Interruption of continuous opioid exposure exacerbates drug-evoked adaptations in the mesolimbic dopamine system

Abstract

Drug-evoked adaptations in the mesolimbic dopamine system are postulated to drive opioid abuse and addiction. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. We exposed male and female mice to morphine for one week, with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with either naloxone-precipitated or spontaneous withdrawal. Continuous morphine exposure caused tolerance to the psychomotor-activating effects of morphine, whereas both intermittent and interrupted morphine exposure caused long-lasting psychomotor sensitization. Given links between locomotor sensitization and mesolimbic dopamine signaling, we used fiber photometry and a genetically encoded dopamine sensor to conduct longitudinal measurements of dopamine dynamics in the nucleus accumbens. Locomotor sensitization caused by interrupted morphine exposure was accompanied by enhanced dopamine signaling in the nucleus accumbens. To further assess downstream consequences on striatal gene expression, we used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in both nucleus accumbens and dorsal striatum, dramatically increasing differential gene expression and engaging unique signaling pathways. Our study indicates that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may, therefore, represent a strategy to minimize iatrogenic effects on brain reward circuits.

GPCR-Based Dopamine Sensors—A Detailed Guide to Inform Sensor Choice for In Vivo Imaging

“…Finally, dLight1.3a and dLight1.3b variants display a combination of low affinity (K d > 1000 nM) but very higher dynamic ranges (2–3 × higher than that of dLight1.2). dLight1.3b has already demonstrated its use in vivo in the NAc using fiber photometry [ 101 , 108 , 226 ]. Because of the higher threshold of DA concentration required for sensor activation, these sensors are less well suited for brain regions with low DA.…”

“…In Supplementary Table S2 we present an overview of previously published in vivo applications of DA biosensors from the dLight, RdLight and GRAB-DA families in rodent animal models [ 38 , 58 , 60 , 61 , 98 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 224 , 226 , 227 , 228 ]. The large majority of experiments was performed in either the dorsal striatum or the NAc where the DA concentration reaches its maximal levels.…”

“…Previous work by us and others found that the green sensors dLight1.1 ( Figure 1 ), dLight1.3b, GRAB-DA1h, 1m and DA2h, 2m are compatible with red-shifted optogenetic stimulation using fiber photometry in rodents. Hence, robust increases in fluorescence in the NAc or dorsal striatum were detected in response to VTA or SNc red-shifted (ChrimsonR, C1V1) optogenetic stimulation [ 58 , 60 , 61 , 226 ]. Moreover, we found that RdLight1 is compatible with optogenetic stimulation with the green opsin ChR2 ( Figure 1 ) [ 59 ].…”

Mu Opioid Receptor Gene Dosage Influences Reciprocal Social Behaviors and Nucleus Accumbens Microcircuitry

“…Quantitative RT-PCR was performed as previously described [26]. Primer sequences for Oprm1 and beta-actin (control) can be found in Table S1.…”

“…Measurement of thermal antinociception and open field locomotion after morphine administration were performed as previously described [26]. To evaluate social behavior, we used a battery of previously described assays: social conditioned place preference [21,27,28]; reciprocal social interaction [29]; the standard threechamber test of sociability and preference for social novelty [30]; and a real-time preference test for typical social interaction [31].…”