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Powerful associations that link drugs of abuse with cues in the drug-paired environment often serve as prepotent relapse triggers. Drug-associated contexts and cues activate ensembles of nucleus accumbens (NAc) neurons, including D1-class medium spiny neurons (MSNs) that typically promote, and D2-class MSNs that typically oppose, drug seeking. We found that in mice, cocaine conditioning upregulated transiently the activity-regulated transcription factor, Neuronal PAS Domain Protein 4 (NPAS4), in a small subset of NAc neurons. The NPAS4+ NAc ensemble was required for cocaine conditioned place preference. We also observed that NPAS4 functions within NAc D2-, but not D1-, MSNs to support cocaine-context associations and cue-induced cocaine, but not sucrose, seeking. Together, our data show that the NPAS4+ ensemble of NAc neurons is essential for cocaine-context associations in mice, and that NPAS4 itself functions in NAc D2-MSNs to support cocaine-context associations by suppressing drug-induced counteradaptations that oppose relapse-related behaviour.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos , Cocaína , Sinais (Psicologia) , Neurônios , Núcleo Accumbens , Animais , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Cocaína/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Camundongos , Masculino , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Comportamento de Procura de Droga , Receptores de Dopamina D2/metabolismoRESUMO
Return to use, or relapse, is a major challenge in the treatment of opioid use disorder (OUD). Relapse can be precipitated by several factors, including exposure to drug-conditioned cues. Identifying successful treatments to mitigate cue-induced relapse has been challenging, perhaps due to extinction memory recall (EMR) deficits. Previously, inhibition of estradiol (E2) signaling in the basolateral amygdala (BLA) impaired heroin-cue EMR. This effect was recapitulated by antagonism of BLA estrogen receptors (ER) in a sex-specific manner such that blocking ERα in males, but ERß in females, impaired EMR. However, it is unclear whether increased E2 signaling, in the BLA or systemically, enhances heroin-cue EMR. We hypothesized that ERß agonism would enhance heroin-cue EMR in a sex- and region-specific manner. To determine the capacity of E2 signaling to improve EMR, we pharmacologically manipulated ERß across several translationally designed experiments. First, male and female rats acquired heroin or sucrose self-administration. Next, during a cued extinction session, we administered diarylpropionitrile (DPN, an ERß agonist) and tested anxiety-like behavior on an open field. Subsequently, we assessed EMR in a cue-induced reinstatement test and, finally, measured ERß expression in several brain regions. Across all experiments, females took more heroin and sucrose than males and had greater responses during heroin-cued extinction. Administration of DPN in the BLA enhanced EMR in females only, driven by ERß's impacts on memory consolidation. Interestingly, however, systemic DPN administration improved EMR for heroin cues in both sexes across several different tests, but did not impact sucrose-cue EMR. Immunohistochemical analysis of ERß expression across several different brain regions showed that females only had greater expression of ERß in the basal nucleus of the BLA. Here, in several preclinical experiments, we demonstrated that ERß agonism enhances heroin-cue EMR and has potential utility in combatting cue-induced relapse.
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Sinais (Psicologia) , Receptor beta de Estrogênio , Extinção Psicológica , Heroína , Rememoração Mental , Animais , Masculino , Feminino , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/metabolismo , Heroína/farmacologia , Ratos , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Rememoração Mental/efeitos dos fármacos , Rememoração Mental/fisiologia , Nitrilas/farmacologia , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Propionatos/farmacologia , Fatores Sexuais , Autoadministração , Ratos Sprague-Dawley , Dependência de Heroína/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Binge drinking is common among adolescents despite mounting evidence linking it to various adverse health outcomes that include heightened pain perception. The prelimbic (PrL) cortex is vulnerable to insult from adolescent alcohol exposure and receives input from the basolateral amygdala (BLA) while sending projections to the ventrolateral periaqueductal gray (vlPAG) - two brain regions implicated in nociception. In this study, adolescent intermittent ethanol (AIE) exposure was carried out in male and female rats using a vapor inhalation procedure. Assessments of mechanical and thermal sensitivity revealed that AIE exposure induced protracted mechanical allodynia. To investigate synaptic function at BLA inputs onto defined populations of PrL neurons, retrobeads and viral labelling were combined with optogenetics and slice electrophysiology. Recordings from retrobead labelled cells in the PrL revealed AIE reduced BLA driven feedforward inhibition of neurons projecting from the PrL to the vlPAG, resulting in augmented excitation/inhibition (E/I) balance and increased intrinsic excitability. Consistent with this finding, recordings from virally tagged PrL parvalbumin interneurons (PVINs) demonstrated that AIE exposure reduced both E/I balance at BLA inputs onto PVINs and PVIN intrinsic excitability. These findings provide compelling evidence that AIE alters synaptic function and intrinsic excitability within a prefrontal nociceptive circuit.
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Corticostriatal projection neurons from prelimbic medial prefrontal cortex to the nucleus accumbens core critically regulate drug-seeking behaviors, yet the underlying encoding dynamics whereby these neurons contribute to drug seeking remain elusive. Here we use two-photon calcium imaging to visualize the activity of corticostriatal neurons in mice from the onset of heroin use to relapse. We find that the activity of these neurons is highly heterogeneous during heroin self-administration and seeking, with at least 8 distinct neuronal ensembles that display both excitatory and inhibitory encoding dynamics. These neuronal ensembles are particularly apparent during relapse, where excitatory responses are amplified compared to heroin self-administration. Moreover, we find that optogenetic inhibition of corticostriatal projection neurons attenuates heroin seeking regardless of the relapse trigger. Our results reveal the precise corticostriatal activity dynamics underlying drug-seeking behaviors and support a key role for this circuit in mediating relapse to drug seeking.
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Dependence is a hallmark of alcohol use disorder characterized by excessive alcohol intake and withdrawal symptoms. The central nucleus of the amygdala (CeA) is a key brain structure underlying the synaptic and behavioral consequences of ethanol dependence. While accumulating evidence suggests that astrocytes regulate synaptic transmission and behavior, there is a limited understanding of the role astrocytes play in ethanol dependence. The present study used a combination of viral labeling, super resolution confocal microscopy, 3D image analysis, and slice electrophysiology to determine the effects of chronic intermittent ethanol (CIE) exposure on astrocyte plasticity in the CeA. During withdrawal from CIE exposure, we observed increased GABA transmission, an upregulation in astrocytic GAT3 levels, and an increased proximity of astrocyte processes near CeA synapses. Furthermore, GAT3 levels and synaptic proximity were positively associated with voluntary ethanol drinking in dependent rats. Slice electrophysiology confirmed that the upregulation in astrocytic GAT3 levels was functional, as CIE exposure unmasked a GAT3-sensitive tonic GABA current in the CeA. A causal role for astrocytic GAT3 in ethanol dependence was assessed using viral-mediated GAT3 overexpression and knockdown approaches. However, GAT3 knockdown or overexpression had no effect on somatic withdrawal symptoms, dependence-escalated ethanol intake, aversion-resistant drinking, or post-dependent ethanol drinking in male or female rats. Moreover, intra-CeA pharmacological inhibition of GAT3 also did not alter dependent ethanol drinking. Together, these findings indicate that ethanol dependence induces GABAergic dysregulation and astrocyte plasticity in the CeA. However, astrocytic GAT3 does not appear necessary for the drinking related phenotypes associated with dependence.
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Lack of behavioral suppression typifies substance use disorders, yet the neural circuit underpinnings of drug-induced behavioral disinhibition remain unclear. Here, we employ deep-brain two-photon calcium imaging in heroin self-administering mice, longitudinally tracking adaptations within a paraventricular thalamus to nucleus accumbens behavioral inhibition circuit from the onset of heroin use to reinstatement. We find that select thalamo-accumbal neuronal ensembles become profoundly hypoactive across the development of heroin seeking and use. Electrophysiological experiments further reveal persistent adaptations at thalamo-accumbal parvalbumin interneuronal synapses, whereas functional rescue of these synapses prevents multiple triggers from initiating reinstatement of heroin seeking. Finally, we find an enrichment of µ-opioid receptors in output- and cell-type-specific paraventricular thalamic neurons, which provide a mechanism for heroin-induced synaptic plasticity and behavioral disinhibition. These findings reveal key circuit adaptations that underlie behavioral disinhibition in opioid dependence and further suggest that recovery of this system would reduce relapse susceptibility.
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Heroína , Transtornos Relacionados ao Uso de Opioides , Ratos , Camundongos , Animais , Heroína/farmacologia , Ratos Sprague-Dawley , Autoadministração/métodos , Neurônios , Núcleo Accumbens/fisiologiaRESUMO
Aim: N-acetylcysteine (NAC) decreases inflammation and could augment perioperative analgesia. Materials & methods: This prospective pilot trial examined postoperative opioid consumption at 12 h following intraoperative NAC. In phase I, 20 adults scheduled for posterior spine surgery were randomized to NAC (0, 50, 100 and 150 mg/kg) to determine the optimal dose. In phase II, 30 patients were randomized to placebo or NAC (150 mg/kg). Opioid consumption, pain ratings and time to opioid rescue were recorded. Results: Postoperative opioid consumption was reduced in the NAC group 19.3% at 12 h and 20% at 18 and 36 h. Opioid consumption was reduced 22-24% in the NAC group at all times after adjusting for intraoperative opioid administration. NAC subjects reported lower pain scores relative to placebo. Conclusion: Subjects randomized to NAC consumed less postoperative opioids and reported less pain versus placebo. Larger randomized controlled trials are needed to further evaluate NAC for analgesia. Clinical Trial Registration: NCT04562597 (ClinicalTrials.gov).
N-acetylcysteine (NAC) is a powerful anti-inflammatory drug used to treat some types of poisoning. It could help pain for patients after surgery. This study looked at how much pain medicine patients needed after back surgery when they received NAC or no drug (placebo). In the first 20 patients, people randomly received placebo or a small, medium or large dose of NAC (0, 50, 100, and 150 mg/kg) with five patients in each group. Since there were only a small number of patients, it was difficult to see any definite differences, and the next 30 patient patients randomly received placebo or the large dose of NAC (150 mg/kg). Patients that were given NAC received 1622% less opioids in the first 2 days after surgery compared with those that were given placebo. NAC patients also took longer to request pain medications after surgery and reported lower pain scores in the first 2 days after surgery relative to placebo.
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Acetilcisteína , Analgésicos Opioides , Adulto , Humanos , Acetilcisteína/uso terapêutico , Analgésicos Opioides/uso terapêutico , Método Duplo-Cego , Dor Pós-Operatória/tratamento farmacológico , Projetos Piloto , Estudos ProspectivosRESUMO
Return to methamphetamine (meth) use is part of an overarching addictive disorder hallmarked by cognitive sequela and cortical dysfunction in individuals who use meth chronically. In rats, long access meth self-administration produces object recognition memory deficits due to drug-induced plasticity within the perirhinal cortex (PRH). PRH projections are numerous and include the medial prefrontal cortex (mPFC). To evaluate the role of the PRH-mPFC reciprocal circuit in novel object recognition memory, a rgAAV encoding GFP-tagged Cre recombinase was infused into the PRH or the mPFC and rats were tested for recognition memory. On test day, one group explored both familiar and novel objects. A second group explored only familiar objects. GFP and Fos expression were visualized in the mPFC or PRH. During exploration, PRH neurons receiving input from the mPFC were equally activated by exploration of novel and familiar objects. In contrast, PRH neurons that provide input to the mPFC were disproportionately activated by novel objects. Further, the percent of Fos + cells in the PRH positively correlated with recognition memory. As such, the flow of communication appears to be from the PRH to the mPFC. In agreement with this proposed directionality, chemogenetic inhibition of the PRH-mPFC circuit impaired object recognition memory, whereas chemogenetic activation in animals with a history of long access meth self-administration reversed the meth-induced recognition memory deficit. This finding informs future work aimed at understanding the role of the PRH, mPFC, and their connectivity in meth associated memory deficits. These data suggest a more complex circuitry governing recognition memory than previously indicated with anatomical or lesion studies.
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Metanfetamina , Ratos , Animais , Reconhecimento Psicológico , Transtornos da Memória/metabolismo , Córtex Pré-Frontal/metabolismo , Percepção VisualRESUMO
Clinical and preclinical studies indicate that adaptations in corticostriatal neurotransmission significantly contribute to heroin relapse vulnerability. In animal models, heroin self-administration and extinction produce cellular adaptations in both neurons and astrocytes within the nucleus accumbens (NA) core that are required for cue-induced heroin seeking. Specifically, decreased glutamate clearance and reduced association of perisynaptic astrocytic processes with NAcore synapses allow glutamate release from prelimbic (PrL) cortical terminals to engage synaptic and structural plasticity in NAcore medium spiny neurons. Normalizing astrocyte glutamate homeostasis with drugs like the antioxidant N-acetylcysteine (NAC) prevents cue-induced heroin seeking. Surprisingly, little is known about heroin-induced alterations in astrocytes or pyramidal neurons projecting to the NAcore in the PrL cortex (PrL-NAcore). Here, we observe functional adaptations in the PrL cortical astrocyte following heroin self-administration (SA) and extinction as measured by the electrophysiologically evoked plasmalemmal glutamate transporter 1 (GLT-1)-dependent current. We likewise observed the increased complexity of the glial fibrillary acidic protein (GFAP) cytoskeletal arbor and increased association of the astrocytic plasma membrane with synaptic markers following heroin SA and extinction training in the PrL cortex. Repeated treatment with NAC during extinction reversed both the enhanced astrocytic complexity and synaptic association. In PrL-NAcore neurons, heroin SA and extinction decreased the apical tuft dendritic spine density and enlarged dendritic spine head diameter in male Sprague-Dawley rats. Repeated NAC treatment during extinction prevented decreases in spine density but not dendritic spine head expansion. Moreover, heroin SA and extinction increased the co-registry of the GluA1 subunit of AMPA receptors in both the dendrite shaft and spine heads of PrL-NAcore neurons. Interestingly, the accumulation of GluA1 immunoreactivity in spine heads was further potentiated by NAC treatment during extinction. Finally, we show that the NAC treatment and elimination of thrombospondin 2 (TSP-2) block cue-induced heroin relapse. Taken together, our data reveal circuit-level adaptations in cortical dendritic spine morphology potentially linked to heroin-induced alterations in astrocyte complexity and association at the synapses. Additionally, these data demonstrate that NAC reverses PrL cortical heroin SA-and-extinction-induced adaptations in both astrocytes and corticostriatal neurons.
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Acetilcisteína , Heroína , Ratos , Animais , Masculino , Ratos Sprague-Dawley , Heroína/farmacologia , Acetilcisteína/farmacologia , Astrócitos , Sinapses , Glutamatos , RecidivaRESUMO
Chronic stress can produce reward system deficits (i.e., anhedonia) and other common symptoms associated with depressive disorders, as well as neural circuit hypofunction in the medial prefrontal cortex (mPFC). However, the molecular mechanisms by which chronic stress promotes depressive-like behavior and hypofrontality remain unclear. We show here that the neuronal activity-regulated transcription factor, NPAS4, in the mPFC is regulated by chronic social defeat stress (CSDS), and it is required in this brain region for CSDS-induced changes in sucrose preference and natural reward motivation in the mice. Interestingly, NPAS4 is not required for CSDS-induced social avoidance or anxiety-like behavior. We also find that mPFC NPAS4 is required for CSDS-induced reductions in pyramidal neuron dendritic spine density, excitatory synaptic transmission, and presynaptic function, revealing a relationship between perturbation in excitatory synaptic transmission and the expression of anhedonia-like behavior in the mice. Finally, analysis of the mice mPFC tissues revealed that NPAS4 regulates the expression of numerous genes linked to glutamatergic synapses and ribosomal function, the expression of upregulated genes in CSDS-susceptible animals, and differentially expressed genes in postmortem human brains of patients with common neuropsychiatric disorders, including depression. Together, our findings position NPAS4 as a key mediator of chronic stress-induced hypofrontal states and anhedonia-like behavior.
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Anedonia , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Derrota Social , Animais , Humanos , Camundongos , Anedonia/fisiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Depressão , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/fisiologia , Comportamento Social , Estresse Psicológico/psicologia , Sinapses/metabolismoRESUMO
Over the last 15 years, the field of neuroscience has evolved toward recognizing the critical role of astroglia in shaping neuronal synaptic activity and along with the pre- and postsynapse is now considered an equal partner in tripartite synaptic transmission and plasticity. The relative youth of this recognition and a corresponding deficit in reagents and technologies for quantifying and manipulating astroglia relative to neurons continues to hamper advances in understanding tripartite synaptic physiology. Nonetheless, substantial advances have been made and are reviewed herein. We review the role of astroglia in synaptic function and regulation of behavior with an eye on how tripartite synapses figure into brain pathologies underlying behavioral impairments in psychiatric disorders, both from the perspective of measures in postmortem human brains and more subtle influences on tripartite synaptic regulation of behavior in animal models of psychiatric symptoms. Our goal is to provide the reader a well-referenced state-of-the-art understanding of current knowledge and predict what we may discover with deeper investigation of tripartite synapses using reagents and technologies not yet available.
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Astrócitos , Transtornos Mentais , Animais , Humanos , Adolescente , Astrócitos/fisiologia , Transmissão Sináptica/fisiologia , Sinapses/fisiologia , Neurônios/fisiologia , Plasticidade Neuronal/fisiologiaRESUMO
Suppression of dangerous or inappropriate reward-motivated behaviors is critical for survival, whereas therapeutic or recreational opioid use can unleash detrimental behavioral actions and addiction. Nevertheless, the neuronal systems that suppress maladaptive motivated behaviors remain unclear, and whether opioids disengage those systems is unknown. In a mouse model using two-photon calcium imaging in vivo, we identify paraventricular thalamostriatal neuronal ensembles that are inhibited upon sucrose self-administration and seeking, yet these neurons are tonically active when behavior is suppressed by a fear-provoking predator odor, a pharmacological stressor, or inhibitory learning. Electrophysiological, optogenetic, and chemogenetic experiments reveal that thalamostriatal neurons innervate accumbal parvalbumin interneurons through synapses enriched with calcium permeable AMPA receptors, and activity within this circuit is necessary and sufficient for the suppression of sucrose seeking regardless of the behavioral suppressor administered. Furthermore, systemic or intra-accumbal opioid injections rapidly dysregulate thalamostriatal ensemble dynamics, weaken thalamostriatal synaptic innervation of downstream neurons, and unleash reward-seeking behaviors in a manner that is reversed by genetic deletion of thalamic µ-opioid receptors. Overall, our findings reveal a thalamostriatal to parvalbumin interneuron circuit that is both required for the suppression of reward seeking and rapidly disengaged by opioids.
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Analgésicos Opioides , Parvalbuminas , Camundongos , Animais , Analgésicos Opioides/farmacologia , Cálcio , Recompensa , SacaroseRESUMO
Astrocytes are critical components of neural circuits positioned in close proximity to the synapse, allowing them to rapidly sense and respond to neuronal activity. One repeatedly observed biomarker of astroglial activation is an increase in intracellular Ca2+ levels. These astroglial Ca2+ signals are often observed spreading throughout various cellular compartments from perisynaptic astroglial processes, to major astrocytic branches and on to the soma or cell body. Here we review recent evidence demonstrating that astrocytic Ca2+ events are remarkably heterogeneous in both form and function, propagate through the astroglial syncytia, and are directly linked to the ability of astroglia to influence local neuronal activity. As many of the cellular functions of astroglia can be linked to intracellular Ca2+ signaling, and the diversity and heterogeneity of these events becomes more apparent, there is an increasing need for novel experimental strategies designed to better understand the how these signals evolve in parallel with neuronal activity. Here we review the recent advances that enable the characterization of both subcellular and population-wide astrocytic Ca2+ dynamics. Additionally, we also outline the experimental design required for simultaneous in vivo Ca2+ imaging in the context of neuronal or astroglial manipulation, highlighting new experimental strategies made possible by recent advances in viral vector, imaging, and quantification technologies. Through combined usage of these reagents and methodologies, we provide a conceptual framework to study how astrocytes functionally integrate into neural circuits and to what extent they influence and direct the synaptic activity underlying behavioral responses.
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Background: Prelimbic cortical projections to the nucleus accumbens core are critical for cue-induced cocaine seeking, but the identity of the accumbens neuron(s) targeted by this projection, and the transient neuroadaptations contributing to relapse within these cells, remain unknown. Methods: Male Sprague-Dawley rats underwent cocaine or sucrose self-administration, extinction, and cue-induced reinstatement. Pathway-specific chemogenetics, patch-clamp electrophysiology, in vivo electrochemistry, and high-resolution confocal microscopy were used to identify and characterize a small population of nucleus accumbens core neurons that receive dense prelimbic cortical input to determine their role in regulating cue-induced cocaine and natural reward seeking. Results: Chemogenetic inhibition of prelimbic cortical projections to the nucleus accumbens core suppressed cue-induced cocaine relapse and normalized real-time cue-evoked increases in accumbens glutamate release to that of sucrose seeking animals. Furthermore, chemogenetic inhibition of the population of nucleus accumbens core neurons receiving the densest prelimbic cortical input suppressed cocaine, but not sucrose seeking. These neurons also underwent morphological plasticity during the peak of cocaine seeking in the form of dendritic spine expansion and increased ensheathment by astroglial processes at large spines. Conclusion: We identified and characterized a unique subpopulation of nucleus accumbens neurons that receive dense prelimbic cortical input. The functional specificity of this subpopulation is underscored by their ability to mediate cue-induced cocaine relapse, but not sucrose seeking. This subset of cells represents a novel target for addiction therapeutics revealed by anterograde targeting to interrogate functional circuits imbedded within a known network.
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Alcohol consumption in adolescence causes multiple acute negative changes in neural and behavioral function that persist well into adulthood and possibly throughout life. The medial prefrontal cortex (mPFC) and dorsal hippocampus are critical for executive function and memory and are especially vulnerable to adolescent ethanol exposure. We have reported that astrocytes, particularly in the mPFC, change both in morphology and synaptic proximity during adolescence. Moreover, adolescent intermittent ethanol (AIE) exposure produces enduring effects on both astrocyte function and synaptic proximity in the adult hippocampal formation, and the latter effect was reversed by the clinically used agent gabapentin (Neurontin), an anticonvulsant and analgesic that is an inhibitor of the VGCC α2δ1 subunit. These findings underscore the importance of investigating AIE effects on astrocytes in the mPFC, a region that undergoes marked changes in structure and connectivity during adolescence. Using astrocyte-specific viral labeling and immunohistochemistry, mPFC astrocytic morphology and colocalization with AMPA-(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) glutamate receptor 1 (GluA1), an AMPA receptor subunit and established neuronal marker of excitatory synapses, were assessed to quantify the proximity of astrocyte processes with glutamatergic synaptic puncta. AIE exposure significantly reduced astrocyte-synaptic proximity in adulthood, an effect that was reversed by sub-chronic gabapentin treatment in adulthood. There was no effect of AIE on astrocytic glutamate homeostasis machinery or neuronal synaptic proteins in the mPFC. These findings indicate a possible glial-neuronal mechanism underlying the effects of AIE on frontal lobe-mediated behaviors and suggest a specific therapeutic approach for the amelioration of those effects.
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Binge drinking during adolescence is highly prevalent despite increasing evidence of its long-term impact on behaviors associated with modulation of behavioral flexibility by the medial prefrontal cortex (mPFC). In the present study, male and female rats underwent adolescent intermittent ethanol (AIE) exposure by vapor inhalation. After aging to adulthood, retrograde bead labelling and viral tagging were used to identify populations of neurons in the prelimbic region (PrL) of the mPFC that project to specific subcortical targets. Electrophysiological recording from bead-labelled neurons in PrL slices revealed that AIE did not alter the intrinsic excitability of PrL neurons that projected to either the NAc or the BLA. Similarly, recordings of spontaneous inhibitory and excitatory post-synaptic currents revealed no AIE-induced changes in synaptic drive onto either population of projection neurons. In contrast, AIE exposure was associated with a loss of dopamine receptor 1 (D1), but no change in dopamine receptor 2 (D2), modulation of evoked firing of both populations of projection neurons. Lastly, confocal imaging of proximal and apical dendritic tufts of viral-labelled PrL neurons that projected to the nucleus accumbens (NAc) revealed AIE did not alter the density of dendritic spines. Together, these observations provide evidence that AIE exposure results in disruption of D1 receptor modulation of PrL inputs to at least two major subcortical target regions that have been implicated in AIE-induced long-term changes in behavioral control.
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Methamphetamine (meth) causes enduring changes within the medial prefrontal cortex (mPFC) and the nucleus accumbens (NA). Projections from the mPFC to the NA have a distinct dorsal-ventral distribution, with the prelimbic (PL) mPFC projecting to the NAcore, and the infralimbic (IL) mPFC projecting to the NAshell. Inhibition of these circuits has opposing effects on cocaine relapse. Inhibition of PL-NAcore reduces cued reinstatement of cocaine seeking and IL-NAshell inhibition reinstates cocaine seeking. Meth, however, exhibits a different profile, as pharmacological inhibition of either the PL or IL decrease cued reinstatement of meth-seeking. The potentially opposing roles of the PL-NAcore and IL-NAshell projections remain to be explored in the context of cued meth seeking. Here we used an intersectional viral vector approach that employs a retrograde delivery of Cre from the NA and Cre-dependent expression of DREADD in the mPFC, in both male and female rats to inhibit or activate these parallel pathways. Inhibition of the PL-NAcore circuit reduced cued reinstatement of meth seeking under short and long-access meth self-administration and after withdrawal with and without extinction. Inhibition of the IL-NAshell also decreased meth cued reinstatement. Activation of the parallel circuits was without an effect. These studies show that inhibition of the PL-NAcore or the IL-NAshell circuits can inhibit reinstated meth seeking. Thus, the neural circuitry mediating cued reinstatement of meth seeking is similar to cocaine in the dorsal, but not ventral, mPFC-NA circuit.
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Fator 2 Ativador da Transcrição/farmacologia , Sinais (Psicologia) , Comportamento de Procura de Droga/efeitos dos fármacos , Metanfetamina , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Astroglia are key regulators of synaptic function, playing central roles in homeostatic ion buffering, energy dynamics, transmitter uptake, maintenance of neurotransmitter pools, and regulation of synaptic plasticity through release of neuroactive chemicals. Given the myriad of crucial homeostatic and signaling functions attributed to astrocytes and the variety of neurotransmitter receptors expressed by astroglia, they serve as prime cellular candidates for establishing maladaptive synaptic plasticity following drug exposure. Initial studies on astroglia and addiction have placed drug-mediated disruptions in the homeostatic regulation of glutamate as a central aspect of relapse vulnerability. However, the generation of sophisticated tools to study and manipulate astroglia have proven that the interaction between addictive substances, astroglia, and relapse-relevant synaptic plasticity extends far beyond the homeostatic regulation of glutamate. Here we present astroglial systems impacted by drug exposure and discuss how changes in astroglial biology contribute to addiction biology.
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Astrócitos , Sinapses , Ácido Glutâmico , Humanos , Plasticidade Neuronal , Transdução de SinaisRESUMO
Chronic use of drugs of abuse affects neuroimmune signaling; however, there are still many open questions regarding the interactions between neuroimmune mechanisms and substance use disorders (SUDs). Further, chronic use of drugs of abuse can induce glutamatergic changes in the brain, but the relationship between the glutamate system and neuroimmune signaling in addiction is not well understood. Therefore, the purpose of this review is to bring into focus the role of neuroimmune signaling and its interactions with the glutamate system following chronic drug use, and how this may guide pharmacotherapeutic treatment strategies for SUDs. In this review, we first describe neuroimmune mechanisms that may be linked to aberrant glutamate signaling in addiction. We focus specifically on the nuclear factor-kappa B (NF-κB) pathway, a potentially important neuroimmune mechanism that may be a key player in driving drug-seeking behavior. We highlight the importance of astroglial-microglial crosstalk, and how this interacts with known glutamatergic dysregulations in addiction. Then, we describe the importance of studying non-neuronal cells with unprecedented precision because understanding structure-function relationships in these cells is critical in understanding their role in addiction neurobiology. Here we propose a working model of neuroimmune-glutamate interactions that underlie drug use motivation, which we argue may aid strategies for small molecule drug development to treat substance use disorders. Together, the synthesis of this review shows that interactions between glutamate and neuroimmune signaling may play an important and understudied role in addiction processes and may be critical in developing more efficacious pharmacotherapies to treat SUDs.