Anxiolytic effects of endocannabinoid enhancing compounds: A systematic review and meta-analysis.

The endocannabinoid system is a promising candidate for anxiolytic therapy, but translation to the clinic has been lagging. We meta-analyzed the evidence for anxiety-reduction by compounds that facilitate endocannabinoid signaling in humans and animals. To identify areas of specific potential, effects of moderators were assessed. Literature was searched in Pubmed and Embase up to May 2021. A placebo/vehicle-control group was required and in human studies, randomization. We excluded studies that co-administered other substances. Risk of bias was assessed with SYRCLE's RoB tool and Cochrane RoB 2.0. We conducted three-level random effects meta-analyses and explored sources of heterogeneity using Bayesian regularized meta-regression (BRMA). The systematic review yielded 134 studies. We analyzed 120 studies (114 animal, 6 human) that investigated cannabidiol (CBD, 61), URB597 (39), PF-3845 (6) and AM404 (14). Pooled effects on conditioned and unconditioned anxiety in animals (with the exception of URB597 on unconditioned anxiety) and on experimentally induced anxiety in humans favored the investigational drugs over placebo/vehicle. Publication year was negatively associated with effects of CBD on unconditioned anxiety. Compared to approach avoidance tests, tests of repetitive-compulsive behavior were associated with larger effects of CBD and URB597, and the social interaction test with smaller effects of URB597. Larger effects of CBD on unconditioned anxiety were observed when anxiety pre-existed. Studies reported few side effects at therapeutic doses. The evidence quality was low with indications of publication bias. More clinical trials are needed to translate the overall positive results to clinical applications.

Large-scale remote fear conditioning: Demonstration of associations with anxiety using the FLARe smartphone app.

OBJECTIVES: We aimed to examine differences in fear conditioning between anxious and nonanxious participants in a single large sample. MATERIALS AND METHODS: We employed a remote fear conditioning task (FLARe) to collect data from participants from the Twins Early Development Study (n = 1,146; 41% anxious vs. 59% nonanxious). Differences between groups were estimated for their expectancy of an aversive outcome towards a reinforced conditional stimulus (CS+) and an unreinforced conditional stimulus (CS-) during acquisition and extinction phases. RESULTS: During acquisition, the anxious group (vs. nonanxious group) showed greater expectancy towards the CS-. During extinction, the anxious group (vs. nonanxious group) showed greater expectancy to both CSs. These comparisons yielded effect size estimates (d = 0.26-0.34) similar to those identified in previous meta-analyses. CONCLUSION: The current study demonstrates that remote fear conditioning can be used to detect differences between groups of anxious and nonanxious individuals, which appear to be consistent with previous meta-analyses including in-person studies.

No consistent startle modulation by reward.

Previous studies have not clearly demonstrated whether motivational tendencies during reward feedback are mainly characterized by appetitive responses to a gain or mainly by aversive consequences of reward omission. In the current study this issue was addressed employing a passive head or tails game and using the startle reflex as an index of the appetitive-aversive continuum. A second aim of the current study was to use startle-reflex modulation as a means to compare the subjective value of monetary rewards of varying magnitude. Startle responses after receiving feedback that a potential reward was won or not won were compared with a baseline condition without a potential gain. Furthermore, startle responses during anticipation of no versus potential gain were compared. Consistent with previous studies, startle-reflex magnitudes were significantly potentiated when participants anticipated a reward compared to no reward, which may reflect anticipatory arousal. Specifically for the largest reward (20-cents) startle magnitudes were potentiated when a reward was at stake but not won, compared to a neutral baseline without potential gain. In contrast, startle was not inhibited relative to baseline when a reward was won. This suggests that startle modulation during feedback is better characterized in terms of potentiation when missing out on reward rather than in terms of inhibition as a result of winning. However, neither of these effects were replicated in a more targeted second experiment. The discrepancy between these experiments may be due to differences in motivation to obtain rewards or differences in task engagement. From these experiments it may be concluded that the nature of the processing of reward feedback and reward cues is very sensitive to experimental parameters and settings. These studies show how apparently modest changes in these parameters and settings may lead to quite different modulations of appetitive/aversive motivation. A future experiment may shed more light on the question whether startle-reflex modulation after feedback is indeed mainly characterized by the aversive consequences of reward omission for relatively large rewards.

Latent class growth analyses reveal overrepresentation of dysfunctional fear conditioning trajectories in patients with anxiety-related disorders compared to controls.

Recent meta-analyses indicated differences in fear acquisition and extinction between patients with anxiety-related disorders and comparison subjects. However, these effects are small and may hold for only a subsample of patients. To investigate individual trajectories in fear acquisition and extinction across patients with anxiety-related disorders (N = 104; before treatment) and comparison subjects (N = 93), data from a previous study (Duits et al., 2017) were re-analyzed using data-driven latent class growth analyses. In this explorative study, subjective fear ratings, shock expectancy ratings and startle responses were used as outcome measures. Fear and expectancy ratings, but not startle data, yielded distinct fear conditioning trajectories across participants. Patients were, compared to controls, overrepresented in two distinct dysfunctional fear conditioning trajectories: impaired safety learning and poor fear extinction to danger cues. The profiling of individual patterns allowed to determine that whereas a subset of patients showed trajectories of dysfunctional fear conditioning, a significant proportion of patients (≥50 %) did not. The strength of trajectory analyses as opposed to group analyses is that it allows the identification of individuals with dysfunctional fear conditioning. Results suggested that dysfunctional fear learning may also be associated with poor treatment outcome, but further research in larger samples is needed to address this question.

Reduction of conditioned avoidance via contingency reversal.

There is an increased interest in how excessive avoidance can diminish. Avoidance reduction is typically tested by using Extinction with Response Prevention (ExRP) protocols, where feared stimuli are presented without any aversive outcome while avoidance is prevented. These effects, however, often do not persist. Here, we tested whether pairing an avoidance response with the presence of an aversive event would reduce avoidance more than ExRP. Participants (N = 58) first saw a picture of a square (A) being paired with a shock whereas another picture of a square (B) not being paired with a shock. Then, they learned to press a button during the presentation of A to avoid the shock. Afterwards, the ExRP group saw unreinforced presentations of A and B without being able to press the avoidance button, whereas the Contingency Reversal group (ConR) received a shock whenever they pressed the button in presence of A. In the test phase, participants saw unreinforced presentations of A and B. Results showed that after successful acquisition of fear and avoidance, in the test phase the ConR group avoided A less often than did the ExRP group. Research on contingency reversal could prove helpful for developing avoidance reduction protocols.

Cannabidiol enhancement of exposure therapy in treatment refractory patients with phobias: study protocol of a randomized controlled trial.

BACKGROUND: Phobic anxiety disorders are among the most prevalent psychiatric disorders and are burdensome in terms of loss of quality of life and work productivity. Evidence-based treatments are relatively successful in the majority of patients, especially exposure therapy. However, a substantial subset of patients fails to achieve or stay in remission. Preclinical and genetic research have yielded evidence that the cannabinoid system is involved in the extinction of fear, presumed to underlie the beneficial effects of exposure therapy in phobic disorders. A cannabinoid constituent that may enhance endocannabinoid signaling is cannabidiol (CBD), a non-psychoactive component of cannabis. Hence, the addition of CBD to exposure therapy is expected to strengthen effects of treatment. To determine the added benefit of CBD on exposure therapy, we conduct a randomized controlled trial, in which patients in whom previous treatment as usual has not yielded sufficient response receive either CBD or placebo preceding 8 exposure sessions in a double-blind fashion. A subsidiary aim is to explore which (combination of) clinical, behavioral and genetic profiles of patients are related to treatment response. METHODS/DESIGN: This is an 8-week multicenter, randomized, double-blind, placebo-controlled trial. Seventy-two patients with social phobia or panic disorder with agoraphobia with incomplete response to earlier treatment will be included from outpatient clinics in the Netherlands. Patients are randomized to augmentation of exposure therapy with 300 mg CBD or placebo. The study medication is administered orally, 2 h preceding each of the eight 90 min exposure sessions. Measurements will take place at baseline, first administration of medication, every session, mid-treatment, last administration of medication, post-treatment and at 3 and 6 months' follow-up. The primary outcome measure is the score on the Fear Questionnaire (FQ). In addition, determinants of the expected treatment enhancing effect of CBD will be explored. DISCUSSION: This is the first trial to investigate whether the addition of CBD to exposure therapy is effective in reducing phobic symptoms in treatment refractory patients with social phobia or panic disorder with agoraphobia. TRIAL REGISTRATION: Netherlands Trial Register NTR5100 . Registered 13 March 2015. Protocol version: issue date 17 Jan 2018, protocol amendment number 7.

How Human Amygdala and Bed Nucleus of the Stria Terminalis May Drive Distinct Defensive Responses.

The ability to adaptively regulate responses to the proximity of potential danger is critical to survival and imbalance in this system may contribute to psychopathology. The bed nucleus of the stria terminalis (BNST) is implicated in defensive responding during uncertain threat anticipation whereas the amygdala may drive responding upon more acute danger. This functional dissociation between the BNST and amygdala is however controversial, and human evidence scarce. Here we used data from two independent functional magnetic resonance imaging studies [n = 108 males and n = 70 (45 females)] to probe how coordination between the BNST and amygdala may regulate responses during shock anticipation and actual shock confrontation. In a subset of participants from Sample 2 (n = 48) we demonstrate that anticipation and confrontation evoke bradycardic and tachycardic responses, respectively. Further, we show that in each sample when going from shock anticipation to the moment of shock confrontation neural activity shifted from a region anatomically consistent with the BNST toward the amygdala. Comparisons of functional connectivity during threat processing showed overlapping yet also consistently divergent functional connectivity profiles for the BNST and amygdala. Finally, childhood maltreatment levels predicted amygdala, but not BNST, hyperactivity during shock anticipation. Our results support an evolutionary conserved, defensive distance-dependent dynamic balance between BNST and amygdala activity. Shifts in this balance may enable shifts in defensive reactions via the demonstrated differential functional connectivity. Our results indicate that early life stress may tip the neural balance toward acute threat responding and via that route predispose for affective disorder.SIGNIFICANCE STATEMENT Previously proposed differential contributions of the BNST and amygdala to fear and anxiety have been recently debated. Despite the significance of understanding their contributions to defensive reactions, there is a paucity of human studies that directly compared these regions on activity and connectivity during threat processing. We show strong evidence for a dissociable role of the BNST and amygdala in threat processing by demonstrating in two large participant samples that they show a distinct temporal signature of threat responding as well as a discriminable pattern of functional connections and differential sensitivity to early life threat.

The Effects of ß-Adrenergic Blockade on the Degrading Effects of Eye Movements on Negative Autobiographical Memories.

BACKGROUND: Eye movement desensitization and reprocessing (EMDR) is an effective treatment for posttraumatic stress disorder. During EMDR, patients make horizontal eye movements (EMs) while simultaneously recalling a traumatic memory, which renders the memory less vivid and emotional when it is later recalled again. Recalling highly emotional autobiographical memories enhances noradrenergic neurotransmission. Noradrenaline (NA) strengthens memory (re)consolidation. However, memories become less vivid after recall+EMs. Therefore, NA might either play no significant role or serve to strengthen memories that are degraded by EMs. The present study was designed to test the latter hypothesis. We predicted that blocking NA would abolish the memory degrading effects of EMs. METHODS: Fifty-six healthy participants selected three negative autobiographical memories. One was then recalled while making EMs, one was recalled without EMs, and one was not recalled. Vividness and emotionality of the memories as well as heart rate and skin conductance level during memory retrieval were measured before, directly after, and 24 hours after the EM task. Before the task, participants received a placebo or the noradrenergic ß-receptor blocker propranolol (40 mg). RESULTS: There were no effects of EMs on memory emotionality or psychophysiological measures in the propranolol and placebo groups. However, in the placebo group, but not in the propranolol group, memory vividness significantly decreased from pretest to posttest and follow-up after recall+EMs relative to the control conditions. CONCLUSIONS: Blocking NA abolished the effects of EMs on the vividness of emotional memories, indicating that NA is crucial for EMDR effectiveness and possibly strengthens the reconsolidation of the degraded memory.

Enhancing effects of contingency instructions on fear acquisition and extinction in anxiety disorders.

Explicit instructions regarding stimulus-threat associations increase acquisition and extinction of fear in healthy participants. The current study aimed to investigate the effect of contingency instructions on fear acquisition and extinction in patients with anxiety disorders. Patients with various anxiety disorders (N = 104) and healthy comparison participants (N = 93) participated in a differential fear conditioning task (within-subjects design). Approximately halfway through the acquisition phase, participants were instructed about the stimulus-threat association, and approximately halfway through the extinction phase, participants were informed that the unconditioned stimulus (US) would no longer be administered. Outcome measures were: fear-potentiated startle, skin conductance, fearfulness ratings, and US expectancy ratings. Patients demonstrated overall increased physiological and subjective fear responses during acquisition and extinction phases, relative to the comparison group. There were no major differences in fear acquisition and extinction between patients with different anxiety disorders. During acquisition, instructions led to increased discrimination of fear responses between a danger cue (conditioned stimulus [CS]+) and safety cue (CS-) in both patients and comparison participants. Moreover, instructions strengthened extinction of fear responses in the patient and comparison group. Patients and healthy comparison participants are better able to discriminate between danger and safety cues when they have been explicitly informed about cues that announce a threat situation. Considering the analogies between fear extinction procedures and exposure therapy, this suggests that specific instructions on stimulus-threat associations during exposure therapy might improve short-term treatment efficacy. The question remains for future studies whether instructions have a positive effect on extinction learning in the longer term. (PsycINFO Database Record

Don't fear 'fear conditioning': Methodological considerations for the design and analysis of studies on human fear acquisition, extinction, and return of fear.

The so-called 'replicability crisis' has sparked methodological discussions in many areas of science in general, and in psychology in particular. This has led to recent endeavours to promote the transparency, rigour, and ultimately, replicability of research. Originating from this zeitgeist, the challenge to discuss critical issues on terminology, design, methods, and analysis considerations in fear conditioning research is taken up by this work, which involved representatives from fourteen of the major human fear conditioning laboratories in Europe. This compendium is intended to provide a basis for the development of a common procedural and terminology framework for the field of human fear conditioning. Whenever possible, we give general recommendations. When this is not feasible, we provide evidence-based guidance for methodological decisions on study design, outcome measures, and analyses. Importantly, this work is also intended to raise awareness and initiate discussions on crucial questions with respect to data collection, processing, statistical analyses, the impact of subtle procedural changes, and data reporting specifically tailored to the research on fear conditioning.

Threat expectancy bias and treatment outcome in patients with panic disorder and agoraphobia.

BACKGROUND AND OBJECTIVES: Previous studies suggest that patients with panic disorder and agoraphobia (PD/A) tend to overestimate the associations between fear-relevant stimuli and threat. This so-called threat expectancy bias is thought to play a role in the development and treatment of anxiety disorders. The current study tested 1) whether patients with PD/A (N = 71) show increased threat expectancy ratings to fear-relevant and fear-irrelevant stimuli relative to a comparison group without an axis I disorder (N=65), and 2) whether threat expectancy bias before treatment predicts treatment outcome in a subset of these patients (n = 51). METHODS: In a computerized task, participants saw a series of panic-related and neutral words and rated for each word the likelihood that it would be followed by a loud, aversive sound. RESULTS: Results showed higher threat expectancy ratings to both panic-related and neutral words in patients with PD/A compared to the comparison group. Threat expectancy ratings did not predict treatment outcome. LIMITATIONS: This study only used expectancy ratings and did not include physiological measures. Furthermore, no post-treatment expectancy bias task was added to shed further light on the possibility that expectancy bias might be attenuated by treatment. CONCLUSIONS: Patients show higher expectancies of aversive outcome following both fear-relevant and fear-irrelevant stimuli relative to the comparison group, but this does not predict treatment outcome.

High Current Anxiety Symptoms, But Not a Past Anxiety Disorder Diagnosis, are Associated with Impaired Fear Extinction.

Although impaired fear extinction has repeatedly been demonstrated in patients with anxiety disorders, little is known about whether these impairments persist after treatment. The current comparative exploratory study investigated fear extinction in 26 patients treated for their anxiety disorder in the years preceding the study as compared to 17 healthy control subjects. Fear-potentiated startle and subjective fear were measured in a cue and context fear conditioning paradigm within a virtual reality environment. Results indicated no differences in fear extinction between treated anxiety patients and control subjects. However, scores on the Beck Anxiety Inventory across all participants revealed impaired extinction of fear potentiated startle in subjects with high compared to low anxiety symptoms over the past week. Taken together, this exploratory study found no support for impaired fear extinction in treated anxiety patients, and implies that current anxiety symptoms rather than previous patient status determine the success of extinction.

Lifelong disturbance of serotonin transporter functioning results in fear learning deficits: Reversal by blockade of CRF1 receptors.

The inability to associate aversive events with relevant cues (i.e. fear learning) may lead to maladaptive anxiety. To further study the role of the serotonin transporter (SERT) in fear learning, classical fear conditioning was studied in SERT knockout rats (SERT(-/-)) using fear potentiation of the startle reflex. Next, fear acquisition and concomitant development of contextual conditioned fear were monitored during training. To differentiate between developmental and direct effects of reduced SERT functioning, effects of acute and chronic SSRI treatment were studied in adult rats. Considering the known interactions between serotonin and corticotropin-releasing factor (CRF), we studied the effect of the CRFR1 antagonist CP154,526 on behavioral changes observed and determined CRF1 receptor levels in SERT(-/-) rats. SERT(-/-) showed blunted fear potentiation and enhanced contextual fear, which resulted from a deficit in fear acquisition. Paroxetine treatment did not affect acquisition or expression of fear-potentiated startle, suggesting that disturbed fear learning in SERT(-/-) results from developmental changes and not from reduced SERT functioning. Although CRF1 receptor levels did not differ significantly between genotypes, CP154,526 treatment normalized both cue- and contextual fear in SERT(-/-) during acquisition, but not expression of fear-potentiated startle. The disrupted fear acquisition and concomitant increase in contextual conditioned fear-potentiated startle fear in SERT(-/-) resembles the associative learning deficit seen in patients with panic disorder and suggests that normal SERT functioning is crucial for the development of an adequate fear neuro-circuitry. Moreover, the normalization of fear acquisition by CP154,526 suggests a role for central CRF signaling in the generalization of fear.

Dorsomedial Prefrontal Cortex Mediates the Impact of Serotonin Transporter Linked Polymorphic Region Genotype on Anticipatory Threat Reactions.

BACKGROUND: Excessive anticipatory reactions to potential future adversity are observed across a range of anxiety disorders, but the neurogenetic mechanisms driving interindividual differences are largely unknown. We aimed to discover and validate a gene-brain-behavior pathway by linking presumed genetic risk for anxiety-related psychopathology, key neural activity involved in anxious anticipation, and resulting aversive emotional states. METHODS: The functional neuroanatomy of aversive anticipation was probed through functional magnetic resonance imaging in two independent samples of healthy subjects (n = 99 and n = 69), and we studied the influence of genetic variance in the serotonin transporter linked polymorphic region (5-HTTLPR). Skin conductance and startle data served as objective psychophysiological indices of the intensity of individuals' anticipatory responses to potential threat. RESULTS: Threat cues signaling risk of future electrical shock activated the dorsomedial prefrontal cortex (dmPFC), anterior insula, bed nucleus of the stria terminalis, thalamus, and midbrain consistently across both samples. Threat-related dmPFC activation was enhanced in 5-HTTLPR short allele carriers in sample 1 and this effect was validated in sample 2. Critically, we show that this region mediates the increase in anticipatory psychophysiological reactions in short allele carriers indexed by skin conductance (experiment 1) and startle reactions (experiment 2). CONCLUSIONS: The converging results from these experiments demonstrate that innate 5-HTTLPR linked variation in dmPFC activity predicts psychophysiological responsivity to pending threats. Our results reveal a neurogenetic pathway mediating interindividual variability in anticipatory responses to threat and yield a novel mechanistic account for previously reported associations between genetic variability in serotonin transporter function and stress-related psychopathology.

The impact of cue learning, trait anxiety and genetic variation in the serotonin 1A receptor on contextual fear.

In everyday life, aversive events are usually associated with certain predictive cues. Normally, the acquisition of these contingencies enables organisms to appropriately respond to threat. Presence of a threat cue clearly signals 'danger', whereas absence of such cues signals a period of 'safety'. Failure to identify threat cues may lead to chronic states of anxious apprehension in the context in which the threat has been imminent, which may be instrumental in the pathogenesis of anxiety disorders. In this study, existing data from 150 healthy volunteers in a cue and context virtual reality fear conditioning paradigm were reanalyzed. The aim was to further characterize the impact of cue acquisition and trait anxiety, and of a single nucleotide polymorphism in the serotonin 1A receptor gene (5-HTR1A, rs6295), on cued fear and contextual anxiety before and after fear contingencies were explicitly introduced. Fear conditioned responding was quantified with fear potentiation of the eyeblink startle reflex and subjective fear ratings. First, we replicated previous findings that the inability to identify danger cues during acquisition leads to heightened anxious apprehension in the threat context. Second, in subjects who did not identify the danger cue initially, contextual fear was associated with trait anxiety after the contingencies were explicitly instructed. Third, genetic variability within 5-HTR1A (rs6295) was associated with contextual fear independent of awareness or trait anxiety. These findings confirm that failure to acquire cue contingencies impacts contextual fear responding, in association with trait anxiety. The observed 5-HTR1A effect is in line with models of anxiety, but needs further replication.

No impact of deep brain stimulation on fear-potentiated startle in obsessive-compulsive disorder.

Deep brain stimulation (DBS) of the ventral internal capsule is effective in treating therapy refractory obsessive-compulsive disorder (OCD). Given the close proximity of the stimulation site to the stria terminalis (BNST), we hypothesized that the striking decrease in anxiety symptoms following DBS could be the result of the modulation of contextual anxiety. However, the effect of DBS in this region on contextual anxiety is as of yet unknown. Thus, the current study investigated the effect of DBS on contextual anxiety in an experimental threat of shock paradigm. Eight patients with DBS treatment for severe OCD were tested in a double-blind crossover design with randomly assigned 2-week periods of active and sham stimulation. DBS resulted in significant decrease of obsessive-compulsive symptoms, anxiety, and depression. However, even though the threat manipulation resulted in a clear context-potentiated startle effect, none of the parameters derived from the startle recordings was modulated by the DBS. This suggests that DBS in the ventral internal capsule is effective in treating anxiety symptoms of OCD without modulating the startle circuitry. We hypothesize that the anxiety symptoms present in OCD are likely distinct from the pathological brain circuits in defensive states of other anxiety disorders.

Impaired fear inhibition learning predicts the persistence of symptoms of posttraumatic stress disorder (PTSD).

Recent cross-sectional studies have shown that the inability to suppress fear under safe conditions is a key problem in people with posttraumatic stress disorder (PTSD). The current longitudinal study examined whether individual differences in fear inhibition predict the persistence of PTSD symptoms. Approximately 2 months after deployment to Afghanistan, 144 trauma-exposed Dutch soldiers were administered a conditional discrimination task (AX+/BX-). In this paradigm, A, B, and X are neutral stimuli. X combined with A is paired with a shock (AX+ trials); X combined with B is not (BX- trials). Fear inhibition was measured (AB trials). Startle electromyogram responses and shock expectancy ratings were recorded. PTSD symptoms were measured at 2 months and at 9 months after deployment. Results showed that greater startle responses during AB trials in individuals who discriminated between danger (AX+) and safety (BX-) during conditioning, predicted higher PTSD symptoms at 2 months and 9 months post-deployment. The predictive effect at 9 months remained significant after controlling for critical incidents during previous deployments and PTSD symptoms at 2 months. Responses to AX+ or BX- trials, or discrimination learning (AX+ minus BX-) did not predict PTSD symptoms. It is concluded that impaired fear inhibition learning seems to be involved in the persistence of PTSD symptoms.

Human fear acquisition deficits in relation to genetic variants of the corticotropin releasing hormone receptor 1 and the serotonin transporter.

The ability to identify predictors of aversive events allows organisms to appropriately respond to these events, and failure to acquire these fear contingencies can lead to maladaptive contextual anxiety. Recently, preclinical studies demonstrated that the corticotropin-releasing factor and serotonin systems are interactively involved in adaptive fear acquisition. Here, 150 healthy medication-free human subjects completed a cue and context fear conditioning procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex (FPS) was measured to assess both uninstructed fear acquisition and instructed fear expression. All participants were genotyped for polymorphisms located within regulatory regions of the corticotropin releasing hormone receptor 1 (CRHR1 - rs878886) and the serotonin transporter (5HTTLPR). These polymorphisms have previously been linked to panic disorder and anxious symptomology and personality, respectively. G-allele carriers of CRHR1 (rs878886) showed no acquisition of fear conditioned responses (FPS) to the threat cue in the uninstructed phase, whereas fear acquisition was present in C/C homozygotes. Moreover, carrying the risk alleles of both rs878886 (G-allele) and 5HTTLPR (short allele) was associated with increased FPS to the threat context during this phase. After explicit instructions regarding the threat contingency were given, the cue FPS and context FPS normalized in all genotype groups. The present results indicate that genetic variability in the corticotropin-releasing hormone receptor 1, especially in interaction with the 5HTTLPR, is involved in the acquisition of fear in humans. This translates prior animal findings to the human realm.

Individual differences in predicting aversive events and modulating contextual anxiety in a context and cue conditioning paradigm.

Deficient fear conditioning leads to maladaptive contextual anxiety as predicting danger is a key factor in regulating anxiety. A virtual reality conditioning task was used to evaluate cue learning and contextual anxiety with fear-potentiated startle and subjective fear in two experiments. In Experiment 1, failure to condition to a cue resulted in a constant state of context anxiety (subjective fearfulness and startle). Trait anxiety was unrelated to learning cue contingencies but the participants who failed to learn scored lower on a self-report measure of attentional control. Part of the group that learned the cue contingency failed to deduce safety of the context and hence did not reduce their contextual anxiety. Experiment 2 specifically focused on isolating this process and demonstrated an inverse association between trait anxiety and adaptive modulation of contextual anxiety. In conclusion, predicting threat aids in but not automatically implies successful regulation of contextual anxiety. High trait anxiety may increase risk of deficient modulation of contextual anxiety.

Testing the effects of Δ9-THC and D-cycloserine on extinction of conditioned fear in humans.

Preclinical evidence implicates several neurotransmitter systems in the extinction of conditioned fear. These results are of great interest, because the reduction of acquired fear associations is critical in therapies for anxiety disorders. We tested whether findings with respect to the N-methyl-D-aspartate (NMDA) and cannabinoid receptor (CB) systems in animals carry over to healthy human subjects. To that end, we administered selected doses of D-cycloserine (partial NMDA receptor agonist, 250 mg), delta-9-tetrahydrocannabinol (THC, CB(1) receptor agonist, 10 mg), or placebo prior to the extinction session of a 3-day conditioning protocol. D-cycloserine did not affect within-session extinction, or the retention of extinction in healthy human participants, in contrast with patient data but in line with previous reports in healthy volunteers. During extinction training, Δ9-THC reduced conditioned skin conductance responses, but not fear-potentiated startle. This effect was not retained at the retention test 2 days later, suggesting it was dependent on acute effects of the drug. Our findings implicate that facilitation of the CB(1) or NMDA system with the substances used in this study does not affect conditioned fear extinction lastingly in healthy humans. The apparent discrepancy between these findings and the results from (pre-)clinical trials is discussed in terms of room for improvement in these systems in healthy volunteers, and the lack of specificity of THC as a CB(1) agonist.