Eliciting men's preferences for decision-making relative to treatments of localized prostate cancer with a good or moderate prognosis.

PURPOSE: In diseases where there is no real consensus regarding treatment modalities, promoting shared decision-making can contribute to improving safety and quality of care. This is the case in low- or intermediate-risk localized prostate cancer (PC) treatment. The aim of this study was to investigate the preferences guiding men's decisions regarding the characteristics of the treatment strategies for PC to help physicians adopt a more patient-centered approach. METHODS: This prospective multicenter study used a discrete choice experiment (DCE). The attributes and the modalities were identified from a qualitative study and a literature review. Relative preferences were estimated using a logistic regression model. Interaction terms (demographic, clinical and socio-economic characteristics) were added to the model to assess heterogeneity in preferences. RESULTS: 652 men were enrolled in the study and completed a questionnaire with 12 pairs of hypothetical therapeutic alternatives between which they had to choose. Men's choices were significantly negatively influenced by the risk of impotence and urinary incontinence, death, and the length and frequency of care. They preferred treatments with a rescue possibility in case of deterioration or recurrence and the use of innovative technology. Surprisingly, the possibility of undergoing prostate ablation negatively influenced their choice. The results also highlighted differences in trade-offs according to socio-economic level. CONCLUSION: This study confirmed the importance of considering patients' preferences in the decision-making process. It appears essential to better understand these preferences to allow physicians to improve communication and promote case-by-case decision-making.

Criteria for indication and treatment modification in a cohort of patients with prostate cancer treated with hormone therapy.

BACKGROUND: No published studies have specifically assessed whether treatment modifications to androgen deprivation therapy (ADT) for prostate cancer (PCa) are frequently carried out in routine clinical practice. The current study was conducted to determine what proportion of patients who had initiated hormone therapy with a gonadotropin-releasing hormone (GnRH) analogue then had their treatment regimen modified during the first 24 months. METHODS: A prospective, noninterventional study was carried out in routine clinical practice in France. Patients with locally advanced or metastatic PCa were followed up for 2 years after treatment initiation with a GnRH analogue. The primary endpoint was the proportion of patients with a modification to their initial hormone therapy. RESULTS: In total, 1301 patients were enrolled into the study by 204 physicians, and the primary endpoint could be evaluated for 891 patients. The GnRH analogue treatment was initiated for metastatic PCa (24.2%), locally advanced PCa without planned local treatment (20.6%), locally advanced PCa in association with radiotherapy (31.6%), and biochemical recurrence after local treatment (21.4%). Hormonal treatment was modified in 43.8% (390/891) of patients during the 24-month follow-up period after GnRH analogue initiation. In 61.3% of cases (239/390), the type of modification involved a change of GnRH analogue formulation or switch to another GnRH analogue. A total of five significant predictive factors for GnRH analogue treatment modification were identified: metastatic stage; physician sector; physician speciality; presence or absence of urinary symptoms; and intermittent versus continuous ADT. CONCLUSIONS: This study shows that in 43.8% of the patients with advanced PCa, ADT is modified in the first 2 years after initiation in routine clinical practice. Predictive factors for alteration of ADT were metastatic stage and the choice of an intermittent schedule.

Rapid stress-induced transcriptomic changes in the brain depend on beta-adrenergic signaling.

Acute exposure to stressful experiences can rapidly increase anxiety and cause neuropsychiatric disorders. The effects of stress result in part from the release of neurotransmitters and hormones, which regulate gene expression in different brain regions. The fast neuroendocrine response to stress is largely mediated by norepinephrine (NE) and corticotropin releasing hormone (CRH), followed by a slower and more sustained release of corticosterone. While corticosterone is an important regulator of gene expression, it is not clear which stress-signals contribute to the rapid regulation of gene expression observed immediately after stress exposure. Here, we demonstrate in mice that 45 min after an acute swim stress challenge, large changes in gene expression occur across the transcriptome in the hippocampus, a region sensitive to the effects of stress. We identify multiple candidate genes that are rapidly and transiently altered in both males and females. Using a pharmacological approach, we show that most of these rapidly induced genes are regulated by NE through ß-adrenergic receptor signaling. We find that CRH and corticosterone can also contribute to rapid changes in gene expression, although these effects appear to be restricted to fewer genes. These results newly reveal a widespread impact of NE on the transcriptome and identify novel genes associated with stress and adrenergic signaling.

Discovery of highly selective brain-penetrant vasopressin 1a antagonists for the potential treatment of autism via a chemogenomic and scaffold hopping approach.

From a micromolar high throughput screening hit 7, the successful complementary application of a chemogenomic approach and of a scaffold hopping exercise rapidly led to a low single digit nanomolar human vasopressin 1a (hV1a) receptor antagonist 38. Initial optimization of the mouse V1a activities delivered suitable tool compounds which demonstrated a V1a mediated central in vivo effect. This novel series was further optimized through parallel synthesis with a focus on balancing lipophilicity to achieve robust aqueous solubility while avoiding P-gp mediated efflux. These efforts led to the discovery of the highly potent and selective brain-penetrant hV1a antagonist RO5028442 (8) suitable for human clinical studies in people with autism.

Pharmacology of basimglurant (RO4917523, RG7090), a unique metabotropic glutamate receptor 5 negative allosteric modulator in clinical development for depression.

Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and second-generation antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wake-promoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.

Selection criteria for initiation and renewal of luteinizing hormone-releasing hormone agonist therapy in patients with prostate cancer: a French prospective observational study.

OBJECTIVES: To define the profile of patients with prostate cancer (PCa) receiving a 3-month or 6-month formulation of luteinizing hormone-releasing hormone (LHRH) agonist in France and the reasons for choosing between formulations. METHODS: This prospective 1-year observational study included patients with PCa starting LHRH agonist therapy in everyday practice. Reasons for prescription and patient preference were recorded at inclusion, 3 or 6 months, and 12 months. The percentage of patients with a renewed initial prescription was recorded during follow up. RESULTS: A total of 1438 patients with PCa were included. Hormonotherapy was initiated more frequently with a 6-month (n = 903; 62.8%) than with a 3-month formulation (n = 535; 37.2%). The initial prescription was renewed in most patients after 3 or 6 months (86.1%) and 12 months (71%); 170 patients switched from a 3-month to a 6-month formulation during follow up. Presence of metastases influenced initial prescription (odds ratio 0.439; 95% confidence interval 1.095-1.892), with a 3-month formulation more often prescribed than a 6-month formulation to men with metastatic PCa at diagnosis (21.3% versus 15.8%, respectively). The most frequent reasons given by physicians for choosing the 6-month formulation were 'simplification of therapeutic regimen' (86.9%) or 'fewer unnecessary visits' (46.8%). Similar reasons were given for switching from a 3-month to a 6-month formulation during follow up. The most frequent reasons given by physicians to initiate therapy with a 3-month formulation were 'usual practice/habit' (55.5%) or 'closer patient management' (46.2%). 'Closer patient management' and 'reassuring effect upon patient' were the main reasons for switching from a 6-month to a 3-month formulation during follow up. Approximately 80% of patients were satisfied with the formulation they were prescribed and patients' reasons for preferring one formulation over another were similar to the physicians' reasons for prescribing these formulations. CONCLUSIONS: Slow-release formulations of LHRH agonists are useful therapies for physicians treating patients with PCa and there may be a preference for the 6-month formulation.

Quality of life of 1276 elderly patients with prostate cancer, starting treatment with a gonadotropin-releasing hormone agonist: results of a French observational study.

This French observational, longitudinal, prospective study described the health-related quality of life (HRQoL) of elderly men (≥75 years old) with prostate cancer after initiating gonadotropin-releasing hormone (GnRH) agonist therapy. At baseline and 3-6 months after baseline, European Organisation for Research and Treatment of Cancer quality of life questionnaire-core 30 (QLQ-C30) and prostate-specific (QLQ-PR25) questionnaires were completed by patients. Data from 1276 patients were analyzed. At baseline, mean (±SD) age was 80 (±4.1) years, 29.1% of patients had Gleason scores ≥8 and 24.9% had metastases. At baseline, increasing age, presence of metastasis and presence of comorbidity had a negative impact on QLQ-C30 and QLQ-PR25 scores. At follow-up, improvement in emotional-functioning (2.8; p < 0.001), social-functioning (1.7; p = 0.011), global HRQoL (1.6; p = 0.029), sleep-disturbance (-2.1; p = 0.011), appetite-loss (-4.0; p < 0.001) and pain (-4.1; p < 0.001) QLQ-C30 scores were observed. In addition, there was a worsening in treatment-related symptom (8.6; p < 0.001), sexual-activity (-5.5; p < 0.001) and sexual-functioning (-22.6; p < 0.001) QLQ-PR25 scores, and an improvement in urinary symptoms (-3.7; p < 0.001) and incontinence aid (-2.9; p = 0.023) QLQ-PR25 scores. This study shows that, apart from the expected impact on sexual functioning domains, HRQoL is not adversely affected by 3-6 months of GnRH agonist therapy in older men with prostate cancer.

Prefrontal tetanic stimulation, following fear reconditioning, facilitates expression of previously acquired extinction.

We have recently shown that post-extinction retraining of rats, with a shock intensity that is too weak to induce by itself significant fear acquisition, impairs the recall of fear extinction memory. Tetanic stimulation (TS) of the medial prefrontal cortex (mPFC), applied before or following this retraining, facilitates extinction recall. Here we investigated whether mPFC TS can also facilitate expression of fear extinction when rats are retrained with the same shock intensity as during the initial fear acquisition. Rats were implanted with stimulating electrodes in the mPFC and were trained to acquire freezing to a conditioning chamber, in which they had to enter freely. In Experiment 1, extinction of this response was followed by reconditioning and then another extinction training. Acquired freezing was extinguished successfully, while reacquired freezing, which was associated with increased chamber entry latencies, was resistant to subsequent extinction. Both reacquired freezing and increased chamber entry latencies were absent in rats that received post-reconditioning mPFC TS. In Experiment 2, post-conditioning mPFC TS had no effect on initially acquired freezing. In Experiment 3, rats were submitted to reconditioning without experiencing extinction training. In this condition, both reacquired freezing and increased chamber entry latencies were still present in rats that received post-reconditioning mPFC TS. These findings provide additional evidence for the fundamental role of the mPFC in maintaining expression of fear extinction.

[Diagnosis and management of severe adverse events occurring during BCG therapy for non-muscle invasive bladder cancer (NMIBC)]. / Diagnostic et prise en charge des événements indésirables sévères survenant au décours des instillations endovésicales de BCG pour le traitement des tumeurs de vessie n'infiltrant pas le muscle (TVNIM).

BCG therapy, which is the standard treatment for non-muscle invasive bladder tumours with high risk of recurrence and progression, has potential life-threatening adverse effects (AEs). Rapid deterioration of general condition in a patient with history of bladder tumour should question about an ongoing treatment with BCG and specify the date of the last instillation. Trauma during catheterization and untreated concomitant urinary infection upon instillations are risk factors of severe AEs. In emergency, the diagnosis of severe AEs of BCG therapy is only based on the medical questioning with the notion of current BCG treatment and risk-bearing event upon instillation. Management of AEs is related to their pathophysiological mechanisms and relies on a combination of antibiotics against BCG, the symptomatic treatment, and corticosteroid therapy which has shown to improve patient outcomes.

Low-frequency stimulation of the ventral hippocampus facilitates extinction of contextual fear.

Difficulties to treat fear-associated disorders, including posttraumatic stress disorder, are thought to result from dysfunction in fear extinction learning and/or memory. Animal studies on extinction modulation are therefore promising for the development of new treatments. Recent rat studies, including ones using low-frequency stimulation (LFS), have demonstrated that the ventral hippocampus (VH) modulates extinction memory. The present study explores whether the VH also modulates extinction learning. For this, rats were implanted with stimulating electrodes in the VH and experienced contextual fear conditioning, followed 6 or 24 h later by VH LFS and three sessions of extinction training. We found that, whatever the delay used (6 or 24 h), animals that received VH LFS displayed persistent low levels of freezing from the second extinction session, whereas control rats showed low levels of freezing only during the third session. In animals submitted to a stress condition (provoked by a single inescapable foot-shock followed by three sessions of situational reminders) prior to fear conditioning, VH LFS also reduced freezing levels, which, in contrast, remained high in control rats during the course of extinction training. These data suggest that LFS, targeting the VH, may be useful in reducing fear responses during extinction learning.

Prefrontal high-frequency stimulation prevents sub-conditioning procedure-provoked, but not acute stress-provoked, reemergence of extinguished fear.

We have recently shown that post-extinction exposure of rats to a sub-conditioning procedure (SCP, i.e., retraining with a shock intensity that is too weak to induce by itself significant fear conditioning) or to acute stress provokes reemergence of extinguished fear. Furthermore, this SCP effect can be abolished by high-frequency stimulation (HFS) of the medial prefrontal cortex (mPFC), when applied following the SCP. The aim of the present study was to test whether HFS of the mPFC is effective in preventing both SCP-induced and acute stress-provoked fear reemergence. Rats implanted with stimulating electrodes in the mPFC were trained to acquire high levels of freezing to conditioned auditory cue. This fear response was then extinguished. Three weeks later, no spontaneous recovery was observed, but rats exposed to either the SCP or acute stress again exhibited high levels of freezing. HFS of the mPFC, applied before provoking fear reemergence, prevented the effects of SCP, but not acute stress. These data suggest that acute stress may have more impact on functions of the mPFC and/or associated structures than a situational reminder of fear conditioning.

Post-extinction fluoxetine treatment prevents stress-induced reemergence of extinguished fear.

RATIONALE: The post-extinction exposure of rats to a sub-conditioning procedure (SCP; i.e., retraining with a shock intensity that is too weak to induce by itself significant fear conditioning) has been reported to provoke the reemergence of extinguished fear. This phenomenon can be prevented by chronic fluoxetine treatment. OBJECTIVES: We sought to examine another potential inducer of fear reemergence, acute stress, in rats and determine whether fluoxetine prevents this phenomenon. METHODS: Because in previous studies fluoxetine was administered before extinction, we first analyzed its effect on the SCP-associated reemergence of auditory-cued conditioned fear in rats injected after extinction to avoid any interaction between fluoxetine and extinction learning. Next, we used the same protocol but replaced the SCP with acute stress. RESULTS: We found that the SCP and acute stress, which were carried out 3 weeks after fear extinction, similarly provoked the reemergence of extinguished fear in rats injected with vehicle during the 3-week period. In contrast, the animals treated with fluoxetine during this period behaved similarly to those not exposed to an inducer of fear reemergence. CONCLUSIONS: Our data establish acute stress as an inducer of fear reemergence. The results provide further support for the hypothesis that fluoxetine interfered with mechanisms that reactivated extinguished fear, even when administered after fear extinction.

Brain-specific overexpression of trace amine-associated receptor 1 alters monoaminergic neurotransmission and decreases sensitivity to amphetamine.

Trace amines (TAs) such as ß-phenylethylamine, p-tyramine, or tryptamine are biogenic amines found in the brain at low concentrations that have been implicated in various neuropsychiatric disorders like schizophrenia, depression, or attention deficit hyperactivity disorder. TAs are ligands for the recently identified trace amine-associated receptor 1 (TAAR1), an important modulator of monoamine neurotransmission. Here, we sought to investigate the consequences of TAAR1 hypersignaling by generating a transgenic mouse line overexpressing Taar1 specifically in neurons. Taar1 transgenic mice did not show overt behavioral abnormalities under baseline conditions, despite augmented extracellular levels of dopamine and noradrenaline in the accumbens nucleus (Acb) and of serotonin in the medial prefrontal cortex. In vitro, this was correlated with an elevated spontaneous firing rate of monoaminergic neurons in the ventral tegmental area, dorsal raphe nucleus, and locus coeruleus as the result of ectopic TAAR1 expression. Furthermore, Taar1 transgenic mice were hyposensitive to the psychostimulant effects of amphetamine, as it produced only a weak locomotor activation and failed to alter catecholamine release in the Acb. Attenuating TAAR1 activity with the selective partial agonist RO5073012 restored the stimulating effects of amphetamine on locomotion. Overall, these data show that Taar1 brain overexpression causes hyposensitivity to amphetamine and alterations of monoaminergic neurotransmission. These observations confirm the modulatory role of TAAR1 on monoamine activity and suggest that in vivo the receptor is either constitutively active and/or tonically activated by ambient levels of endogenous agonist(s).

Dual hypocretin receptor antagonism is more effective for sleep promotion than antagonism of either receptor alone.

The hypocretin (orexin) system is involved in sleep/wake regulation, and antagonists of both hypocretin receptor type 1 (HCRTR1) and/or HCRTR2 are considered to be potential hypnotic medications. It is currently unclear whether blockade of either or both receptors is more effective for promoting sleep with minimal side effects. Accordingly, we compared the properties of selective HCRTR1 (SB-408124 and SB-334867) and HCRTR2 (EMPA) antagonists with that of the dual HCRTR1/R2 antagonist almorexant in the rat. All 4 antagonists bound to their respective receptors with high affinity and selectivity in vitro. Since in vivo pharmacokinetic experiments revealed poor brain penetration for SB-408124, SB-334867 was selected for subsequent in vivo studies. When injected in the mid-active phase, SB-334867 produced small increases in rapid-eye-movement (REM) and non-REM (NR) sleep. EMPA produced a significant increase in NR only at the highest dose studied. In contrast, almorexant decreased NR latency and increased both NR and REM proportionally throughout the subsequent 6 h without rebound wakefulness. The increased NR was due to a greater number of NR bouts; NR bout duration was unchanged. At the highest dose tested (100 mg/kg), almorexant fragmented sleep architecture by increasing the number of waking and REM bouts. No evidence of cataplexy was observed. HCRTR1 occupancy by almorexant declined 4-6 h post-administration while HCRTR2 occupancy was still elevated after 12 h, revealing a complex relationship between occupancy of HCRT receptors and sleep promotion. We conclude that dual HCRTR1/R2 blockade is more effective in promoting sleep than blockade of either HCRTR alone. In contrast to GABA receptor agonists which induce sleep by generalized inhibition, HCRTR antagonists seem to facilitate sleep by reducing waking "drive".

Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics.

BACKGROUND: Trace amines, compounds structurally related to classical biogenic amines, represent endogenous ligands of the trace amine-associated receptor 1 (TAAR1). Because trace amines also influence the activity of other targets, selective ligands are needed for the elucidation of TAAR1 function. Here we report on the identification and characterization of the first selective and potent TAAR1 partial agonist. METHODS: The TAAR1 partial agonist RO5203648 was evaluated for its binding affinity and functional activity at rodent and primate TAAR1 receptors stably expressed in HEK293 cells, for its physicochemical and pharmacokinetic properties, for its effects on the firing frequency of monoaminergic neurons ex vivo, and for its properties in vivo with genetic and pharmacological models of central nervous system disorders. RESULTS: RO5203648 showed high affinity and potency at TAAR1, high selectivity versus other targets, and favorable pharmacokinetic properties. In mouse brain slices, RO5203648 increased the firing frequency of dopaminergic and serotonergic neurons in the ventral tegmental area and the dorsal raphe nucleus, respectively. In various behavioral paradigms in rodents and monkeys, RO5203648 demonstrated clear antipsychotic- and antidepressant-like activities as well as potential anxiolytic-like properties. Furthermore, it attenuated drug-taking behavior and was highly effective in promoting attention, cognitive performance, and wakefulness. CONCLUSIONS: With the first potent and selective TAAR1 partial agonist, RO5203648, we show that TAAR1 is implicated in a broad range of relevant physiological, behavioral, and cognitive neuropsychiatric dimensions. Collectively, these data uncover important neuromodulatory roles for TAAR1 and suggest that agonists at this receptor might have therapeutic potential in one or more neuropsychiatric domains.

Imaging trait anxiety in high anxiety F344 rats: Focus on the dorsomedial prefrontal cortex.

Functional magnetic resonance imaging (fMRI) has become an important method in clinical psychiatry research whereas there are still only few comparable preclinical investigations. Herein, we report that fMRI in rats can provide key information regarding brain areas underlying anxiety behavior. Perfusion as surrogate for neuronal activity was measured by means of arterial spin labeling-based fMRI in various brain areas of high anxiety F344 rats and control Sprague-Dawley rats. In one of these areas, the dorsomedial prefrontal cortex (dmPFC), c-Fos labeling was compared between these two strains with immunolabeling. The effects of a neurotoxic ibotenic acid lesion of the dmPFC in F344 rats were examined in a social approach-avoidance anxiety procedure and fMRI. Regional brain activity of high anxiety F344 rats was different in selective cortical and subcortical areas as compared to that of low anxiety Sprague-Dawley rats; the largest difference (i.e. hyperactivity) was measured in the dmPFC. Independently, c-Fos labeling confirmed that F344 rats show increased dmPFC activity. The functional role was confirmed by neurotoxic lesion of the dmPFC that reversed the high anxiety-like behavior and partially normalized the brain activity pattern of F344 rats. The current findings may have translational value as increased activity is reported in an equivalent cortical area in patients with social anxiety, suggesting that pharmacological or functional inhibition of activity in this brain area should be explored to alleviate social anxiety in patients.

Glycine reuptake inhibitor RG1678: a pharmacologic characterization of an investigational agent for the treatment of schizophrenia.

Dysfunctional N-methyl-d-aspartate (NMDA) receptor neurotransmission has been implicated in the pathophysiology of schizophrenia. It is thought that this abnormal functioning can be corrected by increasing availability of the NMDA co-agonist glycine through inhibition of glycine transporter type 1 (GlyT1). Herein is described the pharmacologic profile of RG1678, a potent and noncompetitive glycine reuptake inhibitor. In vitro, RG1678 noncompetitively inhibited glycine uptake at human GlyT1 with a concentration exhibiting half-maximal inhibition (IC(50)) of 25 nM and competitively blocked [(3)H]ORG24598 binding sites at human GlyT1b in membranes from Chinese hamster ovary cells. In hippocampal CA1 pyramidal cells, RG1678 enhanced NMDA-dependent long-term potentiation at 100 nM but not at 300 nM. In vivo, RG1678 dose-dependently increased cerebrospinal fluid and striatal levels of glycine measured by microdialysis in rats. Additionally RG1678 attenuated hyperlocomotion induced by the psychostimulant d-amphetamine or the NMDA receptor glycine site antagonist L-687,414 in mice. RG1678 also prevented the hyper-response to d-amphetamine challenge in rats treated chronically with phencyclidine, an NMDA receptor open-channel blocker. In the latter experiment, a decrease in ex vivo striatal [(3)H]raclopride binding was also measured. These data demonstrate that RG1678 is a potent, noncompetitive glycine reuptake inhibitor that can modulate both glutamatergic and dopaminergic neurotransmission in animal experiments that model aspects of schizophrenia. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

fMRI fingerprint of unconditioned fear-like behavior in rats exposed to trimethylthiazoline.

Unconditioned fear plays an important yet poorly understood role in anxiety disorders, and only few neuroimaging studies have focused on evaluating the underlying neuronal mechanisms. In rodents the predator odor trimethylthiazoline (TMT), a synthetic component of fox feces, is commonly used to induce states of unconditioned fear. In this study, arterial spin labeling-based functional magnetic resonance imaging (fMRI) was applied to detect TMT-induced regional modulations of neuronal activity in Wistar rats. During TMT exposure the rats displayed increased freezing behavior and reduced exploration in the odor-associated area. Neuronal activity was selectively increased in the dorsal periaqueductal gray, superior colliculus and medial thalamus and reduced in the median raphe, locus coeruleus, nucleus accumbens shell, ventral tegmental area, ventral pallidum and entorhinal piriform cortex. This fMRI fingerprint involving distinct neuronal pathways was used to describe a schematic model of fear processing. Key brain areas known to underlie fear and anxiety-related autonomic and behavioral responses as well as centers of motivational processing were identified as being part of this functional circuitry of innate fear. Thus, preclinical fMRI studies based on unconditioned fear methods may provide a valuable translational approach to better characterize etiological and pathological processes underlying anxiety disorders.

TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity.

The trace amine-associated receptor 1 (TAAR1), activated by endogenous metabolites of amino acids like the trace amines p-tyramine and ß-phenylethylamine, has proven to be an important modulator of the dopaminergic system and is considered a promising target for the treatment of neuropsychiatric disorders. To decipher the brain functions of TAAR1, a selective TAAR1 agonist, RO5166017, was engineered. RO5166017 showed high affinity and potent functional activity at mouse, rat, cynomolgus monkey, and human TAAR1 stably expressed in HEK293 cells as well as high selectivity vs. other targets. In mouse brain slices, RO5166017 inhibited the firing frequency of dopaminergic and serotonergic neurons in regions where Taar1 is expressed (i.e., the ventral tegmental area and dorsal raphe nucleus, respectively). In contrast, RO5166017 did not change the firing frequency of noradrenergic neurons in the locus coeruleus, an area devoid of Taar1 expression. Furthermore, modulation of TAAR1 activity altered the desensitization rate and agonist potency at 5-HT(1A) receptors in the dorsal raphe, suggesting that TAAR1 modulates not only dopaminergic but also serotonergic neurotransmission. In WT but not Taar1(-/-) mice, RO5166017 prevented stress-induced hyperthermia and blocked dopamine-dependent hyperlocomotion in cocaine-treated and dopamine transporter knockout mice as well as hyperactivity induced by an NMDA antagonist. These results tie TAAR1 to the control of monoamine-driven behaviors and suggest anxiolytic- and antipsychotic-like properties for agonists such as RO5166017, opening treatment opportunities for psychiatric disorders.

Re-emergence of extinguished auditory-cued conditioned fear following a sub-conditioning procedure: effects of hippocampal and prefrontal tetanic stimulations.

Post-extinction exposure of rats to a sub-conditioning procedure can evoke conditioned fear, which may correspond to fear return and/or fear learning potentiation. The aim of the present study was to clarify this issue and examine the effects of tetanic stimulation of the hippocampus (HPC) and medial prefrontal cortex (mPFC), two brain regions implicated in post-extinction modulation of conditioned fear. Rats were initially submitted to five tone-shock pairings with either a 0.7-mA or 0.1-mA shock. Tone-evoked freezing was observed only with the higher shock intensity, indicating that the 0.1-mA shock corresponded to a sub-conditioning procedure. All conditioned rats underwent fear extinction with 20 tone-alone trials. When retrained with the sub-conditioning procedure, they displayed again tone-evoked freezing, except when the initial tone was unpaired or a new tone was paired with the 0.1-mA shock, demonstrating fear return rather than fear learning potentiation. We also found that HPC and mPFC tetanic stimulations, applied 24h after the sub-conditioning procedure, similarly reduced this fear return. However, mPFC inactivation abolished temporary HPC tetanus effect, whereas HPC inactivation did not interfere with mPFC tetanus effect. These data confirm our previous findings and reveal the nature of HPC-mPFC interactions in post-extinction modulation of conditioned fear.