sought to elucidate the effect of chronic methamphetamine administration based on varying drug administration periods. Method Chronic Drug Exposure: The MA group was administered 0.9% saline for the initial 4 weeks followed by MA for the subsequent 7 weeks (5-8 weeks at doses of 0.1-0.75mg/kg; and 9-11 weeks at a dose of 0.75mg/kg). MRI Procedure On the MRI scanning day, anesthesia was induced using atropine, ipratropium, and ketamine hydrochloride injections. After oral intubation, anesthesia was maintained with 1.5% isoflurane mixed with oxygen. Monkeys were seated in a custom-built primate chair with a head-fixation system and custom RF coil, then placed in the MRI bore for imaging. The isoflurane level was reduced to 1% during the imaging procedure. Imaging Protocol MA monkeys underwent resting-state fMRI at 5 time points (baseline, 4, 5, 7, 9, 11 weeks) and four healthy control (HC) monkeys at baseline, 5, and 11 weeks. Seed-based correlation analysis was employed to produce functional connectivity maps with the nucleus accumbens as ROIs. Voxel-wise tests were conducted using the GLM in SPM12 to study RSFC changes over MA administration duration and intergroup differences. Image Processing Performed in SPM12, where rsfMRI data were realigned, coregistered with structural T1 data, spatially normalized, and smoothed. Other processes included motion correction, global signal normalization, and band pass filtering. Results Altered functional connectivity was observed between the striatum and medial prefrontal cortex in the monkey with chronic exposure to MA. Discussion & Conclusion The alterations in functional connectivity observed in the monkey striatum due to chronic MA exposure provide valuable insights into the neural mechanisms that could underlie behavioral abnormalities and drug dependence resulting from long-term MA exposure.