Facilitate Extinction Learning Research Articles

State of the Science: Prolonged exposure therapy for the treatment of posttraumatic stress disorder.

Prolonged exposure therapy (PE) is a well-established first-line treatment for posttraumatic stress disorder (PTSD) that is based on emotional processing theory. PE has been rigorously evaluated and tested in a large number of clinical trials in many countries covering a wide range of trauma populations. In this review, we summarize the evidence base supporting the efficacy of PE across populations, including adults with sexual assault-related PTSD and mixed trauma-related PTSD, military populations, and adolescents. We highlight important strengths and gaps in the research on PE with individuals from marginalized communities. We discuss the efficacy of PE on associated psychopathology and in the presence of the most commonly comorbid conditions, either alone or integrated with other treatments. In addition, we provide an overview of research examining strategies to augment PE. Much of this work remains preliminary, but numerous trials have tested PE in combination with other psychological or pharmacological approaches, interventions to facilitate extinction learning, and behavioral approaches, in the hopes of further increasing the efficiency and efficacy of PE. There are now several trials testing PE in novel formats that may have advantages over standard in-person PE, such as lower dropout and increased scalability. We examine this recent work on new models of delivering PE, including massed treatment, telehealth, and brief adaptations for primary care, all of which have the potential to increase access to PE. Finally, we highlight several promising areas for future research.

The effect of SSRIs on fear learning: a systematic review and meta-analysis.

Selective serotonin reuptake inhibitors (SSRIs) are considered first-line medication for anxiety-like disorders such as panic disorder, generalized anxiety disorder, and post-traumatic stress disorder. Fear learning plays an important role in the development and treatment of these disorders. Yet, the effect of SSRIs on fear learning are not well known. We aimed to systematically review the effect of six clinically effective SSRIs on acquisition, expression, and extinction of cued and contextual conditioned fear. We searched the Medline and Embase databases, which yielded 128 articles that met the inclusion criteria and reported on 9 human and 275 animal experiments. Meta-analysis showed that SSRIs significantly reduced contextual fear expression and facilitated extinction learning to cue. Bayesian-regularized meta-regression further suggested that chronic treatment exerts a stronger anxiolytic effect on cued fear expression than acute treatment. Type of SSRI, species, disease-induction model, and type of anxiety test used did not seem to moderate the effect of SSRIs. The number of studies was relatively small, the level of heterogeneity was high, and publication bias has likely occurred which may have resulted in an overestimation of the overall effect sizes. This review suggests that the efficacy of SSRIs may be related to their effects on contextual fear expression and extinction to cue, rather than fear acquisition. However, these effects of SSRIs may be due to a more general inhibition of fear-related emotions. Therefore, additional meta-analyses on the effects of SSRIs on unconditioned fear responses may provide further insight into the actions of SSRIs.

Facilitated extinction of conditioned fear responses by delta 9-tetrahyrdrocannabidol in humans: a pilot study.

We sought to determine whether acute delta 9-tetrahyrdrocannabidol (THC) administration would facilitate fear extinction in young occasional cannabis users, given that animal models indicate THC facilitates extinction learning, and recent studies indicate THC administration may also enhance threat memory extinction in humans. On each of the 2days, 24+hour THC-deprived participants were conditioned to fear visual stimuli in a delay conditioning and extinction paradigm. Both CS+ and CS- were faces of negative emotional valence, with the CS+ paired with mild electric shock. Throughout both conditioning and extinction paradigms, EEG was measured to quantify event-related potentials for these learning processes. Following conditioning, individuals, in a randomized and counter-balanced order, smoked either an active THC cigarette (26.25mg/2.7% THC) or a placebo marijuana cigarette (0.002% THC) on 1day and the opposite cigarette on the second day. After smoking, CS+ and CS- were presented without shock, resulting in extinction of conditioned fear. Relative to placebo, THC facilitated extinction of the conditioned response to the CS+, as reflected by reductions in late positive potential amplitude during extinction learning. The results indicate that acute THC administration may facilitate extinction of the conditioned fear response in humans.

NYX-783, A Novel Positive Allosteric Modulator of the N-Methyl D-Aspartate Receptor, Increases NMDAR-Mediated Signaling in the Infralimbic Prefrontal Cortex to Facilitate Extinction Learning in PTSD-Relevant Rodent Models

Treatment options for post-traumatic stress disorder (PTSD) are limited. N-methyl D-aspartate receptor (NMDAR) hypofunction in the prefrontal cortex (PFC) is implicated in the development and maintenance of PTSD through dysregulation of the cognitive control of emotion necessary for appropriate response to non-harmful stimuli.

FAAH polymorphism (rs324420) modulates extinction recall in healthy humans: an fMRI study

Gold standard treatments for anxiety- and trauma-related disorders focus on exposure therapy promoting extinction learning and extinction retention. However, its efficacy is limited. Preclinical and particularly animal research has been able to demonstrate that homozygosity for the fatty acid amide hydrolase (FAAH) C385A allele, similar to FAAH inhibition, is associated with elevated concentrations of anandamide (AEA) and facilitates extinction learning and extinction recall. However, in humans, the underlying neurobiological processes are less well understood, and further knowledge might enhance the development of more effective therapies. In this functional magnetic resonance imaging (fMRI) study, a fear conditioning, fear extinction and extinction recall paradigm was conducted with 55 healthy male adults. They were genotyped for the FAAH single-nucleotide polymorphism (SNP) rs324420 to investigate differences related to extinction recall in neural activation and State–Trait Anxiety Inventory (STAI) ratings between AC heterozygotes and CC homozygotes (FAAH C385A SNP). Differential brain activation upon an unextinguished relative to an extinguished stimulus, was greater in AC heterozygotes as compared to CC homozygotes in core neural structures previously related to extinction recall, such as the medial superior frontal gyrus, the dorsal anterior cingulate and the anterior and middle insular cortex. Furthermore, AC heterozygotes displayed higher AEA levels and lower STAI-state ratings. Our data can be interpreted in line with previous suggestions of more successful extinction recall in A-allele carriers with elevated AEA levels. Data corroborate the hypothesis that the endocannabinoid system, particularly AEA, plays a modulatory role in the extinction of aversive memory.

Randomized controlled experimental study of hydrocortisone and D-cycloserine effects on fear extinction in PTSD

Fear extinction underlies prolonged exposure, one of the most well-studied treatments for posttraumatic stress disorder (PTSD). There has been increased interest in exploring pharmacological agents to enhance fear extinction learning in humans and their potential as adjuncts to PE. The objective of such adjuncts is to augment the clinical impact of PE on the durability and magnitude of symptom reduction. In this study, we examined whether hydrocortisone (HC), a corticosteroid, and D-Cycloserine (DCS), an N-methyl-D-aspartate receptor partial agonist, enhance fear extinction learning and consolidation in individuals with PTSD. In a double-blind placebo-controlled 3-group experimental design, 90 individuals with full or subsyndromal PTSD underwent fear conditioning with stimuli that were paired (CS+) or unpaired (CS−) with shock. Extinction learning occurred 72 h later and extinction retention was tested one week after extinction. HC 25 mg, DCS 50 mg or placebo was administered one hour prior to extinction learning. During extinction learning, the DCS and HC groups showed a reduced differential CS+/CS− skin conductance response (SCR) compared to placebo (b = −0.19, CI = −0.01 to −37, p = 0.042 and b = −0.25, CI = −08 to −0.43, p = 0.005, respectively). A nonsignificant trend for a lower differential CS+/CS− SCR in the DCS group, compared to placebo, (b = −0.25, CI = 0.04 to −0.55, p = 0.089) was observed at retention testing, one week later. A single dose of HC and DCS facilitated fear extinction learning in participants with PTSD symptoms. While clinical implications have yet to be determined, our findings suggest that glucocorticoids and NMDA agonists hold promise for facilitating extinction learning in PTSD.

A common genetic variant in fatty acid amide hydrolase is linked to alterations in fear extinction neural circuitry in a racially diverse, nonclinical sample of adults.

Poor fear extinction learning and recall are linked to the development of fear-based disorders, like posttraumatic stress disorder, and are associated with aberrant activation of fear-related neural circuitry. This includes greater amygdala activation during extinction learning and lesser hippocampal and ventromedial prefrontal cortex (vmPFC) activation during recall. Emerging data indicate that genetic variation in fatty acid amide hydrolase (FAAH C385A; rs324420) is associated with increased peripheral endocannabinoid (eCB) levels and lesser threat-related amygdala reactivity. Preclinical studies link increased eCB signaling to better extinction learning and recall, thus FAAH C385A may protect against the development of trauma-related psychopathology by facilitating extinction learning. However, how this FAAH variant affects fear extinction neural circuitry remains unknown. In the present study, we used a novel, immersive-reality fear extinction paradigm paired with functional neuroimaging to assess FAAH C385A effects on fear-related neural circuitry and conditioned fear responding (US expectancy ratings, subjective units of distress, and skin conductance responding) in healthy adults from an urban area (Detroit, MI; N=59; C/C=35, A-carrier=24). We found lesser amygdala activation in A-allele carriers, compared to C/C homozygotes, during early extinction recall. Likewise, we found lesser dorsal anterior cingulate cortex and greater hippocampus activation in early extinction learning in A-carriers compared to C/C homozygotes. We found no effects of FAAH C385A on vmPFC activation or behavioral fear indices. These data support and extend previous findings that FAAH genetic variation, associated with increased eCB signaling and subsequent enhanced fear extinction, may predict individual differences in successful fear learning.

Fluoroethylnormemantine, a Novel NMDA Receptor Antagonist, for the Prevention and Treatment of Stress-Induced Maladaptive Behavior

BackgroundMajor depressive disorder is a common, recurrent illness. Recent studies have implicated the NMDA receptor in the pathophysiology of major depressive disorder. (R,S)-ketamine, an NMDA receptor antagonist, is an effective antidepressant but has numerous side effects. Here, we characterized a novel NMDA receptor antagonist, fluoroethylnormemantine (FENM), to determine its effectiveness as a prophylactic and/or antidepressant against stress-induced maladaptive behavior. MethodsSaline, memantine (10 mg/kg), (R,S)-ketamine (30 mg/kg), or FENM (10, 20, or 30 mg/kg) was administered before or after contextual fear conditioning in 129S6/SvEv mice. Drug efficacy was assayed using various behavioral tests. Protein expression in the hippocampus was quantified with immunohistochemistry or Western blotting. In vitro radioligand binding was used to assay drug binding affinity. Patch clamp electrophysiology was used to determine the effect of drug administration on glutamatergic activity in ventral hippocampal cornu ammonis 3 (vCA3) 1 week after injection. ResultsGiven after stress, FENM decreased behavioral despair and reduced perseverative behavior. When administered after re-exposure, FENM facilitated extinction learning. As a prophylactic, FENM attenuated learned fear and decreased stress-induced behavioral despair. FENM was behaviorally effective in both male and female mice. (R,S)-ketamine, but not FENM, increased expression of c-fos in vCA3. Both (R,S)-ketamine and FENM attenuated large-amplitude AMPA receptor–mediated bursts in vCA3, indicating a common neurobiological mechanism for further study. ConclusionsOur results indicate that FENM is a novel drug that is efficacious when administered at various times before or after stress. Future work will further characterize FENM’s mechanism of action with the goal of clinical development.

Selective δ-opioid receptor agonist, KNT-127, facilitates extinction learning of contextual fear via fear circuitry in mice.

Selective δ-opioid receptor agonist, KNT-127, facilitates extinction learning of contextual fear via fear circuitry in mice.

Kaempferol Facilitated Extinction Learning in Contextual Fear Conditioned Rats via Inhibition of Fatty-Acid Amide Hydrolase.

Background: Fear, stress, and anxiety-like behaviors originate from traumatic events in life. Stress response is managed by endocannabinoids in the body by limiting the uncontrolled retrieval of aversive memories. Pharmacotherapy-modulating endocannabinoids, especially anandamide, presents a promising tool for treating anxiety disorders. Here, we investigated the effect of kaempferol, a flavonoid, in the extinction of fear related memories and associated anxiety-like behavior. Methods: The ability of kaempferol to inhibit fatty-acid amide hydrolase (FAAH, the enzyme that catabolizes anandamide) was assessed in vitro using an enzyme-linked immunosorbent assay (ELISA) kit. For animal studies (in vivo), the extinction learning was evaluated using contextual fear conditioning (CFC, a behavioral paradigm based on ability to learn and remember aversive stimuli). Furthermore, an elevated plus-maze (EPM) model was used for measuring anxiety-like behavior, while serum corticosterone served as a biochemical indicator of anxiety. Lastly, the interaction of kaempferol with FAAH enzyme was also assessed in silico (computational study). Results: Our data showed that kaempferol inhibited the FAAH enzyme with an IC50 value of 1 µM. In CFC, it reduced freezing behavior in rats. EPM data demonstrated anxiolytic activity as exhibited by enhanced number of entries and time spent in the open arm. No change in blood corticosterone levels was noted. Our computational study showed that Kaempferol interacted with the catalytic amino acids (SER241, PHE192, PHE381, and THR377) of FAAH enzyme Conclusion: Our study demonstrate that kaempferol facilitated the extinction of aversive memories along with a reduction of anxiety. The effect is mediated through the augmentation of endocannabinoids via the inhibition of FAAH enzyme.

Sex differences in the effects of a combined behavioral and pharmacological treatment strategy for cocaine relapse prevention in an animal model of cue exposure therapy

Brief interventions of environmental enrichment (EE) or the glycine transporter-1 inhibitor Org24598 administered with cocaine-cue extinction training were shown previously to inhibit reacquisition of cocaine self-administration in male rats trained to self-administer a moderate 0.3 mg/kg dose of cocaine. Determining how EE and Org24598 synergize in combination in an animal model of cue exposure therapy is novel. Important changes made in this investigation were increasing the cocaine training dose to 1.0 mg/kg and determining sex differences. Adult male and female rats self-administering 1.0 mg/kg cocaine for 35–40 daily sessions exhibited an addiction-like phenotype under a second-order schedule of cocaine delivery and cue presentation. Rats next underwent 6 weekly extinction training sessions for which treatments consisted of EE or NoEE and Vehicle or Org24598 (3.0 mg/kg in males; 3.0 or 7.5 mg/kg in females). Rats then were tested for reacquisition of cocaine self-administration for 15 daily sessions. In males, the combined EE +3.0 mg/kg Org24598 treatment facilitated extinction learning and inhibited reacquisition of cocaine self-administration to a greater extent than no treatment and to individual EE or 3.0 mg/kg Org24598 treatments. In females, EE +7.5 mg/kg Org24598 facilitated extinction learning, but did not inhibit reacquisition of cocaine self-administration. Thus, there were sex differences in the ability of EE + Org24598 administered in conjunction with extinction training to inhibit cocaine relapse in rats exhibiting an addiction-like phenotype. These findings suggest that this multimodal treatment approach might be a feasible option during cue exposure therapy in cocaine-dependent men, but not women.

SUN-235 Deficient Fear Extinction in PRKAR1A-Defective Mice

Background: The role of the cAMP/PKA signaling in molecular pathways involved in fear memory is well established: PKA is required for fear memory formation and is a constraint for fear extinction. Previously we reported that a Prkar1a heterozygote (HZ) mouse that was developed in our lab to investigate Carney complex (CNC), the disease caused by PRKAR1A mutations, showed brain region-specific increased PKA activity that was associated with anxiety-like behavioral phenotype and threat bias (Keil, 2010, 2013). We hypothesized that Prkar1a+/- (HZ) mice would have deficits in fear extinction behavior. Brain derived neurotrophic factor (BDNF) has a critical role in formation of fear memory and its transcription is regulated by PKA/CREB. A mouse model with down regulation of PKA provides an opportunity for the first time to investigate the effect of altered PKA signaling on fear conditioning and extinction.Method: Fear conditioning, fear extinction learning, and fear extinction recall were tested in adult male HZ and wild-type (WT) mice as follows: fear conditioning training followed 24hr later by extinction training (new context), then 24hr later by extinction recall training. Percentage of time freezing was used to assess conditioned fear response. We measured BDNF gene expression in brain regions after completion of extinction recall training.Results: As expected, fear conditioning (learning) behavior was similar in HZ and WT mice. However, HZ mice showed a significant deficit in the early phase of fear extinction learning compared to WT. There was no difference in extinction recall between genotypes. Alterations in BDNF gene expression in the prefrontal cortex and amygdala was associated with deficit in fear extinction.Conclusion: Mice with a downregulation of Prkar1a gene demonstrate intact fear conditioning but impaired fear extinction learning, consistent with prior studies that report that PKA inhibition is necessary to facilitate extinction learning. Prkar1a+/- mice provide a valuable model to investigate impaired fear extinction to identify mechanisms for therapeutic targets for anxiety and trauma-related disorders.

Nicotine reduction does not alter essential value of nicotine or reduce cue-induced reinstatement of nicotine seeking

Reduction of nicotine content in tobacco products is a regulatory control strategy intended to decrease smoking dependence, and is hypothesized to produce gradual reductions of nicotine intake. Rats were initially trained to self-administer 0.06 mg/kg/infusion nicotine (Phase 1), which was followed by a threshold procedure to determine nicotine demand via a behavioral economics (BE) paradigm (Phase 2). Rats then either self-administered the training dose (high dose group), or were switched to a low dose of nicotine (0.001 mg/kg/infusion; low dose group) in Phase 3. Both groups then underwent a second threshold procedure and demand curves were re-determined (Phase 4). In Phase 5, responding for nicotine was extinguished over the course of 21 sessions. Cue-induced reinstatement was then evaluated (Phase 6). Rats in the low dose group maintained a steady amount of infusions, and thus, did not compensate for nicotine reduction. Rats in the low dose group also showed similar demand elasticity and nicotine seeking (Phase 6) compared to the high dose group, indicating that nicotine reduction did not decrease nicotine demand or seeking. Further, both groups displayed resistance to extinction, indicating that nicotine reduction did not facilitate extinction learning. These results suggest that although compensation of intake does not occur, decreasing the dose of nicotine does not alter nicotine reinforcement value or relapse vulnerability. Further, these results indicate persistence of nicotine-motivated behavior after self-administration of a low nicotine dose. Translationally, these results suggest that alternative strategies may be needed to achieve positive smoking cessation outcomes.

Selective agonists of the δ-opioid receptor, KNT-127 and SNC80, act differentially on extinction learning of contextual fear memory in mice

We reported previously that KNT-127 and SNC80, selective agonists of the δ-opioid receptor (DOP), had potent anxiolytic-like effects in rodents. In this study, we evaluated whether KNT-127 and SNC80 influence extinction learning of contextual fear memory in the mice fear conditioning test. On day 1, the mice were contextually conditioned with eight trials (footshock; 0.8 mA, 1-s, 30-s interval). On day 2, the mice were re-exposed to the conditioning chamber for 6 min as an extinction training (re-exposure 1), 30 min after drug administration. On day 3, the mice were re-exposed to the chamber for 6 min as a memory testing (re-exposure 2). In re-exposure 1, KNT-127 and SNC80 significantly reduced the freezing behavior. In re-exposure 2, KNT-127, but not SNC80, significantly reduced the freezing behavior. These effects of KNT-127 were antagonized by the DOP antagonist naltrindole. KNT-127 increased the phosphorylated ERK levels in the amygdala and hippocampus, but not in the medial prefrontal cortex 60 min after re-exposure 1. These results suggest that both KNT-127 and SNC80 produced anxiolytic-like effects in the re-exposure 1, however, in contrast to SNC80, KNT-127 facilitated extinction learning of contextual fear memory in the re-exposure 2. Further, we suggest that amygdaloid and hippocampal MAPK/ERK signaling serves as the key mediators of the enhancement of extinction learning of contextual fear memory via DOPs after KNT-127 treatment. We propose that, although the DOP agonists KNT-127 and SNC80 produce anxiolytic-like effects on contextually conditioned fear, these drugs have different mechanisms on extinction learning of contextual fear memory.

Brain and Cognition for Addiction Medicine: From Prevention to Recovery Neural Substrates for Treatment of Psychostimulant-Induced Cognitive Deficits.

Addiction to psychostimulants like cocaine, methamphetamine, and nicotine poses a continuing medical and social challenge both in the United States and all over the world. Despite a desire to quit drug use, return to drug use after a period of abstinence is a common problem among individuals dependent on psychostimulants. Recovery for psychostimulant drug-dependent individuals is particularly challenging because psychostimulant drugs induce significant changes in brain regions associated with cognitive functions leading to cognitive deficits. These cognitive deficits include impairments in learning/memory, poor decision making, and impaired control of behavioral output. Importantly, these drug-induced cognitive deficits often impact adherence to addiction treatment programs and predispose abstinent addicts to drug use relapse. Additionally, these cognitive deficits impact effective social and professional rehabilitation of abstinent addicts. The goal of this paper is to review neural substrates based on animal studies that could be pharmacologically targeted to reverse psychostimulant-induced cognitive deficits such as impulsivity and impairment in learning and memory. Further, the review will discuss neural substrates that could be used to facilitate extinction learning and thus reduce emotional and behavioral responses to drug-associated cues. Moreover, the review will discuss some non-pharmacological approaches that could be used either alone or in combination with pharmacological compounds to treat the above-mentioned cognitive deficits. Psychostimulant addiction treatment, which includes treatment for cognitive deficits, will help promote abstinence and allow for better rehabilitation and integration of abstinent individuals into society.

Sign-tracking behavior is difficult to extinguish and resistant to multiple cognitive enhancers.

The attribution of incentive-motivational value to drug-related cues underlies relapse and craving in drug addiction. One method of addiction treatment, cue-exposure therapy, utilizes repeated presentations of drug-related cues in the absence of drug (i.e., extinction learning); however, its efficacy has been limited due to an incomplete understanding of extinction and relapse processes after cues have been imbued with incentive-motivational value. To investigate this, we used a Pavlovian conditioned approach procedure to screen for rats that attribute incentive-motivational value to reward-related cues (sign-trackers; STs) or those that do not (goal-trackers; GTs). In Experiment 1, rats underwent Pavlovian extinction followed by reinstatement and spontaneous recovery tests. For comparison, a separate group of rats underwent PCA training followed by operant conditioning, extinction, and tests of reinstatement and spontaneous recovery. In Experiment 2, three cognitive enhancers (sodium butyrate, D-cycloserine, and fibroblast growth factor 2) were administered following extinction training to facilitate extinction learning. STs but not GTs displayed enduring resistance to Pavlovian, but not operant, extinction and were more susceptible to spontaneous recovery. In addition, none of the cognitive enhancers tested affected extinction learning. These results expand our understanding of extinction learning by demonstrating that there is individual variation in extinction and relapse processes and highlight potential difficulties in applying extinction-based therapies to drug addiction treatment in the clinic.

Systemic administration of a delta opioid receptor agonist, KNT-127, facilitates extinction learning of fear memory in rats

Strategies to facilitate extinction of fear memory have attracted increasing attention for enhancing the effectiveness of exposure therapy for anxiety disorders. Previously, we demonstrated that systemic administration of a delta opioid receptor agonist, KNT-127, has clear anxiolytic-like effects in rats, without impairing memory. These observations led us to hypothesize that KNT-127 might be an appropriate therapeutic agent for anxiety disorders when combined with exposure therapy. In the present study, we demonstrate that KNT-127 (3 mg/kg) facilitates extinction learning of fear memory using the contextual fear conditioning test. As expected, a partial agonist at the glycine-binding site on the glutamatergic N-methyl-d-aspartate receptor, d-cycloserine (15 mg/kg), facilitated extinction learning of contextual fear in rats. In contrast, a benzodiazepine anxiolytic, diazepam (1 mg/kg), impaired the fear extinction learning. Interestingly, the facilitatory effect of KNT-127 on extinction learning was observed not only after a 10-min re-exposure, but also after a much shorter (2-min) re-exposure to the context, while d-cycloserine was ineffective at facilitating extinction when a short-duration exposure was given. Our findings may suggest that administration of a delta opioid receptor agonist might have therapeutic efficacy when combined with exposure therapy for treating a range of anxiety disorders.

Administration of a delta opioid receptor agonist KNT-127 to the basolateral amygdala has robust anxiolytic-like effects in rats.

We previously reported that systemic administration of a selective delta opioid receptor (DOP) agonist, KNT-127, produced potent anxiolytic-like effects in rats. Interestingly, DOPs are highly distributed in the basolateral region of the amygdala (BLA). In this study, we investigated the effect of intra-BLA administration of KNT-127 on anxiety-like behaviors in rats. In the elevated plus maze test, bilateral injection of KNT-127 into the BLA significantly and dose-dependently increased time spent in the open arms. The magnitude of KNT-127 (0.08μg/0.2μl)-induced anxiolytic-like effects was similar to muscimol (0.1μg/0.2μl), which is a selective agonist for the gamma amino butyric acid type A receptors. Further, anxiolytic-like effects of KNT-127 were abolished by pretreatment with naltrindole, a selective DOP antagonist, suggesting that KNT-127-induced anxiolytic-like effects are mediated by DOPs. These anxiolytic-like effects were confirmed using another innate anxiety model, the open field test. Interestingly, intra-BLA administration of KNT-127 also induced anxiolytic-like effects in the contextual fear conditioning test. Moreover, these effects were also abolished by naltrindole pretreatment. Finally, we demonstrated that intra-BLA administration of KNT-127 facilitates extinction learning of contextual fear in conditioned rats. Altogether, our findings clearly demonstrate that intra-BLA administration of KNT-127 in rats has robust anxiolytic-like effects not only in innate anxiety-like behavioral tests but also in the contextual fear conditioning test.

CAN EXPOSURE-BASED CBT EXTEND IV KETAMINE’S EFFECTS IN OCD? AN OPEN-LABEL TRIAL

Abtract Introduction A single subanesthetic intravenous (IV) dose of ketamine leads to rapid anti-obsessional effects in obsessive-compulsive disorder (OCD) patients with near-constant intrusive obsessions, but these effects usually do not persist. We tested whether a brief course of exposure-based cognitive behavioral therapy (CBT) could extend ketamine’s effects in a two week pilot open trial and if this effect was maintained (without additional treatment) two weeks later. Our rationale was: 1) ketamine is reported to enhance plasticity and extinction learning in rodents, and 2) enhanced extinction learning may facilitate CBT gains, as reported in trials that combined CBT with agents thought to facilitate extinction learning (e.g. D-cycloserine). Mimicking those trials, CBT was abbreviated (i.e. 10 one-hour exposure sessions) but delivered during the putative time interval when ketamine facilitates extinction learning (within 14 days). Methods Ten unmedicated OCD outpatients (aged 18-55) with near-constant intrusive obsessions (>8 hours/day) and at least moderate symptoms (Y-BOCS score ≥16) were recruited. Exclusion criteria included severe depression (HDRS >25), current CBT, and comorbid psychiatric or medical conditions that made participation unsafe. In an open-label design, participants received a single 40-minute IV infusion of ketamine (dose=0.5 mg/kg), followed by 10 one-hour exposure sessions delivered over two weeks. The CBT treatment was planned in a 90-minute session the day before the ketamine infusion. At baseline, during the infusion, at 20, 90, 110, 230 minutes post-infusion, patients rated their obsessional severity using the OCD-VAS. At baseline and weekly for four weeks post-ketamine, an independent evaluator, blind to study design, evaluated patients using the Y-BOCS, which appraises obsessive and compulsive symptoms over the prior week. Treatment response was defined a priori as ≥35% Y-BOCS reduction at week 2. Y-BOCS outcomes were analyzed using mixed-effects regression to model symptoms as a function of time. Results Of the 10 patients who started ketamine, nine completed the infusion. Eight reported a rapid reduction in obsessive severity as measured by the OCD-VAS, which persisted up to 230 minutes post-infusion in seven patients. Eight completed the 10 hours of exposure and the two week follow-up and were included in the Y-BOCS analyses. From baseline to four weeks post-infusion, OCD severity, as measured by the YBOCS, was significantly decreased over time (F=14.36, df=4,28, p Conclusions These results corroborate prior findings that IV ketamine can rapidly reduce obsessions in unmedicated OCD patients. The data suggest that a brief course of CBT may help some individuals maintain the improvement they experienced from ketamine; however, this needs to be formally tested in a randomized controlled trial to determine whether the improvement seen after two weeks of CBT is due to the addition of CBT, or whether the effects of ketamine persist longer in some than previously described.

A mind cleared by walnut oil: The effects of polyunsaturated and saturated fat on extinction learning

The treatment of anxiety-based psychopathology often hinges upon extinction learning. Research in nutritional neuroscience has observed that the regular consumption of perilla oil (50% alpha-linolenic acid (ALA)) facilitates extinction learning in rats (Yamamoto et al., 1988). However, acute facilitation of extinction learning by oils rich in ALA has not been reported for rats or humans, though the acute consumption of rapeseed oil (10% ALA) has been observed to improve cognitive processing speed in humans (Jones, Sünram-Lea, & Wesnes, 2012). For this reason, the present laboratory work examined the effects of adding walnut oil (12% ALA) to a chocolate milkshake on the acquisition, generalization, and extinction of a fear-based prediction in young adults. It compared performance between subjects. The other participants consumed a similar milkshake with either an equicaloric amount of cream (saturated fat), or with no added fat (control). Acquisition and generalization of the fear-based prediction were similar for all groups. However, those who consumed walnut oil extinguished most rapidly and profoundly. Implications for extinction learning are discussed.