Pub Date : 2025-08-22DOI: 10.1016/j.addicn.2025.100225
Hillary Schwarb , Robert J. Roy , Alisha L. Schaefer , Robert J.R. Blair , Nicholas A. Hubbard
As methamphetamine use rates continue to climb, understanding its relationship with physical, mental, and cognitive decline is critical. While memory difficulties are common, the underlying neurobiology of these deficits are not well understood. Preclinical work suggests that, at least among male subjects, methamphetamine exposure results in volume loss in the hippocampus, a critical brain region supporting memory outcomes. Human studies investigating the effect of methamphetamine use on hippocampal volume have been equivocal. These inconsistencies may relate to sex differences and varying degrees of use and abstinence in study samples. The current study evaluated hippocampal volume and associated hippocampal-dependent memory in a sex-balanced community sample of people with recent problematic methamphetamine-use experience (N = 90) and methamphetamine-naïve controls (N = 90). While group differences in hippocampal volumes were evident for males with methamphetamine-use experience compared to the control group, no such differences were evident for females. However, hippocampal-dependent memory performance (i.e., delayed verbal recall performance) was impaired for both males and females with methamphetamine-use experience and both hippocampal volume and methamphetamine-use experience explained unique and significant variance in memory performance. These findings highlight the importance of considering sex-differences in methamphetamine addiction research.
{"title":"Sex-dependent hippocampal atrophy among people with methamphetamine-use experience","authors":"Hillary Schwarb , Robert J. Roy , Alisha L. Schaefer , Robert J.R. Blair , Nicholas A. Hubbard","doi":"10.1016/j.addicn.2025.100225","DOIUrl":"10.1016/j.addicn.2025.100225","url":null,"abstract":"<div><div>As methamphetamine use rates continue to climb, understanding its relationship with physical, mental, and cognitive decline is critical. While memory difficulties are common, the underlying neurobiology of these deficits are not well understood. Preclinical work suggests that, at least among male subjects, methamphetamine exposure results in volume loss in the hippocampus, a critical brain region supporting memory outcomes. Human studies investigating the effect of methamphetamine use on hippocampal volume have been equivocal. These inconsistencies may relate to sex differences and varying degrees of use and abstinence in study samples. The current study evaluated hippocampal volume and associated hippocampal-dependent memory in a sex-balanced community sample of people with recent problematic methamphetamine-use experience (<em>N</em> = 90) and methamphetamine-naïve controls (<em>N</em> = 90). While group differences in hippocampal volumes were evident for males with methamphetamine-use experience compared to the control group, no such differences were evident for females. However, hippocampal-dependent memory performance (i.e., delayed verbal recall performance) was impaired for both males and females with methamphetamine-use experience and both hippocampal volume and methamphetamine-use experience explained unique and significant variance in memory performance. These findings highlight the importance of considering sex-differences in methamphetamine addiction research.</div></div>","PeriodicalId":72067,"journal":{"name":"Addiction neuroscience","volume":"17 ","pages":"Article 100225"},"PeriodicalIF":2.2,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-09DOI: 10.1016/j.addicn.2025.100224
Matthew C. Broomer , Caroline E. Clark , Jan Shanelle J. Iringan , Michael W. Wang , Nicholas J. Beacher , Da-Ting Lin
Concurrent abuse of psychostimulants and opioids represents a growing public health concern. However, preclinical models of substance use disorder often situate psychostimulants and opioids similarly within a unified self-administration procedure. This approach may fail to capture important differences in neurobehavioral activity related to each drug type. A large volume of in vivo literature suggests that, within canonical reward-related brain regions such as the nucleus accumbens (NAc), multiple reward-seeking behaviors may be represented by distinct neural populations. This comparison is often made between drug and natural rewards, however there is evidence for a similar distinction between psychostimulants and opioids. Here, we review the evidence for distinct neurobehavioral characteristics of psychostimulant versus opioid self-administration and consider the utility of two experimental approaches—miniscope calcium imaging and deep learning-assisted behavior analysis—in further exploring this topic.
{"title":"Using miniscopes and deep learning to compare neurobehavioral representations of psychostimulant and opioid self-administration","authors":"Matthew C. Broomer , Caroline E. Clark , Jan Shanelle J. Iringan , Michael W. Wang , Nicholas J. Beacher , Da-Ting Lin","doi":"10.1016/j.addicn.2025.100224","DOIUrl":"10.1016/j.addicn.2025.100224","url":null,"abstract":"<div><div>Concurrent abuse of psychostimulants and opioids represents a growing public health concern. However, preclinical models of substance use disorder often situate psychostimulants and opioids similarly within a unified self-administration procedure. This approach may fail to capture important differences in neurobehavioral activity related to each drug type. A large volume of <em>in vivo</em> literature suggests that, within canonical reward-related brain regions such as the nucleus accumbens (NAc), multiple reward-seeking behaviors may be represented by distinct neural populations. This comparison is often made between drug and natural rewards, however there is evidence for a similar distinction between psychostimulants and opioids. Here, we review the evidence for distinct neurobehavioral characteristics of psychostimulant versus opioid self-administration and consider the utility of two experimental approaches—miniscope calcium imaging and deep learning-assisted behavior analysis—in further exploring this topic.</div></div>","PeriodicalId":72067,"journal":{"name":"Addiction neuroscience","volume":"16 ","pages":"Article 100224"},"PeriodicalIF":2.2,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144831445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-06DOI: 10.1016/j.addicn.2025.100222
Nicholas J. Beacher , Michael W. Wang , Jan Shanelle J. Iringan , Caroline E. Clark , D’Ottavio Ginevra , Matthew C. Broomer , Da-Ting Lin
Pharmacokinetic-pharmacodynamics (PKPD) models have been applied to determine real-time drug concentration while in vivo imaging techniques capture real-time behavioral and neural dynamics in preclinical models. Integration of PKPD models with real-time neural activity and deep learning behavior analyses remains underexplored. This short communication explores how opioid and psychostimulant use correlates with sample drug-associated behaviors. We propose a framework for studies synchronizing PKPD modeling with long-term neuronal recordings and deep learning neurobehavioral analyses. We highlight the potential of integrative approaches to understand dynamics of SUDs in preclinical models. Such frameworks could ultimately inform maladaptive drug-related neurobehavioral adaptations.
{"title":"Drug self-administration, drug-specific behaviors, and neurobehavioral deep learning analyses","authors":"Nicholas J. Beacher , Michael W. Wang , Jan Shanelle J. Iringan , Caroline E. Clark , D’Ottavio Ginevra , Matthew C. Broomer , Da-Ting Lin","doi":"10.1016/j.addicn.2025.100222","DOIUrl":"10.1016/j.addicn.2025.100222","url":null,"abstract":"<div><div>Pharmacokinetic-pharmacodynamics (PKPD) models have been applied to determine real-time drug concentration while in vivo imaging techniques capture real-time behavioral and neural dynamics in preclinical models. Integration of PKPD models with real-time neural activity and deep learning behavior analyses remains underexplored. This short communication explores how opioid and psychostimulant use correlates with sample drug-associated behaviors. We propose a framework for studies synchronizing PKPD modeling with long-term neuronal recordings and deep learning neurobehavioral analyses. We highlight the potential of integrative approaches to understand dynamics of SUDs in preclinical models. Such frameworks could ultimately inform maladaptive drug-related neurobehavioral adaptations.</div></div>","PeriodicalId":72067,"journal":{"name":"Addiction neuroscience","volume":"16 ","pages":"Article 100222"},"PeriodicalIF":2.2,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cocaine and oxycodone use disorders represent urgent public health burdens, with limited treatment options for opioid dependence and no approved pharmacotherapies for cocaine-related disorders, highlighting the critical need to uncover novel molecular targets in the addiction neurocircuitry. The basolateral amygdala (BLA) modulates withdrawal and drug-seeking behaviors in substance use disorders (SUDs), but the molecular drivers of these effects are poorly understood. Here, we investigated the role of corticotrophin-releasing hormone binding protein (CRHBP) in the BLA using viral-mediated knockdown, single-nucleus RNA sequencing (snRNA-seq), and operant self-administration in rats. snRNA-seq revealed Crhbp expression in BLA somatostatin-positive interneurons, with minimal presence in the central amygdala. Crhbp knockdown in the BLA decreased cocaine self-administration and cue-induced reinstatement, suggesting a role in sustaining stimulant addiction. Conversely, it increased oxycodone intake and progressive ratio breakpoints, indicating heightened opioid reinforcement, while also elevating cue-induced reinstatement after 24 h of abstinence, reflecting enhanced opioid-seeking. These opposing effects highlight Crhbp’s substance-specific influence on addiction-related behaviors in the BLA. Our findings position Crhbp as a potential therapeutic target gene for tailored interventions in cocaine and opioid SUDs.
{"title":"Corticotrophin-releasing hormone binding protein in the basolateral amygdala: divergent roles in cocaine and opioid addiction like behaviors","authors":"Courtney P. Wood , Arnav Gurha , Caitlin Crook , Angelica Martinez , Selen Dirik , Cloe Moreno , Anirudh Vaiyapuri , Avraham Libster , Francesca Telese , Giordano de Guglielmo","doi":"10.1016/j.addicn.2025.100221","DOIUrl":"10.1016/j.addicn.2025.100221","url":null,"abstract":"<div><div>Cocaine and oxycodone use disorders represent urgent public health burdens, with limited treatment options for opioid dependence and no approved pharmacotherapies for cocaine-related disorders, highlighting the critical need to uncover novel molecular targets in the addiction neurocircuitry. The basolateral amygdala (BLA) modulates withdrawal and drug-seeking behaviors in substance use disorders (SUDs), but the molecular drivers of these effects are poorly understood. Here, we investigated the role of corticotrophin-releasing hormone binding protein (CRHBP) in the BLA using viral-mediated knockdown, single-nucleus RNA sequencing (snRNA-seq), and operant self-administration in rats. snRNA-seq revealed <em>Crhbp</em> expression in BLA somatostatin-positive interneurons, with minimal presence in the central amygdala. <em>Crhbp</em> knockdown in the BLA decreased cocaine self-administration and cue-induced reinstatement, suggesting a role in sustaining stimulant addiction. Conversely, it increased oxycodone intake and progressive ratio breakpoints, indicating heightened opioid reinforcement, while also elevating cue-induced reinstatement after 24 h of abstinence, reflecting enhanced opioid-seeking. These opposing effects highlight <em>Crhbp’s</em> substance-specific influence on addiction-related behaviors in the BLA. Our findings position <em>Crhbp</em> as a potential therapeutic target gene for tailored interventions in cocaine and opioid SUDs.</div></div>","PeriodicalId":72067,"journal":{"name":"Addiction neuroscience","volume":"16 ","pages":"Article 100221"},"PeriodicalIF":2.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144773022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-22DOI: 10.1016/j.addicn.2025.100219
José Pedro Prieto , Rafael Sebastián Fort , Guillermo Eastman , Evangelina Coitiño , Oliver Kaminski , Carlos Ferreiro-Vera , Verónica Sanchez de Medina , María Ana Duhagon , Cecilia Scorza , José Roberto Sotelo-Silveira
Background and purpose
Cannabidiol (CBD), a non-psychotomimetic phytocannabinoid, has emerged as a potential therapeutic agent for psychostimulant use disorders. In recent work, we demonstrated that CBD can attenuate the expression of locomotor sensitization and enhanced metabolic activity in the nucleus accumbens (NAc) generated by the combination of cocaine and caffeine. The diverse CBD's interactions with different molecular targets makes it challenging to unravel the underlying mechanisms and pathways involved in its beneficial effects.
Experimental approach
In this study, we first evaluated the effect of CBD pre-treatment on a locomotor sensitization protocol with combined cocaine plus caffeine in mice. We then used high-throughput RNA-sequencing in mice’s NAc to identify the key pathways and genes involved in CBD attenuating behavioural effects.
Key results
CBD pre-treatment consistently reduced the locomotor sensitization induced by the combination of cocaine and caffeine. The transcriptome analysis revealed a notable enrichment of genes and functional associations related to extracellular matrix organization and cell interactions within the NAc. Additionally, neuroinflammation signalling pathways were also influenced by CBD. Specific genes, such as Tnc, emerged as noteworthy candidates for further investigation.
Conclusion and implications
Our study identifies pathways involved in CBD’s protective effects on cocaine and caffeine-induced sensitization. This provides valuable and novel insights into molecular mechanisms of CBD putatively associated with a protective effect on psychostimulant actions. Identified pathways and genes, particularly those related to extracellular matrix organization, offer potential therapeutic targets for future studies that may open new avenues for psychostimulant use disorder treatment strategies.
{"title":"Canabidiol prevents cocaine and caffeine sensitization modulating expression of extracellular matrix genes in the Nucleus Accumbens of male mice","authors":"José Pedro Prieto , Rafael Sebastián Fort , Guillermo Eastman , Evangelina Coitiño , Oliver Kaminski , Carlos Ferreiro-Vera , Verónica Sanchez de Medina , María Ana Duhagon , Cecilia Scorza , José Roberto Sotelo-Silveira","doi":"10.1016/j.addicn.2025.100219","DOIUrl":"10.1016/j.addicn.2025.100219","url":null,"abstract":"<div><h3>Background and purpose</h3><div>Cannabidiol (CBD), a non-psychotomimetic phytocannabinoid, has emerged as a potential therapeutic agent for psychostimulant use disorders. In recent work, we demonstrated that CBD can attenuate the expression of locomotor sensitization and enhanced metabolic activity in the nucleus accumbens (NAc) generated by the combination of cocaine and caffeine. The diverse CBD's interactions with different molecular targets makes it challenging to unravel the underlying mechanisms and pathways involved in its beneficial effects.</div></div><div><h3>Experimental approach</h3><div>In this study, we first evaluated the effect of CBD pre-treatment on a locomotor sensitization protocol with combined cocaine plus caffeine in mice. We then used high-throughput RNA-sequencing in mice’s NAc to identify the key pathways and genes involved in CBD attenuating behavioural effects.</div></div><div><h3>Key results</h3><div>CBD pre-treatment consistently reduced the locomotor sensitization induced by the combination of cocaine and caffeine. The transcriptome analysis revealed a notable enrichment of genes and functional associations related to extracellular matrix organization and cell interactions within the NAc. Additionally, neuroinflammation signalling pathways were also influenced by CBD. Specific genes, such as Tnc, emerged as noteworthy candidates for further investigation.</div></div><div><h3>Conclusion and implications</h3><div>Our study identifies pathways involved in CBD’s protective effects on cocaine and caffeine-induced sensitization. This provides valuable and novel insights into molecular mechanisms of CBD putatively associated with a protective effect on psychostimulant actions. Identified pathways and genes, particularly those related to extracellular matrix organization, offer potential therapeutic targets for future studies that may open new avenues for psychostimulant use disorder treatment strategies.</div></div>","PeriodicalId":72067,"journal":{"name":"Addiction neuroscience","volume":"16 ","pages":"Article 100219"},"PeriodicalIF":0.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144696712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-22DOI: 10.1016/j.addicn.2025.100220
Shamim Arif , Shekiba Madadi , Murtaza Haidary
Chronic pain and substance use disorder (SUD) frequently co-occur, driven by shared and convergent neurobiological pathways that reinforce a cycle of suffering, maladaptive behavior, and resistance to treatment. This narrative review explores the bidirectional relationship between these conditions, emphasizing the overlapping dysfunctions in the opioidergic and mesolimbic systems. Central components of the brain’s neurocircuitry—including the ventral tegmental area, nucleus accumbens, amygdala, and prefrontal cortex—play pivotal roles in both nociceptive modulation and reward processing, contributing to a common pathophysiological substrate. To conceptualize the transition from acute states to chronicity, theoretical models such as the allostatic load framework, opponent process theory, and mechanisms of negative reinforcement are explored. At the molecular level, maladaptive neuroplastic changes involving CREB, ΔFosB, and BDNF are identified as key drivers of sensitization across both pain and addiction domains. Furthermore, advances in neuroimaging and genomics have begun to reveal biomarkers and genetic signatures that hold promise for stratified diagnosis and intervention. Ultimately, this review highlights the need for dual-targeted pharmacotherapies, non-addictive analgesics, and personalized treatment strategies that address the shared mechanisms underpinning chronic pain and SUD. A unified, neurobiologically informed approach may offer more effective and sustainable outcomes for individuals afflicted by this challenging comorbidity.
{"title":"Neurobiological convergence of pain and substance use disorders: A focus on opioidergic and mesolimbic circuitry","authors":"Shamim Arif , Shekiba Madadi , Murtaza Haidary","doi":"10.1016/j.addicn.2025.100220","DOIUrl":"10.1016/j.addicn.2025.100220","url":null,"abstract":"<div><div>Chronic pain and substance use disorder (SUD) frequently co-occur, driven by shared and convergent neurobiological pathways that reinforce a cycle of suffering, maladaptive behavior, and resistance to treatment. This narrative review explores the bidirectional relationship between these conditions, emphasizing the overlapping dysfunctions in the opioidergic and mesolimbic systems. Central components of the brain’s neurocircuitry—including the ventral tegmental area, nucleus accumbens, amygdala, and prefrontal cortex—play pivotal roles in both nociceptive modulation and reward processing, contributing to a common pathophysiological substrate. To conceptualize the transition from acute states to chronicity, theoretical models such as the allostatic load framework, opponent process theory, and mechanisms of negative reinforcement are explored. At the molecular level, maladaptive neuroplastic changes involving CREB, ΔFosB, and BDNF are identified as key drivers of sensitization across both pain and addiction domains. Furthermore, advances in neuroimaging and genomics have begun to reveal biomarkers and genetic signatures that hold promise for stratified diagnosis and intervention. Ultimately, this review highlights the need for dual-targeted pharmacotherapies, non-addictive analgesics, and personalized treatment strategies that address the shared mechanisms underpinning chronic pain and SUD. A unified, neurobiologically informed approach may offer more effective and sustainable outcomes for individuals afflicted by this challenging comorbidity.</div></div>","PeriodicalId":72067,"journal":{"name":"Addiction neuroscience","volume":"16 ","pages":"Article 100220"},"PeriodicalIF":0.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144704414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1016/j.addicn.2025.100218
Ashley Lutzke, Ariana L. Velazquez, Sarah Trapp, Andrew S. Vore, Hannah E. Burzynski, Maeve E. Johnston, Terrence Deak
Chronic stress and alcohol consumption influence various features of neuroimmune reactivity, including neurobehavioral outcomes, induction of neuroimmune genes, blood-brain barrier (BBB) permeability, and core body temperature regulation. The goal of the present studies was to characterize a novel model of chronic ethanol intake in which exogenous corticosterone (CORT), a principal end-product of the Hypothalamic-Pituitary-Adrenal (HPA) axis, was co-consumed in 10 % ethanol. In adolescence (P28–32), pair-housed Sprague-Dawley rats were given a single bottle containing 10 % ethanol with varying concentrations of CORT (0, 25, 50, or 100µg/mL) for 48 h, followed by 48 h of tap water. This four-day sequence was repeated for 12 cycles, ending in early adulthood (P76–80). In Experiment 1, following CORT and ethanol exposure, rats were challenged with restraint stress (30 min), and changes in neuroimmune gene expression were evaluated. Rats with a history of 10 % ethanol + 100µg/mL CORT showed increased interleukin (IL)-6 mRNA expression in the hippocampus relative to water comparators. Experiment 2 probed BBB permeability after perfusion with FITC-labeled dextran (20 kDa), and no changes were found. Remaining experiments evaluated the effects of ethanol/CORT drinking on ethanol-induced hypothermia (Experiment 3) and polyinosinic:polycytidylic acid (Poly I:C)-induced fever (Experiment 4). In females, ethanol consumption (regardless of CORT) delayed return to baseline following the hypothermic response, and in males, 25µg/mL CORT exclusively suppressed fever following Poly I:C challenge. Together, these findings validate a concurrent exposure model of intermittent CORT and ethanol which is translationally relevant to the adolescent experience, and uncovered ethanol- and CORT-induced changes in adult neuroimmune reactivity.
{"title":"Concurrent consumption of ethanol and corticosterone during adolescence alters neuroimmune sensitivity in Sprague Dawley rats","authors":"Ashley Lutzke, Ariana L. Velazquez, Sarah Trapp, Andrew S. Vore, Hannah E. Burzynski, Maeve E. Johnston, Terrence Deak","doi":"10.1016/j.addicn.2025.100218","DOIUrl":"10.1016/j.addicn.2025.100218","url":null,"abstract":"<div><div>Chronic stress and alcohol consumption influence various features of neuroimmune reactivity, including neurobehavioral outcomes, induction of neuroimmune genes, blood-brain barrier (BBB) permeability, and core body temperature regulation. The goal of the present studies was to characterize a novel model of chronic ethanol intake in which exogenous corticosterone (CORT), a principal end-product of the Hypothalamic-Pituitary-Adrenal (HPA) axis, was co-consumed in 10 % ethanol. In adolescence (P28–32), pair-housed Sprague-Dawley rats were given a single bottle containing 10 % ethanol with varying concentrations of CORT (0, 25, 50, or 100µg/mL) for 48 h, followed by 48 h of tap water. This four-day sequence was repeated for 12 cycles, ending in early adulthood (P76–80). In Experiment 1, following CORT and ethanol exposure, rats were challenged with restraint stress (30 min), and changes in neuroimmune gene expression were evaluated. Rats with a history of 10 % ethanol + 100µg/mL CORT showed increased interleukin (IL)-6 mRNA expression in the hippocampus relative to water comparators. Experiment 2 probed BBB permeability after perfusion with FITC-labeled dextran (20 kDa), and no changes were found. Remaining experiments evaluated the effects of ethanol/CORT drinking on ethanol-induced hypothermia (Experiment 3) and polyinosinic:polycytidylic acid (Poly I:C)-induced fever (Experiment 4). In females, ethanol consumption (regardless of CORT) delayed return to baseline following the hypothermic response, and in males, 25µg/mL CORT exclusively suppressed fever following Poly I:C challenge. Together, these findings validate a concurrent exposure model of intermittent CORT and ethanol which is translationally relevant to the adolescent experience, and uncovered ethanol- and CORT-induced changes in adult neuroimmune reactivity.</div></div>","PeriodicalId":72067,"journal":{"name":"Addiction neuroscience","volume":"16 ","pages":"Article 100218"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-18DOI: 10.1016/j.addicn.2025.100217
Nicole M. Hinds , Ireneusz D. Wojtas , Desta M. Pulley , Stephany J. McDonald , Colton D. Spencer , Milena Sudarikov , Nicole E. Hubbard , Colin M. Kulick-Soper , Samantha de Guzman , Sara Hayden , Jessica J. Debski , Bianca Patel , Douglas P. Fox , Daniel F. Manvich
Psychosocial stressors are known to promote cocaine craving and relapse in humans but are infrequently employed in preclinical relapse models. Consequently, the underlying neural circuitry by which these stressors drive cocaine seeking has not been thoroughly explored. Using Fos expression analyses, we sought to examine whether the ventromedial hypothalamus (VMH) or periaqueductal gray (PAG), two critical components of the brain’s medial hypothalamic defense system, are activated during psychosocial stress-induced cocaine seeking. Adult male and female rats self-administered cocaine (0.5 mg/kg/inf IV, fixed-ratio 1 schedule, 2 h/session) over 20 sessions. On sessions 11, 14, 17, and 20, a tactile cue was present in the operant chamber that signaled impending social defeat stress (n= 16, 8/sex), footshock stress (n= 12, 6/sex), or a no-stress control condition (n= 12, 6/sex) immediately after the session’s conclusion. Responding was subsequently extinguished, and rats were tested for reinstatement of cocaine seeking during re-exposure to the tactile cue that signaled their impending stress/no-stress post-session event. All experimental groups displayed significant reinstatement of cocaine seeking, but Fos analyses indicated that neural activity within the rostrolateral PAG (rPAGl) was selectively correlated with cocaine-seeking magnitude in the socially-defeated rats. rPAGl activation was also associated with active-defense coping behaviors during social defeat encounters and with Fos expression in prelimbic prefrontal cortex and orexin-negative cells of the lateral hypothalamus/perifornical area in males, but not females. These findings suggest a potentially novel role for the rPAGl in psychosocial stress-induced cocaine seeking.
{"title":"Fos expression in the periaqueductal gray, but not the ventromedial hypothalamus, is correlated with psychosocial stress-induced cocaine-seeking behavior in rats","authors":"Nicole M. Hinds , Ireneusz D. Wojtas , Desta M. Pulley , Stephany J. McDonald , Colton D. Spencer , Milena Sudarikov , Nicole E. Hubbard , Colin M. Kulick-Soper , Samantha de Guzman , Sara Hayden , Jessica J. Debski , Bianca Patel , Douglas P. Fox , Daniel F. Manvich","doi":"10.1016/j.addicn.2025.100217","DOIUrl":"10.1016/j.addicn.2025.100217","url":null,"abstract":"<div><div>Psychosocial stressors are known to promote cocaine craving and relapse in humans but are infrequently employed in preclinical relapse models. Consequently, the underlying neural circuitry by which these stressors drive cocaine seeking has not been thoroughly explored. Using Fos expression analyses, we sought to examine whether the ventromedial hypothalamus (VMH) or periaqueductal gray (PAG), two critical components of the brain’s medial hypothalamic defense system, are activated during psychosocial stress-induced cocaine seeking. Adult male and female rats self-administered cocaine (0.5 mg/kg/inf IV, fixed-ratio 1 schedule, 2 h/session) over 20 sessions. On sessions 11, 14, 17, and 20, a tactile cue was present in the operant chamber that signaled impending social defeat stress (<em>n</em> <em>=</em> 16, 8/sex), footshock stress (<em>n</em> <em>=</em> 12, 6/sex), or a no-stress control condition (<em>n</em> <em>=</em> 12, 6/sex) immediately after the session’s conclusion. Responding was subsequently extinguished, and rats were tested for reinstatement of cocaine seeking during re-exposure to the tactile cue that signaled their impending stress/no-stress post-session event. All experimental groups displayed significant reinstatement of cocaine seeking, but Fos analyses indicated that neural activity within the rostrolateral PAG (rPAGl) was selectively correlated with cocaine-seeking magnitude in the socially-defeated rats. rPAGl activation was also associated with active-defense coping behaviors during social defeat encounters and with Fos expression in prelimbic prefrontal cortex and orexin-negative cells of the lateral hypothalamus/perifornical area in males, but not females. These findings suggest a potentially novel role for the rPAGl in psychosocial stress-induced cocaine seeking.</div></div>","PeriodicalId":72067,"journal":{"name":"Addiction neuroscience","volume":"16 ","pages":"Article 100217"},"PeriodicalIF":0.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144472380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-15DOI: 10.1016/j.addicn.2025.100216
Karl T. Schmidt, Sofia M. Nelson, Alexis E. O’Shall, Ava R. Holmes, Sunil S. Das, M․Pilar Mengotti Estrada, Sam M. Shaffer, Miranda Listman, Holly P. Rahurahu
Stress impacts the behavioral effects of drugs including cocaine. However, the extent of these impacts may rely on the modality of stressor. One such measure of cocaine’s effects is the drug discrimination procedure where rats are trained to respond based on interoceptive stimuli. Using this procedure, we asked whether three stress modalities (restraint, yohimbine, or wet bedding) produced effects similar to cocaine and/or altered cocaine’s discriminative stimulus properties. Previous studies suggest restraint stress substitutes for cocaine in male rats. Here we show similar results that restraint partially substitutes for cocaine depending on the training dose, in males but not females. Yohimbine under some conditions inhibits the interoceptive effects of cocaine in males but not females. Wet bedding was ineffective. Furthermore, the days to reach training criteria differed between the sexes with female rats learning to discriminate faster than male rats across two training doses. Taken together, these data highlight interactions between stressors and sex to modulate the interoceptive effects of cocaine.
{"title":"The impacts of sex and acute stress modalities on the interoceptive stimulus properties of cocaine in rats","authors":"Karl T. Schmidt, Sofia M. Nelson, Alexis E. O’Shall, Ava R. Holmes, Sunil S. Das, M․Pilar Mengotti Estrada, Sam M. Shaffer, Miranda Listman, Holly P. Rahurahu","doi":"10.1016/j.addicn.2025.100216","DOIUrl":"10.1016/j.addicn.2025.100216","url":null,"abstract":"<div><div>Stress impacts the behavioral effects of drugs including cocaine. However, the extent of these impacts may rely on the modality of stressor. One such measure of cocaine’s effects is the drug discrimination procedure where rats are trained to respond based on interoceptive stimuli. Using this procedure, we asked whether three stress modalities (restraint, yohimbine, or wet bedding) produced effects similar to cocaine and/or altered cocaine’s discriminative stimulus properties. Previous studies suggest restraint stress substitutes for cocaine in male rats. Here we show similar results that restraint partially substitutes for cocaine depending on the training dose, in males but not females. Yohimbine under some conditions inhibits the interoceptive effects of cocaine in males but not females. Wet bedding was ineffective. Furthermore, the days to reach training criteria differed between the sexes with female rats learning to discriminate faster than male rats across two training doses. Taken together, these data highlight interactions between stressors and sex to modulate the interoceptive effects of cocaine.</div></div>","PeriodicalId":72067,"journal":{"name":"Addiction neuroscience","volume":"16 ","pages":"Article 100216"},"PeriodicalIF":0.0,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144314106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-15DOI: 10.1016/j.addicn.2025.100215
Kelly K. Wingfield , Teodora Misic , Sophia A. Miracle , Carly S. McDermott , Kaahini Jain , Nalia M. Abney , Kayla T. Richardson , Mia B. Rubman , Jacob A. Beierle , Elisha M. Wachman , Camron D. Bryant
Concomitant with the opioid epidemic, there has been a rise in pregnant women diagnosed with opioid use disorder and infants born with neonatal opioid withdrawal syndrome (NOWS). NOWS refers to withdrawal signs following cessation of prenatal opioid exposure that comprise neurological, gastrointestinal, and autonomic system dysfunction. A critical indicator of NOWS severity is excessive, high-pitched crying.
However, NOWS evaluation is mostly subjective, and additional cry features may not be easily recognized during clinical assessment. Thus, there is a need for more objective measures of NOWS severity. We used a third trimester-approximate opioid exposure paradigm to model NOWS traits in genetically similar inbred substrains of FVB/N mice (NJ, NCrl, NHsd, and NTac). Pups were injected twice daily from postnatal day 1 (P1) to P14 with morphine (10 mg/kg, s.c.) or saline (20 microliters/g, s.c.).
Because there were very few minor substrain differences in spontaneous withdrawalinduced ultrasonic vocalization (USV) profiles, we collapsed across substrains to evaluate the effects of morphine withdrawal on additional USV properties. We identified syllable sequences unique to morphine-withdrawn and saline-control FVB/N pups on P7 and P14. We also observed an effect of spontaneous morphine withdrawal on the acoustic properties of USVs on P7 and P14. Some withdrawal traits correlated with acoustic properties of USVs in morphine-withdrawn FVB/N pups on P7 and P14. This in-depth investigation of mouse USV features during spontaneous neonatal opioid withdrawal has implications for predicting neonatal opioid withdrawal severity in mice and applying objective approaches to understanding cries in human infants suffering from NOWS.
{"title":"The acoustic properties, syllable structure, and syllable sequences of ultrasonic vocalizations (USVs) during neonatal opioid withdrawal in FVB/N mouse substrains","authors":"Kelly K. Wingfield , Teodora Misic , Sophia A. Miracle , Carly S. McDermott , Kaahini Jain , Nalia M. Abney , Kayla T. Richardson , Mia B. Rubman , Jacob A. Beierle , Elisha M. Wachman , Camron D. Bryant","doi":"10.1016/j.addicn.2025.100215","DOIUrl":"10.1016/j.addicn.2025.100215","url":null,"abstract":"<div><div>Concomitant with the opioid epidemic, there has been a rise in pregnant women diagnosed with opioid use disorder and infants born with neonatal opioid withdrawal syndrome (NOWS). NOWS refers to withdrawal signs following cessation of prenatal opioid exposure that comprise neurological, gastrointestinal, and autonomic system dysfunction. A critical indicator of NOWS severity is excessive, high-pitched crying.</div><div>However, NOWS evaluation is mostly subjective, and additional cry features may not be easily recognized during clinical assessment. Thus, there is a need for more objective measures of NOWS severity. We used a third trimester-approximate opioid exposure paradigm to model NOWS traits in genetically similar inbred substrains of FVB/N mice (NJ, NCrl, NHsd, and NTac). Pups were injected twice daily from postnatal day 1 (P1) to P14 with morphine (10 mg/kg, s.c.) or saline (20 microliters/g, s.c.).</div><div>Because there were very few minor substrain differences in spontaneous withdrawalinduced ultrasonic vocalization (USV) profiles, we collapsed across substrains to evaluate the effects of morphine withdrawal on additional USV properties. We identified syllable sequences unique to morphine-withdrawn and saline-control FVB/N pups on P7 and P14. We also observed an effect of spontaneous morphine withdrawal on the acoustic properties of USVs on P7 and P14. Some withdrawal traits correlated with acoustic properties of USVs in morphine-withdrawn FVB/N pups on P7 and P14. This in-depth investigation of mouse USV features during spontaneous neonatal opioid withdrawal has implications for predicting neonatal opioid withdrawal severity in mice and applying objective approaches to understanding cries in human infants suffering from NOWS.</div></div>","PeriodicalId":72067,"journal":{"name":"Addiction neuroscience","volume":"16 ","pages":"Article 100215"},"PeriodicalIF":0.0,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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