Novelty-induced locomotor behavior predicts heroin addiction vulnerability in male, but not female, rats

Kuhn, Brittany N; Cannella, Nazzareno; Crow, Ayteria D; Roberts, Analyse T.; Lunerti, Veronica; Allen, Carter; Nall, Rusty W.; Hardiman, Gary; Woods, Leah C. Solberg; Chung, Dongjun; Ciccocioppo, Roberto; Kalivas, Peter W.

doi:10.1007/s00213-022-06235-0

Cited by 12 publications

(17 citation statements)

References 79 publications

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“…In alignment with work done in humans, we showed using a rodent model that analgesic threshold to painful heat stimuli under baseline conditions is heritable [40]. Following opioid use, both humans [41,42] and rats [43] demonstrate opioid-induced hyperalgesia in response to a painful stimuli, a finding replicated in these data [16]. While heritability factors associated with hyperalgesia are unknown, epigenetic modulating of this behavior in a rodent model has been investigated [44].…”

Section: Heritabilitysupporting

confidence: 54%

“…The experimental timeline is shown in Figure 1a. Experimental testing occurred as previously described in Kuhn et al, 2022 [16]. Extensive behavioral analyses for these animals, including sex and site differences, have been conducted and reported in prior publications [16,24], and we refer the reader to these manuscripts for further edification.…”

Section: Behavioral Testingmentioning

confidence: 99%

“…Experimental testing occurred as previously described in Kuhn et al, 2022 [16]. Extensive behavioral analyses for these animals, including sex and site differences, have been conducted and reported in prior publications [16,24], and we refer the reader to these manuscripts for further edification. Underlying genetic variants that may be contributing toward these behaviors are the focus of this manuscript.…”

Section: Behavioral Testingmentioning

confidence: 99%

“…Novelty-induced locomotion has been associated with vulnerability in opioid addiction-related behaviors in both rodent models [16,[45][46][47][48][49] and humans [50], and is a heritable behavior [21,22]. Heritability for this trait is relatively stable and affects behavior both prior to and following heroin, suggesting an enduring genetic contribution to locomotor behaviors that are not greatly affected by factors (e.g., epigenetic changes) associated with prolonged heroin experience.…”

Section: Heritabilitymentioning

confidence: 99%

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Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats

Kuhn,

Cannella,

Chitre

et al. 2024

Preprint

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The increased prevalence of opioid use disorder (OUD) world-wide has made it imperative to disentangle the biological mechanisms contributing to OUD propensity. OUD shows strong heritability, however genetic variants contributing toward vulnerability remain under explored. In the current study, genome-wide association (GWAS) analysis on over 850 male and female heterogeneous stock rats were performed to identify genes underlying heroin-taking, refraining and seeking behaviors. By using an animal model of OUD, we were able to identify genetic variants associated with distinct behaviors contributing to OUD, an experimental design not easily achieved in human GWAS analysis, and not performed to date for OUD GWAS studies. Our findings show, akin to the human population, several heritable traits related with OUD. We also identified genetic variants associated with heroin consumption, escalation of intake, motivation to obtain heroin, and basal levels of analgesic threshold prior to heroin experience, which was behaviorally unrelated to the heroin behaviors. Several of the genes identified are known biomarkers of other substance use disorders and mediators of neurobiological mechanisms underlying addiction-related behaviors. These findings emphasize the need to assess the role of these genetic variants in OUD, thereby augmenting our understanding of risk factors and neurobiological processes associated with OUD vulnerability.

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Section: Heritabilitysupporting

confidence: 54%

Section: Behavioral Testingmentioning

confidence: 99%

Section: Behavioral Testingmentioning

confidence: 99%

Section: Heritabilitymentioning

confidence: 99%

See 2 more Smart Citations

Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats

Kuhn,

Cannella,

Chitre

et al. 2024

Preprint

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“…To better mimic the genetic heterogeneity of the human population, we used NIH heterogeneous stock (HS) rats, an outbred line classically used for genetic and phenotypic studies including GWAS analysis (Solberg Woods and Palmer, 2019). Previous research has shown that these rats are suitable for studying opioid abuse-related behavior (Allen et al, 2021; de Guglielmo et al, 2019; Kallupi et al, 2020; Kuhn et al, 2022). Behavioral measures aimed at evaluating the motivation for heroin and the transition from its use to abuse were also taken.…”

Section: Introductionmentioning

confidence: 99%

Long-access heroin self-administration induces region specific reduction of grey matter volume and microglia reactivity in the rat

Cannella,

Tambalo,

Lunerti

et al. 2024

Preprint

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In opioid use disorder (OUD) patients, a decrease in brain grey matter volume (GMV) has been reported. It is unclear whether this is the consequence of prolonged exposure to opioids or is a predisposing causal factor in OUD development. To investigate this, we conducted a structural MRI longitudinal study in NIH Heterogeneous Stock rats exposed to heroin self-administration and age-matched naïve controls housed in the same controlled environment. Structural MRI scans were acquired before (MRI1) and after (MRI2) a prolonged period of long access heroin self-administration resulting in escalation of drug intake. Heroin intake resulted in reduced GMV in various cortical and sub-cortical brain regions. In drug-naïve controls no difference was found between MRI1and MRI2. Notably, the degree of GMV reduction in the medial prefrontal cortex (mPFC) and the insula positively correlated with the amount of heroin consumed and the escalation of heroin use. In a preliminary gene expression analysis, we identified a number of transcripts linked to immune response and neuroinflammation. This prompted us to hypothesize a link between changes in microglia homeostasis and loss of GMV. For this reason, we analyzed the number and morphology of microglial cells in the mPFC and insula. The number of neurons and their morphology was also evaluated. The primary motor cortex, where no GMV change was observed, was used as negative control. We found no differences in the number of neurons and microglia cells following heroin. However, in the same regions where reduced GMV was detected, we observed a shift towards a rounder shape and size reduction in microglia, suggestive of their homeostatic change towards a reactive state. Altogether these findings suggest that escalation of heroin intake correlates with loss of GMV in specific brain regions and that this phenomenon is linked to changes in microglial morphology.

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Long-access heroin self-administration induces region specific reduction of grey matter volume and microglia reactivity in the rat

Cannella,

Tambalo,

Lunerti

et al. 2024

Brain, Behavior, and Immunity

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Novelty-induced locomotor behavior predicts heroin addiction vulnerability in male, but not female, rats

Cited by 12 publications

References 79 publications

Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats

Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats

Long-access heroin self-administration induces region specific reduction of grey matter volume and microglia reactivity in the rat

Long-access heroin self-administration induces region specific reduction of grey matter volume and microglia reactivity in the rat

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