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1. Stress-induced vulnerability to develop cocaine addiction depends on cofilin modulation

Author

Daiana Rigoni, Maria P. Avalos, Maria J. Boezio, Andrea S. Guzmán, Gaston D. Calfa, Eduardo M. Perassi, Silvia M. Pierotti, Mariano Bisbal, Constanza Garcia-Keller, Liliana M. Cancela, and Flavia Bollati

Subjects
Cofilin, Dendritic spines, Chronic stress, Cocaine self-administration, Actin dynamic, AMPA receptor, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429, Neurophysiology and neuropsychology, QP351-495
Abstract

Actin dynamics in dendritic spines can be associated with the neurobiological mechanisms supporting the comorbidity between stress exposure and cocaine increase rewards. The actin cytoskeleton remodeling in the nucleus accumbens (NA) has been implicated in the expression of stress-induced cross-sensitization with cocaine. The present study evaluates the involvement of cofilin, a direct regulator of actin dynamics, in the impact of stress on vulnerability to cocaine addiction. We assess whether the neurobiological mechanisms that modulate repeated-cocaine administration also occur in a chronic restraint stress-induced cocaine self-administration model. We also determine if chronic stress induces alterations in dendritic spines through dysregulation of cofilin activity in the NA core. Here, we show that the inhibition of cofilin expression in the NA core using viral short-hairpin RNA is sufficient to prevent the cocaine sensitization induced by chronic stress. The reduced cofilin levels also impede a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor surface expression enhancement and promote the reduction of head diameter in animals pre-exposed to stress after a cocaine challenge in the NA core. Moreover, downregulation of cofilin expression prevents facilitation of the acquisition of cocaine self-administration (SA) in male rats pre-exposed to chronic stress without modifying performance in sucrose SA. These findings reveal a novel, crucial role for cofilin in the neurobiological mechanisms underpinning the comorbidity between stress exposure and addiction-related disorders.

Published
2021
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2. Enkephalin as a Pivotal Player in Neuroadaptations Related to Psychostimulant Addiction

Author

Bethania Mongi-Bragato, María P. Avalos, Andrea S. Guzmán, Flavia A. Bollati, and Liliana M. Cancela

Subjects
enkephalin, cocaine, amphetamine, neuroadaptations, addiction, opioid antagonists, Psychiatry, RC435-571
Abstract

Enkephalin expression is high in mesocorticolimbic areas associated with psychostimulant-induced behavioral and neurobiological effects, and may also modulate local neurotransmission in this circuit network. Psychostimulant drugs, like amphetamine and cocaine, significantly increase the content of enkephalin in these brain structures, but we do not yet understand the specific significance of this drug-induced adaptation. In this review, we summarize the neurochemical and molecular mechanism of psychostimulant-induced enkephalin activation in mesocorticolimbic brain areas, and the contribution of this opioid peptide in the pivotal neuroadaptations and long-term behavioral changes underlying psychostimulant addiction. There is evidence suggesting that adaptive changes in enkephalin content in the mesocorticolimbic circuit, induced by acute and chronic psychostimulant administration, may represent a key initial step in the long-term behavioral and neuronal plasticity induced by these drugs.

Published
2018
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3. Multidimensional Effects of Stress on Neuronal Exosome Levels and Simultaneous Transcriptomic Profiles

Author

Hope Kronman, Amarjyot Singh, Shofiul Azam, Andrea S. Guzman, Danielle Zelli, Timothy Lau, Josh Dobbin, Benedetta Bigio, and Carla Nasca

Subjects
Amygdala, Bioinformatic, Chronic stress, Gene expression, Hippocampus, RNA-seq, Psychiatry, RC435-571
Abstract

Background: An excess of exosomes, nanovesicles released from all cells and key regulators of brain plasticity, is an emerging therapeutic target for stress-related mental illnesses. The effects of chronic stress on exosome levels are unknown; even less is known about molecular drivers of exosome levels in the stress response. Methods: We used our state-of-the-art protocol with 2 complementary strategies to isolate neuronal exosomes from plasma, ventral dentate gyrus, basolateral amygdala, and olfactory bulbs of male mice to determine the effects of chronic restraint stress (CRS) on exosome levels. Next, we used RNA sequencing and bioinformatic analyses to identify molecular drivers of exosome levels. Results: We found that CRS leads to an increase in the levels of neuronal exosomes but not total (i.e., not neuronally enriched) exosome levels assayed in plasma and the ventral dentate gyrus, whereas CRS leads to a decrease in neuronal exosome levels but not total exosome levels in the basolateral amygdala. There was a further specificity of effects as shown by a lack of changes in the levels of neuronal exosomes assayed in the olfactory bulbs. In pursuit of advancing translational applications, we showed that acetyl-L-carnitine administration restores the CRS-induced increase in neuronal exosome levels assayed in plasma (the most accessible specimen). Furthermore, the CRS-induced changes in neuronal exosome levels in the ventral dentate gyrus and basolateral amygdala mirrored the opposite pattern of CRS-induced transcriptional changes in these key brain areas, with β-estradiol signaling as a potential upstream driver of neuronal exosome levels. Conclusions: This study provides a foundation for future studies of new forms of local and distant communication in stress neurobiology by demonstrating specific relationships between neuronal exosome levels assayed in plasma and the brain and providing new candidate targets for the normalization of exosome levels.

Published
2025
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4. Endogenous enkephalin is necessary for cocaine‐induced alteration in glutamate transmission within the nucleus accumbens

Author

Liliana M. Cancela, Flavia Bollati, Andrea S. Guzmán, Bethania Mongi-Bragato, María Paula Avalos, and Constanza Garcia-Keller

Subjects
ENKEPHALINS, medicine.medical_specialty, Microdialysis, Enkephalin, SENSITISATION, Glutamic Acid, Endogeny, Nucleus accumbens, Neurotransmission, Nucleus Accumbens, GLUTAMATE, Mice, 03 medical and health sciences, 0302 clinical medicine, Cocaine, Internal medicine, medicine, Animals, 030304 developmental biology, Endogenous opioid, 0303 health sciences, Chemistry, General Neuroscience, Glutamate receptor, purl.org/becyt/ford/3.1 [https], Enkephalins, Proenkephalin, ADDICTION, Endocrinology, PSYCHOSTIMULANTS, purl.org/becyt/ford/3 [https], KNOCKOUT MICE, 030217 neurology & neurosurgery
Abstract

Altered glutamate transmission within the nucleus accumbens (NAc) has been proposed as a central mechanism underlying behavioural sensitisation associated with repeated cocaine exposure. In addition to glutamate, enkephalin, an endogenous opioid peptide derived from proenkephalin, is necessary for the neuroadaptations associated with chronic cocaine. However, the influence of enkephalin on long-term changes in glutamate transmission within the NAc associated with cocaine-induced sensitisation has not been described. This study used knockout proenkephalin mice (KO) to study the influence of endogenous enkephalin on the adaptations in glutamate neurotransmission associated with repeated cocaine treatment. Wild-type (WT) and KO mice were treated with daily cocaine injections for 9 days to induce sensitisation. On days 15 and 21, the animals received a cocaine challenge and locomotor sensitisation was evaluated, and microdialysis was performed to determine accumbens glutamate content on day 21. No expression of behavioural sensitisation to cocaine was evidenced in the KO mice. Consistently, these showed no changes in glutamate transmission in the NAc associated with repeated cocaine. This study reveals the central role of enkephalin in regulating the glutamate mechanisms associated with cocaine sensitisation. Fil: Mongi Bragato, Bethania del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; Argentina Fil: Avalos, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; Argentina Fil: Guzman, Andrea Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; Argentina Fil: Garcia Keller, Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; Argentina Fil: Bollati, Flavia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; Argentina Fil: Cancela, Liliana Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; Argentina

Published
2020
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5. CB1R activation in nucleus accumbens core promotes stress-induced reinstatement of cocaine seeking by elevating extracellular glutamate in a drug-paired context

Author

Andrea S. Guzmán, Miriam Beatriz Virgolini, Liliana M. Cancela, Daiana Rigoni, María Paula Avalos, Marianela A Sanchez, Laura Noemi de Giovanni, Bethania Mongi-Bragato, Flavia Bollati, and Pia V Euliarte

Subjects
0301 basic medicine, AM251, Agonist, Microdialysis, medicine.drug_class, Science, medicine.medical_treatment, Conditioning, Classical, Glutamic Acid, Addiction, Nucleus accumbens, Pharmacology, Nucleus Accumbens, Article, Extinction, Psychological, Rats, Sprague-Dawley, Cocaine-Related Disorders, 03 medical and health sciences, Glutamatergic, 0302 clinical medicine, Cocaine, Receptor, Cannabinoid, CB1, Reward, Stress, Physiological, medicine, Animals, Inverse agonist, Motivation, Multidisciplinary, Behavior, Animal, Chemistry, Glutamate receptor, Neurochemistry, Extinction, Neurotransmitters, Classical conditioning, Rats, Disease Models, Animal, 030104 developmental biology, Medicine, Disease Susceptibility, Cannabinoid, Extracellular Space, Stress and resilience, Biomarkers, 030217 neurology & neurosurgery, medicine.drug
Abstract

Preclinical models of stress-induced relapse to drug use have shown that the dysregulation of glutamatergic transmission within the nucleus accumbens (NA) contributes notably to the reinstatement of cocaine-seeking behavior in rodents. In this sense, there has been increasing interest in the cannabinoid type-1 receptor (CB1R), due to its crucial role in modulating glutamatergic neurotransmission within brain areas involved in drug-related behaviors. This study explored the involvement of CB1R within the NA subregions in the restraint stress-induced reinstatement of cocaine-conditioned place preference (CPP), as well as in the regulation of glutamatergic transmission, by using a pharmacological approach and the in vivo microdialysis sampling technique in freely moving rats. CB1R blockade by the antagonist/inverse agonist AM251 (5 nmol/0.5 μl/side) or CB1R activation by the agonist ACEA (0.01 fmol/0.5 μl/side), prevented or potentiated restraint stress-induced reinstatement of cocaine-CPP, respectively, after local administration into NAcore, but not NAshell. In addition, microdialysis experiments demonstrated that restraint stress elicited a significant increase in extracellular glutamate in NAcore under reinstatement conditions, with the local administration of AM251 or ACEA inhibiting or potentiating this, respectively. Interestingly, this rise specifically corresponded to the cocaine-associated CPP compartment. We also showed that this context-dependent change in glutamate paralleled the expression of cocaine-CPP, and disappeared after the extinction of this response. Taken together, these findings demonstrated the key role played by CB1R in mediating reinstatement of cocaine-CPP after restraint stress, through modulation of the context-specific glutamate release within NAcore. Additionally, CB1R regulation of basal extracellular glutamate was demonstrated and proposed as the underlying mechanism.

Published
2021
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6. Stress-induced vulnerability to develop cocaine addiction depends on cofilin modulation

Author

Flavia Bollati, Eduardo Marcelo Perassi, Andrea S. Guzmán, Liliana M. Cancela, Silvia M. Pierotti, Daiana Rigoni, Mariano Bisbal, Constanza Garcia-Keller, Gaston Diego Calfa, María Paula Avalos, and Maria J. Boezio

Subjects
Neurophysiology and neuropsychology, Dendritic spine, Physiology, media_common.quotation_subject, Neurosciences. Biological psychiatry. Neuropsychiatry, AMPA receptor, macromolecular substances, Nucleus accumbens, Biochemistry, Dendritic spines, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Endocrinology, Downregulation and upregulation, medicine, Chronic stress, Original Research Article, RC346-429, Molecular Biology, Sensitization, media_common, Endocrine and Autonomic Systems, Chemistry, Actin dynamic, Addiction, QP351-495, Cofilin, 030227 psychiatry, Cocaine self-administration, medicine.anatomical_structure, Neurology. Diseases of the nervous system, Neuroscience, 030217 neurology & neurosurgery, RC321-571
Abstract

Actin dynamics in dendritic spines can be associated with the neurobiological mechanisms supporting the comorbidity between stress exposure and cocaine increase rewards. The actin cytoskeleton remodeling in the nucleus accumbens (NA) has been implicated in the expression of stress-induced cross-sensitization with cocaine. The present study evaluates the involvement of cofilin, a direct regulator of actin dynamics, in the impact of stress on vulnerability to cocaine addiction. We assess whether the neurobiological mechanisms that modulate repeated-cocaine administration also occur in a chronic restraint stress-induced cocaine self-administration model. We also determine if chronic stress induces alterations in dendritic spines through dysregulation of cofilin activity in the NA core. Here, we show that the inhibition of cofilin expression in the NA core using viral short-hairpin RNA is sufficient to prevent the cocaine sensitization induced by chronic stress. The reduced cofilin levels also impede a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor surface expression enhancement and promote the reduction of head diameter in animals pre-exposed to stress after a cocaine challenge in the NA core. Moreover, downregulation of cofilin expression prevents facilitation of the acquisition of cocaine self-administration (SA) in male rats pre-exposed to chronic stress without modifying performance in sucrose SA. These findings reveal a novel, crucial role for cofilin in the neurobiological mechanisms underpinning the comorbidity between stress exposure and addiction-related disorders., Highlights • Cofilin is crucial for the development of substance use disorders induced by stress. • Cofilin downregulation prevents stress-induced sensitization to cocaine. • Cofilin modulates stress-induced structural plasticity in the nucleus accumbens core. • Cofilin regulates AMPA receptor expression in stress-induced sensitization to cocaine.

Published
2020

9. Enkephalin as a pivotal player in neuroadaptations related to psychostimulant addiction

Author

Liliana M. Cancela, Bethania Mongi-Bragato, Flavia Bollati, Andrea S. Guzmán, and María Paula Avalos

Subjects
0301 basic medicine, enkephalin, Enkephalin, lcsh:RC435-571, media_common.quotation_subject, amphetamine, cocaine, neuroadaptations, Review, Neurotransmission, Biology, AMPHETAMINE, OPIOID ANTAGONISTS, 03 medical and health sciences, 0302 clinical medicine, Neurochemical, opioid antagonists, lcsh:Psychiatry, Neuroplasticity, medicine, Opioid peptide, Amphetamine, media_common, Psychiatry, Addiction, ENKEPHALIN, NEUROADAPTATIONS, Psychiatry and Mental health, 030104 developmental biology, ADDICTION, Molecular mechanism, addiction, COCAINE, Neuroscience, 030217 neurology & neurosurgery, medicine.drug
Abstract

Enkephalin expression is high in mesocorticolimbic areas associated with psychostimulant-induced behavioral and neurobiological effects, and may also modulate local neurotransmission in this circuit network. Psychostimulant drugs, like amphetamine and cocaine, significantly increase the content of enkephalin in these brain structures, but we do not yet understand the specific significance of this drug-induced adaptation. In this review, we summarize the neurochemical and molecular mechanism of psychostimulant-induced enkephalin activation in mesocorticolimbic brain areas, and the contribution of this opioid peptide in the pivotal neuroadaptations and long-term behavioral changes underlying psychostimulant addiction. There is evidence suggesting that adaptive changes in enkephalin content in the mesocorticolimbic circuit, induced by acute and chronic psychostimulant administration, may represent a key initial step in the long-term behavioral and neuronal plasticity induced by these drugs. Fil: Mongi Bragato, Bethania del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina Fil: Avalos, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina Fil: Guzman, Andrea Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina Fil: Bollati, Flavia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina Fil: Cancela, Liliana Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina

Published
2018
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10. NMDA antagonist MK 801 in nucleus accumbens core but not shell disrupts the restraint stress-induced reinstatement of extinguished cocaine-conditioned place preference in rats

Author

Laura Noemi de Giovanni, Andrea S. Guzmán, Liliana M. Cancela, and Miriam Beatriz Virgolini

Subjects
Male, Restraint, Physical, 0301 basic medicine, Conditioned Place Preference, Time Factors, CIENCIAS MÉDICAS Y DE LA SALUD, media_common.quotation_subject, Nucleous Accumbens, Neurociencias, Context (language use), Nucleus accumbens, Nucleus Accumbens, Mk801, Extinction, Psychological, Developmental psychology, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Cocaine, Dopamine Uptake Inhibitors, Animals, Rats, Wistar, media_common, Analysis of Variance, Stress-Induced Reinstatement, Addiction, Glutamate receptor, Extinction (psychology), Conditioned place preference, Rats, Medicina Básica, 030104 developmental biology, nervous system, Conditioning, Operant, NMDA receptor, Analysis of variance, Dizocilpine Maleate, Psychology, Neuroscience, Locomotion, 030217 neurology & neurosurgery
Abstract

Relapse is a common feature of cocaine addiction. In rodents, it can be elicited by cues, stress or the drug. Restraint stress-induced reinstatement of cocaine-conditioned place preference (CPP) is a useful model to study the mechanisms involved in stress-induced relapse of drug-seeking behavior. There is evidence that the glutamate NMDA receptors are critically involved in drug- and cue-induced reinstatement of seeking behavior and drug-CPP responses. The aim of this study was to investigate the contribution of NMDA receptors within core vs. shell nucleus accumbens (NAc) subregions to restraint stress-induced reinstatement of extinguished cocaine-CPP. After extinction of cocaine-conditioned preference, animals were administered MK 801 systemically or directly into intra-core or intra-shell, and restrained for 30 min or left undisturbed in their home-cages. First, we demonstrated that restraint stress-induced reinstatement of extinguished cocaine-CPP depends on the duration of restraint as well as on the context in which it is applied. Second, this effect was blocked by systemic MK 801 administration either before or after restraint. Third, intra-core but not intra-shell administration abrogated the restraint stress-induced reinstatement. These findings show that NMDA receptors within NAc core, but not shell, play a critical role in restraint stress-induced reinstatement of cocaine-CPP. Fil: de Giovanni, Laura Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina Fil: Guzman, Andrea Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina Fil: Virgolini, Miriam Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina Fil: Cancela, Liliana Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina

Published
2016

11. Impairment of glutamate homeostasis in the nucleus accumbens core underpins cross-sensitization to cocaine following chronic restraint stress

Author

María P. Avalos, Andrea S. Guzman, Constanza Garcia-Keller, Bethania Mongi-Bragato, María A. Esparza, Daiana Rigoni, Marianela A. Sanchez, Gastón D. Calfa, Flavia A. Bollati, and Liliana M. Cancela

Subjects
chronic restraint stress, ceftriaxone, cocaine, dendritic spines, GLT-1, glutamate, Physiology, QP1-981
Abstract

Though the facilitating influence of stress on drug abuse is well documented, the mechanisms underlying this interaction have yet to be fully elucidated. The present study explores the neurobiological mechanisms underpinning the sensitized response to the psychomotor-stimulating effects of cocaine following chronic restraint stress (CRS), emphasizing the differential contribution of both subcompartments of the nucleus accumbens (NA), the core (NAcore) and shell (NAshell), to this phenomenon. Adult male Wistar rats were restrained for 2 h/day for 7 days and, 2 weeks after the last stress exposure (day 21), all animals were randomly assigned to behavioral, biochemical or neurochemical tests. Our results demonstrated that the enduring CRS-induced increase in psychostimulant response to cocaine was paralleled by an increase of extracellular dopamine levels in the NAcore, but not the NAshell, greater than that observed in the non-stress group. Furthermore, we found that CRS induced an impairment of glutamate homeostasis in the NAcore, but not the NAshell. Its hallmarks were increased basal extracellular glutamate concentrations driven by a CRS-induced downregulation of GLT-1, blunted glutamate levels in response to cocaine and postsynaptic structural remodeling in pre-stressed animals. In addition, ceftriaxone, a known GLT-1 enhancer, prevented the CRS-induced GLT-1 downregulation, increased basal extracellular glutamate concentrations and changes in structural plasticity in the NAcore as well as behavioral cross-sensitization to cocaine, emphasizing the biological importance of GLT-1 in the comorbidity between chronic stress exposure and drug abuse. A future perspective concerning the paramount relevance of the stress-induced disruption of glutamate homeostasis as a vulnerability factor to the development of stress and substance use disorders during early life or adulthood of descendants is provided.

Published
2022
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