Disengagement of somatostatin neurons from lateral septum circuitry by oxytocin and vasopressin restores social-fear extinction and suppresses aggression outbursts in Prader-Willi syndrome model.

Background: Responding to social signals by expressing the correct behavior is not only challenged in autism, but also in diseases with high prevalence of autism, like Prader-Willi Syndrome (PWS). Clinical evidence suggests aberrant pro-social behavior in patients can be regulated by intranasal oxytocin (OXT) or vasopressin (AVP). However, what neuronal mechanisms underlie impaired behavioral responses in a socially-aversive context, and how can they be corrected, remains largely unknown. Methods: Using the Magel2 knocked-out (KO) mouse model of PWS (crossed with CRE-dependent transgenic lines), we devised optogenetic, physiological and pharmacological strategies in a social-fear-conditioning paradigm. Pathway specific roles of OXT and AVP signaling were investigated converging on the lateral septum (LS), a region which receives dense hypothalamic inputs. Results: OXT and AVP signaling promoted inhibitory synaptic transmission in the LS, which failure in Magel2KO mice disinhibited somatostatin (SST) neurons and disrupted social-fear extinction. The source of OXT and AVP deficits mapped specifically in the supraoptic nucleus→LS pathway of Magel2KO mice disrupting social-fear extinction, which could be corrected by optogenetic or pharmacological inhibition of SST-neurons in the LS. Interestingly, LS SST-neurons also gated the expression of aggressive behavior, possibly as part of functional units operating beyond local septal circuits. Conclusions: SST cells in the LS play a crucial role in integration and expression of disrupted neuropeptide signals in autism, thereby altering the balance in expression of safety versus fear. Our results uncover novel mechanisms underlying dysfunction in a socially-aversive context, and provides a new framework for future treatments in autism-spectrum disorders.

Estrogen receptor beta signaling enhances extinction memory recall for heroin-conditioned cues in a sex- and region-specific manner.

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.

Exogenous glucocorticoids to improve extinction learning for post-traumatic stress disorder patients with hypothalamic-pituitary-adrenal-axis dysregulation: a study protocol description.

Background: Trauma-focused treatments for post-traumatic stress disorder (PTSD) are effective for many patients. However, relapse may occur when acquired extinction memories fail to generalize beyond treatment contexts. A subgroup of PTSD patients - potentially with substantial exposure to early-life adversity (ELA) - show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which results in lower cortisol levels. Glucocorticoids, including cortisol, appear to facilitate strength and generalization of emotional memories.Objective: We describe the protocol of an integrated PTSD study. We investigate (A) associations between HPA-axis dysregulation, ELA, epigenetic markers, and PTSD treatment outcome (observational study); and (B) effects of exogenous glucocorticoids on strength and generalization of extinction memories and associated neural mechanisms [pharmacological intervention study with functional magnetic resonance imaging (fMRI)]. The objective is to provide proof of concept that PTSD patients with HPA-axis dysregulation often experienced ELA and may show improved strength and generalization of extinction learning after glucocorticoid administration.Method: The observational study (n = 160 PTSD group, n = 30 control group) assesses ELA, follow-up PTSD symptoms, epigenetic markers, and HPA-axis characteristics (salivary cortisol levels during low-dose dexamethasone suppression test and socially evaluated cold-pressor test). The pharmacological intervention study (n = 80 PTSD group, with and without HPA-axis dysregulation) is a placebo-controlled fMRI study with a crossover design. To investigate strength and generalization of extinction memories, we use a differential fear acquisition, extinction, and extinction recall task with spatial contexts within a virtual environment. Prior to extinction learning, 20 mg hydrocortisone or placebo is administered. During next-day recall, strength of the extinction memory is determined by recovery of skin conductance and pupil dilation differential responding, whereas generalization is assessed by comparing responses between different spatial contexts.Conclusion: The integrated study described in the current protocol paper could inform a personalized treatment approach in which these PTSD patients may receive glucocorticoids as a treatment enhancer in trauma-focused therapies.Trial registration: The research project is registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database, https://eudract.ema.europa.eu/, EudraCT number 2020-000712-30.

This protocol reports a proof-of-concept study for glucocorticoids as an enhancer for PTSD treatment.The study examines whether glucocorticoids enhance the strength and generalization of extinction memory.A further aim is to identify HPA-axis-related PTSD subgroups that may particularly benefit.

Cannabidiol effects on fear processing and implications for PTSD: Evidence from rodent and human studies.

Cannabidiol (CBD) modulates aversive memory and its extinction, with potential implications for treating anxiety- and stress-related disorders. Here, we summarize and discuss scientific evidence showing that CBD administered after the acquisition (consolidation) and retrieval (reconsolidation) of fear memory attenuates it persistently in rats and mice. CBD also reduces fear expression and enhances fear extinction. These effects involve the activation of cannabinoid type-1 (CB1) receptors in the dorsal hippocampus, bed nucleus of stria terminalis, and medial prefrontal cortex, comprising the anterior cingulate, prelimbic, and infralimbic subregions. Serotonin type-1A (5-HT1A) receptors also mediate some CBD effects on fear memory. CBD effects on fear memory acquisition vary, depending on the aversiveness of the conditioning procedure. While rodent findings are relatively consistent and encouraging, human studies investigating CBD's efficacy in modulating aversive/traumatic memories are still limited. More studies are needed to investigate CBD's effects on maladaptive, traumatic memories, particularly in post-traumatic stress disorder patients.

An ultra-short-acting benzodiazepine in thalamic nucleus reuniens undermines fear extinction via intermediation of hippocamposeptal circuits.

Benzodiazepines, commonly used for anxiolytics, hinder conditioned fear extinction, and the underlying circuit mechanisms are unclear. Utilizing remimazolam, an ultra-short-acting benzodiazepine, here we reveal its impact on the thalamic nucleus reuniens (RE) and interconnected hippocamposeptal circuits during fear extinction. Systemic or RE-specific administration of remimazolam impedes fear extinction by reducing RE activation through A type GABA receptors. Remimazolam enhances long-range GABAergic inhibition from lateral septum (LS) to RE, underlying the compromised fear extinction. RE projects to ventral hippocampus (vHPC), which in turn sends projections characterized by feed-forward inhibition to the GABAergic neurons of the LS. This is coupled with long-range GABAergic projections from the LS to RE, collectively constituting an overall positive feedback circuit construct that promotes fear extinction. RE-specific remimazolam negates the facilitation of fear extinction by disrupting this circuit. Thus, remimazolam in RE disrupts fear extinction caused by hippocamposeptal intermediation, offering mechanistic insights for the dilemma of combining anxiolytics with extinction-based exposure therapy.

Intense training prevents the amnestic effect of inactivation of dorsomedial striatum and induces high resistance to extinction.

A large body of evidence has shown that treatments that interfere with memory consolidation become ineffective when animals are subjected to an intense learning experience; this effect has been observed after systemic and local administration of amnestic drugs into several brain areas, including the striatum. However, the effects of amnestic treatments on the process of extinction after intense training have not been studied. Previous research demonstrated increased spinogenesis in the dorsomedial striatum, but not in the dorsolateral striatum after intense training, indicating that the dorsomedial striatum is involved in the protective effect of intense training. To investigate this issue, male Wistar rats, previously trained with low, moderate, or high levels of foot shock, were used to study the effect of tetrodotoxin inactivation of dorsomedial striatum on memory consolidation and subsequent extinction of inhibitory avoidance. Performance of the task was evaluated during seven extinction sessions. Tetrodotoxin produced a marked deficit of memory consolidation of inhibitory avoidance trained with low and moderate intensities of foot shock, but normal consolidation occurred when a relatively high foot shock was used. The protective effect of intense training was long-lasting, as evidenced by the high resistance to extinction exhibited throughout the extinction sessions. We discuss the possibility that increased dendritic spinogenesis in dorsomedial striatum may underly this protective effect, and how this mechanism may be related to the resilient memory typical of post-traumatic stress disorder (PTSD).

Differential effects of deep brain stimulation on reinstatement of cocaine seeking in male and female rats.

There are currently no FDA-approved treatments for cocaine use disorder. Recent preclinical and clinical studies showed that deep brain stimulation (DBS) in limbic regions reduced drug seeking behavior. Our previous work indicated that DBS of the nucleus accumbens shell attenuated reinstatement of cocaine seeking, a model of relapse, in male rats. The current experiments were designed to evaluate the effect of electrical DBS on cocaine reinstatement in female rats across the estrous cycle. Rats were allowed to self-administer cocaine and lever responding was subsequently extinguished. Cocaine seeking was reinstated by an acute injection of experimenter-delivered cocaine. The effect of nucleus accumbens shell DBS vs. sham stimulation on cocaine-primed reinstatement was evaluated in female and male rats using a within-subjects counterbalanced design. Consistent with previous work, accumbens shell DBS suppressed cocaine seeking in male rats. In sharp contrast, accumbens shell DBS had no effect on cocaine reinstatement in female rats evaluated in either the estrus or non-estrus phases. These results suggest that changes across the estrous cycle are not responsible for the differences in the effect of DBS on cocaine reinstatement between female and male rats.

Sex differences in extinction and reinstatement of nicotine discrimination in rats: The effects of reinforcer devaluation.

Nicotine functions effectively as an interoceptive operant discriminative stimulus (SD) that sets the occasion for voluntarily emitted behavior to be reinforced by biologically relevant outcomes (e.g., food). This has been demonstrated primarily with male rats. Far less is known about nicotine's operant SD functions in female rats. There are no reports of sex differences in extinction and recovery of the SD functions of nicotine, which may elucidate smoking cessation and relapse. In view of this, eight male and eight female rats were trained to nose poke differentially among quasirandomly intermixed sessions of food reinforcement variable interval (VI-30 s) and nonreinforcement in a go/no-go across session one-manipulanda operant drug discrimination procedure. For half the rats, presession administration of nicotine (0.30 mg/kg, subcutaneous) occasioned reinforcement sessions of nose pokes (i.e., SD); for the remaining rats, it occasioned nonreinforcement (SΔ). Saline sessions occasioned the opposite contingencies. Training was conducted first under feeding restriction and then under free feeding, which was then followed by extinction sessions that were also conducted with free feeding. During discrimination training, response rates for females did not differ from males when conducted under restricted feeding but did so during training and later extinction conducted under free feeding. Females also exhibited greater reinstatement of responding under the nicotine SD but not the SΔ. These data provide additional evidence for sex differences in rats with the discriminative stimulus functions of nicotine under low, but not high, food-drive states-and may have implications for sex/gender differences in smoking cessation and relapse. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Pharmacological manipulations of the dorsomedial and dorsolateral striatum during fear extinction reveal opposing roles in fear renewal.

Systemic manipulations that enhance dopamine (DA) transmission around the time of fear extinction can strengthen fear extinction and reduce conditioned fear relapse. Prior studies investigating the brain regions where DA augments fear extinction focus on targets of mesolimbic and mesocortical DA systems originating in the ventral tegmental area, given the role of these DA neurons in prediction error. The dorsal striatum (DS), a primary target of the nigrostriatal DA system originating in the substantia nigra (SN), is implicated in behaviors beyond its canonical role in movement, such as reward and punishment, goal-directed action, and stimulus-response associations, but whether DS DA contributes to fear extinction is unknown. We have observed that chemogenetic stimulation of SN DA neurons during fear extinction prevents the return of fear in contexts different from the extinction context, a form of relapse called renewal. This effect of SN DA stimulation is mimicked by a DA D1 receptor (D1R) agonist injected into the DS, thus implicating DS DA in fear extinction. Different DS subregions subserve unique functions of the DS, but it is unclear where in the DS D1R agonist acts during fear extinction to reduce renewal. Furthermore, although fear extinction increases neural activity in DS subregions, whether neural activity in DS subregions is causally involved in fear extinction is unknown. To explore the role of DS subregions in fear extinction, adult, male Long-Evans rats received microinjections of either the D1R agonist SKF38393 or a cocktail consisting of GABAA/GABAB receptor agonists muscimol/baclofen selectively into either dorsomedial (DMS) or dorsolateral (DLS) DS subregions immediately prior to fear extinction, and extinction retention and renewal were subsequently assessed drug-free. While increasing D1R signaling in the DMS during fear extinction did not impact fear extinction retention or renewal, DMS inactivation reduced later renewal. In contrast, DLS inactivation had no effect on fear extinction retention or renewal but increasing D1R signaling in the DLS during extinction reduced fear renewal. These data suggest that DMS and DLS activity during fear extinction can have opposing effects on later fear renewal, with the DMS promoting renewal and the DLS opposing renewal. Mechanisms through which the DS could influence the contextual gating of fear extinction are discussed.

Modulation of contextual fear acquisition and extinction by acute and chronic relaxin-3 receptor (RXFP3) activation in the rat retrosplenial cortex.

The retrosplenial cortex (RSC) plays a central role in processing contextual fear conditioning. In addition to corticocortical and thalamocortical projections, the RSC receives subcortical inputs, including a substantial projection from the nucleus incertus in the pontine tegmentum. This GABAergic projection contains the neuropeptide, relaxin-3 (RLN3), which inhibits target neurons via its Gi/o-protein-coupled receptor, RXFP3. To assess this peptidergic system role in contextual fear conditioning, we bilaterally injected the RSC of adult rats with an adeno-associated-virus (AAV), expressing the chimeric RXFP3 agonist R3/I5 or a control AAV, and subjected them to contextual fear conditioning. The R3/I5 injected rats did not display any major differences to control-injected and naïve rats but displayed a significantly delayed extinction. Subsequently, we employed acute bilateral injections of the specific RXFP3 agonist peptide, RXFP3-Analogue 2 (A2), into RSC. While the administration of A2 before each extinction trial had no impact on the extinction process, treatment with A2 before each acquisition trial resulted in delayed extinction. In related anatomical studies, we detected an enrichment of RLN3-immunoreactive nerve fibers in deep layers of the RSC, and a higher level of co-localization of RXFP3 mRNA with vesicular GABA transporter (vGAT) mRNA than with vesicular glutamate transporter-1 (vGLUT1) mRNA across the RSC, consistent with an effect of RLN3/RXFP3 signalling on the intrinsic, inhibitory circuits within the RSC. These findings suggest that contextual conditioning processes in the RSC involve, in part, RLN3 afferent modulation of local inhibitory neurons that provides a stronger memory acquisition which, in turn, retards the extinction process.

Vagus Nerve Stimulation (VNS) Modulates Synaptic Plasticity in the Infralimbic Cortex via Trk-B Receptor Activation to Reduce Drug-Seeking in Male Rats.

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in male rats trained to self-administer cocaine. Pairing 10 d of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay. Systemic blockade of tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in Layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates the extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction.

No harmful effect of propranolol administered prior to fear memory extinction in rats and humans.

Exposure therapy is an evidence-based treatment option for anxiety-related disorders. Many patients also take medication that could, in principle, affect exposure therapy efficacy. Clinical and laboratory evidence indeed suggests that benzodiazepines may have detrimental effects. Large clinical trials with propranolol, a common beta-blocker, are currently lacking, but several preclinical studies do indicate impaired establishment of safety memories. Here, we investigated the effects of propranolol given prior to extinction training in 9 rat studies (N = 215) and one human study (N = 72). A Bayesian meta-analysis of our rat studies provided strong evidence against propranolol-induced extinction memory impairment during a drug-free test, and the human study found no significant difference with placebo. Two of the rat studies actually suggested a small beneficial effect of propranolol. Lastly, two rat studies with a benzodiazepine (midazolam) group provided some evidence for a harmful effect on extinction memory, i.e., impaired extinction retention. In conclusion, our midazolam findings are in line with prior literature (i.e., an extinction retention impairment), but this is not the case for the 10 studies with propranolol. Our data thus support caution regarding the use of benzodiazepines during exposure therapy, but argue against a harmful effect of propranolol on extinction learning.

Treatment with dextroamphetamine decreases the reacquisition of cocaine self-administration: Consistency across social contexts.

RATIONALE: A return to cocaine use following abstinence frequently occurs in a social context, and the presence of other individuals using cocaine may contribute to the likelihood of use. Previous studies have reported that chronic d-amphetamine treatment decreases cocaine self-administration in laboratory animals and reduces a return to cocaine use following abstinence in humans. OBJECTIVE: The purpose of this study was to examine the effects of chronic d-amphetamine treatment on the reacquisition of cocaine use in rats self-administering cocaine in different social contexts. METHODS: Male and female rats were implanted with intravenous catheters and trained to self-administer cocaine during daily 6-hr sessions. After 14 days, cocaine self-administration was extinguished by substituting saline for the cocaine stimulus. At this time, rats were randomized to receive chronic treatment with either d-amphetamine or saline. After 9 days of extinction, cocaine was again made available during daily 6-hr sessions. At this time, rats were further randomized into three social conditions: (1) rats continued self-administering cocaine in isolation, (2) rats self-administered cocaine in the presence of a same-sex partner that also self-administered cocaine, or (3) rats self-administered cocaine in the presence of a same-sex partner that did not have access to cocaine. Daily treatment with d-amphetamine or saline continued for the duration of reacquisition testing. RESULTS: Chronic treatment with d-amphetamine decreased cocaine intake during reacquisition, but these effects were not influenced by the social context. No sex differences were observed. CONCLUSION: These data support previous studies reporting that d-amphetamine decreases cocaine intake and demonstrate its efficacy across social contexts.

Hippocampal D1-like dopamine receptor as a novel target for the effect of cannabidiol on extinction and reinstatement of methamphetamine-induced CPP.

Methamphetamine (METH) is a major health problem without effective pharmacological treatment. Cannabidiol (CBD), a component of the Cannabis sativa plant, is believed to have the potential to inhibit drug-related behavior. However, the neurobiological mechanisms responsible for the effects of CBD remain unclear. Several studies have proposed that the suppressing effects of CBD on drug-seeking behaviors could be through the modulation of the dopamine system. The hippocampus (HIP) D1-like dopamine receptor (D1R) is essential for forming and retrieving drug-associated memory. Therefore, the present study aimed to investigate the role of D1R in the hippocampal CA1 region on the effects of CBD on the extinction and reinstatement of METH-conditioned place preference (CPP). For this purpose, different groups of rats over a 10-day extinction period were administered different doses of intra-CA1 SCH23390 (0.25, 1, or 4 µg/0.5 µl, Saline) as a D1R antagonist before ICV injection of CBD (10 µg/5 µl, DMSO12%). In addition, a different set of animals received intra-CA1 SCH23390 (0.25, 1, or 4 µg/0.5 µl) before CBD injection (50 µg/5 µl) on the reinstatement day. The results revealed that the highest dose of SCH23390 (4 µg) significantly reduced the accelerating effects of CBD on the extinction of METH-CPP (P < 0.01). Furthermore, SCH23390 (1 and 4 µg) in the reinstatement phase notably reversed the preventive effects of CBD on the reinstatement of drug-seeking behavior (P < 0.05 and P < 0.001, respectively). In conclusion, the current study revealed that CBD made a shorter extinction period and suppressed METH reinstatement in part by interacting with D1-like dopamine receptors in the CA1 area of HIP.

Can glucose facilitate fear exposure? Randomized, placebo-controlled trials on the effects of glucose administration on fear extinction processes.

Previous studies showed that glucose has beneficial effects on memory function and can enhance contextual fear learning. To derive potential therapeutic interventions, further research is needed regarding the effects of glucose on fear extinction. In two experimental studies with healthy participants (Study 1: N = 68, 39 females; Study 2: N = 89, 67 females), we investigated the effects of glucose on fear extinction learning and its consolidation. Participants completed a differential fear conditioning paradigm consisting of acquisition, extinction, and return of fear tests: reinstatement, and extinction recall. US-expectancy ratings, skin conductance response (SCR), and fear potentiated startle (FPS) were collected. Participants were pseudorandomized and double-blinded to one of two groups: They received either a drink containing glucose or saccharine 20 min before (Study 1) or immediately after extinction (Study 2). The glucose group showed a significantly stronger decrease in differential FPS during extinction (Study 1) and extinction recall (Study 2). Additionally, the glucose group showed a significantly lower contextual anxiety at test of reinstatement (Study 2). Our findings provide first evidence that glucose supports the process of fear extinction, and in particular the consolidation of fear extinction memory, and thus has potential as a beneficial adjuvant to extinction-based treatments. Registered through the German Clinical Trials Registry (https://www.bfarm.de/EN/BfArM/Tasks/German-Clinical-Trials-Register/_node.html; Study 1: DRKS00010550; Study 2: DRKS00018933).

S-3,4-DCPG, a potent orthosteric agonist for the mGlu8 receptor, facilitates extinction and inhibits the reinstatement of morphine-induced conditioned place preference in male rats.

The limbic system, particularly the NAc, shows a high concentration of metabotropic glutamate receptors (mGluRs). Recent evidence suggests the significant involvement of mGluRs in mental disorders, including substance abuse and addiction. The objective of this study was to examine the involvement of mGlu8 receptors in the NAc in the mechanisms underlying the extinction and reinstatement of conditioned place preference (CPP) induced by morphine. Male Wistar rats underwent surgical implantation of bilateral cannulas in the NAc and were assessed in a CPP protocol. In study 1 at the same time as the extinction phase, the rats were given varying doses of S-3,4-DCPG (0.03, 0.3, and 3 µg/0.5 µl). In study 2, rats that had undergone CPP extinction were given S-3,4-DCPG (0.03, 0.3, and 3 µg/0.5 µl) five minutes prior to receiving a subthreshold dose of morphine (1 mg/kg) in order to reactivate the previously extinguished morphine response. The findings demonstrated that administering S-3,4-DCPG directly into the accumbens nucleus resulted in a decrease in the duration of the CPP extinction phase. Moreover, dose-dependent administration of S-3,4-DCPG into the NAc inhibited CPP reinstatement. The observations imply that microinjection of S-3,4-DCPG as a potent orthosteric agonist with high selectivity for the mGlu8 receptor into the NAc promotes the process of extinction while concurrently exerting inhibitory effects on the reinstatement of morphine-induced CPP. This effect may be associated with the modulation of glutamate engagement within the NAc and the plasticity of reward pathways at the synaptic level.

Mediated learning: A computational rendering of ketamine-induced symptoms.

This article explores the contribution of the double error dynamic asymptote computational associative learning model to understanding the role of mediated learning mechanisms in the generation of spurious associations, as those postulated to characterize schizophrenia. Three sets of simulations for mediated conditioning, mediated extinction, and a mediated enhancement of latent inhibition, a unique model prediction, are presented. For each set of simulations, a parameter that modulates the impact of associative memory retrieval and the dissipation of nonperceptual activated representations through the network was manipulated. The effect of this operation is analyzed and compared to ketamine-induced effects on associative memories and mediated learning. The model's potential to predict these effects and present a plausible error-correction associative mechanism is discussed in the context of animal models of schizophrenia. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Combining brief recall and ketamine treatment prevents stress-primed methamphetamine memory reinstatement via heightening mPFC GABA activity.

This study aimed to assess whether brief recall of methamphetamine (MA) memory, when combined with ketamine (KE) treatment, may prevent stress-primed MA memory reinstatement. Combining 3-min recall and KE facilitated MA memory extinction and resistance to subsequent stress-primed reinstatement. Such combination also produced glutamate metabotropic receptor 5 (mGluR5) upregulation in animals' medial prefrontal cortex (mPFC) γ-amino-butyric acid (GABA) neuron. Accordingly, chemogenetic methods were employed to bi-directionally modulate mPFC GABA activity. Following brief recall and KE-produced MA memory extinction, intra-mPFC mDlx-Gi-coupled-human-muscarinic-receptor 4 (hM4Di)-infused mice receiving compound 21 (C21) treatment showed eminent stress-primed reinstatement, while their GABA mGluR5 expression seemed to be unaltered. Intra-mPFC mDlx-Gq-coupled-human-muscarinic-receptor 3 (hM3Dq)-infused mice undergoing C21 treatment displayed MA memory extinction and resistance to stress-provoked reinstatement. These results suggest that combining a brief recall and KE treatment and exciting mPFC GABA neuron may facilitate MA memory extinction and resistance to stress-primed recall. mPFC GABA neuronal activity plays a role in mediating brief recall/KE-produced effects on curbing the stress-provoked MA seeking.

Cannabidiol (CBD) facilitates cocaine extinction and ameliorates cocaine-induced changes to the gut microbiome in male C57BL/6JArc mice.

Cocaine use disorder (CUD) is a global health problem with no approved medications. One potential treatment target is the gut microbiome, but it is unknown if cocaine induces long-lasting effects on gut microbes. A novel therapeutic candidate for CUD, cannabidiol (CBD), can improve gut function in rodent models. It is possible that protective effects of CBD against cocaine use are mediated by improving gut health. We examined this question in this experiment. Cocaine conditioned place preference (CPP) was conducted in adult male C57BL/6JArc mice. Mice were treated with vehicle or 20 mg/kg CBD prior to all cocaine CPP sessions (N = 11-13/group). Mice were tested drug free 1, 14 and 28 days after cessation of cocaine and CBD treatment. Fecal samples were collected prior to drug treatment and after each test session. Gut microbiome analyses were conducted using 16 s rRNA sequencing and correlated with behavioural parameters. We found a persistent preference for a cocaine-environment in mice, and long-lasting changes to gut microbe alpha diversity. Cocaine caused persistent changes to beta diversity which lasted for 4 weeks. CBD treatment reduced cocaine-environment preference during abstinence from cocaine and returned gut beta diversity measures to control levels. CBD treatment increased the relative abundance of Firmicutes phyla and Oscillospira genus, but decreased Bacteroidetes phyla and Bacteroides acidifaciens species. Preference score in cocaine-treated mice was positively correlated with abundance of Actinobacteria, whereas in mice treated with CBD and cocaine, the preference score was negatively correlated with Tenericutes abundance. Here we show that CBD facilitates cocaine extinction memory and reverses persistent cocaine-induced changes to gut microbe diversity. Furthermore, CBD increases the abundance of gut microbes which have anti-inflammatory properties. This suggests that CBD may act via the gut to reduce the memory of cocaine reward. Our data suggest that improving gut health and using CBD could limit cocaine abuse.

A large-scale c-Fos brain mapping study on extinction of cocaine-primed reinstatement.

Individuals with cocaine addiction can experience many craving episodes and subsequent relapses, which represents the main obstacle to recovery. Craving is often favored when abstinent individuals ingest a small dose of cocaine, encounter cues associated with drug use or are exposed to stressors. Using a cocaine-primed reinstatement model in rat, we recently showed that cocaine-conditioned interoceptive cues can be extinguished with repeated cocaine priming in the absence of drug reinforcement, a phenomenon we called extinction of cocaine priming. Here, we applied a large-scale c-Fos brain mapping approach following extinction of cocaine priming in male rats to identify brain regions implicated in processing the conditioned interoceptive stimuli of cocaine priming. We found that cocaine-primed reinstatement is associated with increased c-Fos expression in key brain regions (e.g., dorsal and ventral striatum, several prefrontal areas and insular cortex), while its extinction mostly disengages them. Moreover, while reinstatement behavior was correlated with insular and accumbal activation, extinction of cocaine priming implicated parts of the ventral pallidum, the mediodorsal thalamus and the median raphe. These brain patterns of activation and inhibition suggest that after repeated priming, interoceptive signals lose their conditioned discriminative properties and that action-outcome associations systems are mobilized in search for new contingencies, a brain state that may predispose to rapid relapse.