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The idea that interconnected neuronal ensembles code for specific behaviors has been around for decades; however, recent technical improvements allow studying these networks and their causal role in initiating and maintaining behavior. In particular, the role of ensembles in drug-seeking behaviors in the context of addiction is being actively investigated. Concurrent with breakthroughs in quantifying ensembles, research has identified a role for synaptic glutamate spillover during relapse. In particular, the transient relapse-associated changes in glutamatergic synapses on accumbens neurons, as well as in adjacent astroglia and extracellular matrix, are key elements of the synaptic plasticity encoded by drug use and the metaplasticity induced by drug-associated cues that precipitate drug-seeking behaviors. Here, we briefly review the recent discoveries related to ensembles in the addiction field and then endeavor to link these discoveries with drug-induced striatal plasticity and cue-induced metaplasticity toward deeper neurobiological understandings of drug seeking.

The idea that interconnected neuronal ensembles code for specific behaviors has been around for decades; however, recent technical improvements allow studying these networks and their causal role in initiating and maintaining behavior. In particular, the role of ensembles in drug-seeking behaviors in the context of addiction is being actively investigated. Concurrent with breakthroughs in quantifying ensembles, research has identified a role for synaptic glutamate spillover during relapse. In particular, the transient relapse-associated changes in glutamatergic synapses on accumbens neurons, as well as in adjacent astroglia and extracellular matrix, are key elements of the synaptic plasticity encoded by drug use and the metaplasticity induced by drug-associated cues that precipitate drug-seeking behaviors. Here, we briefly review the recent discoveries related to ensembles in the addiction field and then endeavor to link these discoveries with drug-induced striatal plasticity and cue-induced metaplasticity toward deeper neurobiological understandings of drug seeking.

Introduction: It is well known that chronic opioid use disorder is associated with alterations in gastrointestinal (GI) function that include constipation, reduced motility, and increased bacterial translocation due to compromised gut barrier function. These signs of disrupted GI function can be associated with alterations in the gut microbiome. However, it is not known if long-access opioid selfadministration has effects on the gut microbiome. Methods: We used 16S rRNA gene sequencing to investigate the gut microbiome in three independent cohorts (N=40 for each) of NIH heterogeneous stock rats before onset of long-access heroin self-administration (i.e., naïve status), at the end of a 15-day period of self-administration, and after post-extinction reinstatement. Measures of microbial a- and b-diversity were evaluated for all phases. High-dimensional class comparisons were carried out with MaAsLin2. PICRUSt2 was used for predicting functional pathways impacted by heroin based on marker gene sequences. Results: Community α-diversity was not altered by heroin at any of the three phases by comparison to saline-yoked controls. Analyses of b-diversity showed that the heroin and saline-yoked groups clustered significantly apart from each other using the Bray-Curtis (community structure) index. Heroin caused significant alterations at the ASV level at the self-administration and extinction phases. At the phylum level, the relative abundance of Firmicutes was increased at the self-administration phase. Deferribacteres was decreased in heroin whereas Patescibacteria was increased in heroin at the extinction phase. Potential biomarkers for heroin emerged from the MaAsLin2 analysis. Bacterial metabolomic pathways relating to degradation of carboxylic acids, nucleotides, nucleosides, carbohydrates, and glycogen were increased by heroin while pathways relating to biosynthesis of vitamins, propionic acid, fatty acids, and lipids were decreased. Discussion: These findings support the view that long access heroin selfadministration significantly alters the structure of the gut microbiome by comparison to saline-yoked controls. Inferred metabolic pathway alterations suggest the development of a microbial imbalance favoring gut inflammation and energy expenditure. Potential microbial biomarkers and related functional pathways likely invoked by heroin self-administration could be targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies.

The infralimbic cortex (IL) regulates the consolidation of extinction learning for fear conditioning. Whether the IL influences the consolidation of extinction learning for cocaine self-administration is unknown. To address this issue, male Sprague-Dawley rats underwent 2 wk of cocaine self-administration followed by extinction training. On the first 5 d of extinction, rats underwent brief (15- or 30-min) extinction sessions and received intra-IL microinjections immediately after each extinction session. On days 6-12 of extinction, rats underwent full-length (2-h) extinction sessions that were used to assess the retention of the extinction learning from the short sessions. IL inactivation via microinjections of the GABA agonists baclofen and muscimol (BM) immediately after the extinction sessions (days 1-5) impaired the retention of extinction learning. Control experiments demonstrated that this effect was not due to inactivation of the prelimbic cortex or due to effects of the drugs on the subsequent day's behavior. In contrast, post-training intra-IL microinjections of the allosteric AMPA receptor potentiator 4-[2-(phenylsulfonylamino)ethylthio]-2,6-ifluorophenoxyacetamide (PEPA) enhanced retention of the extinction learning. As evidence suggests a role for the [beta]-adrenergic receptors in memory consolidation, other rats received microinjections of the [beta][subscript 2]-adrenergic receptor agonist clenbuterol or antagonist ICI-118,551 (ICI). Post-training intra-IL administration of clenbuterol or pre-training administration of ICI enhanced or impaired, respectively, the retention of extinction learning. These data indicate that the IL, and specifically the glutamatergic and [beta]-adrenergic systems in the IL, regulates the consolidation of extinction of cocaine self-administration and that the IL can be manipulated to influence the retention of extinction.