Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: Possible involvement of 5HT1A receptors

Posttraumatic stress disorder (PTSD) is an incapacitating syndrome that follows a traumatic experience. Predator exposure promotes long-lasting anxiogenic effect in rodents, an effect related to symptoms found in PTSD patients. Cannabidiol (CBD) is a non-psychotomimetic component of Cannabis sativa with anxiolytic effects. The present study investigated the anti-anxiety actions of CBD administration in a model of PTSD. Male Wistar rats exposed to a predator (cat) received, 1 h later, singled or repeated i.p. administration of vehicle or CBD. Seven days after the stress animals were submitted to the elevated plus maze. To investigate the involvement of 5HT1A receptors in CBD effects animals were pre-treated with WAY100635, a 5HT1A receptor antagonist. To explore possible neurobiological mechanisms involved in these effects, 5HT1A receptor mRNA and BDNF protein expression were measured in the hippocampus, frontal cortex, amygdaloid complex and dorsal periaqueductal gray. Repeated administration of CBD prevented long-lasting anxiogenic effects promoted by a single predator exposure. Pretreatment with WAY100635 attenuated CBD effects. Seven days after predator exposure 5HT1A mRNA expression was up regulated in the frontal cortex and hippocampus. CBD and paroxetine failed to prevent this effect. No change in BDNF expression was found. In conclusion, predator exposure promotes long-lasting up-regulation of 5HT1A receptor gene expression in the hippocampus and frontal cortex. Repeated CBD administration prevents the long-lasting anxiogenic effects observed after predator exposure probably by facilitating 5HT1A receptors neurotransmission. Our results suggest that CBD has beneficial potential for PTSD treatment and that 5HT1A receptors could be a therapeutic target in this disorder. (C) 2012 Elsevier Ltd. All rights reserved.

Traumatic memories: bridging the gap between functional neuroimaging and psychotherapy

Objective: Neuroimaging studies have highlighted important issues related to structural and functional brain changes found in sufferers of psychological trauma that may influence their ability to synthesize, categorize, and integrate traumatic memories. Methods: Literature review and critical analysis and synthesis. Results: Traumatic memories are diagnostic symptoms of post-traumatic stress disorder (PTSD), and the dual representation theory posits separate memory systems subserving vivid re-experiencing (non-hippocampally dependent) versus declarative autobiographical memories of trauma (hippocampally dependent). But the psychopathological signs of trauma are not static over time, nor is the expression of traumatic memories. Multiple memory systems are activated simultaneously and in parallel on various occasions. Neural circuitry interaction is a crucial aspect in the development of a psychotherapeutic approach that may favour an integrative translation of the sensory fragments of the traumatic memory into a declarative memory system. Conclusion: The relationship between neuroimaging findings and psychological approaches is discussed for greater efficacy in the treatment of psychologically traumatized patients.

Towards a post-traumatic subtype of obsessive-compulsive disorder

We evaluated whether traumatic events are associated with a distinctive pattern of socio-demographic and clinical features of obsessive-compulsive disorder (OCD). We compared socio-demographic and clinical features of 106 patients developing OCD after post-traumatic stress disorder (PTSD; termed post-traumatic OCD), 41 patients developing OCD before PTSD (pre-traumatic OCD), and 810 OCD patients without any history of PTSD (non-traumatic OCD) using multinomial logistic regression analysis. A later age at onset of OCD, self-mutilation disorder, history of suicide plans, panic disorder with agoraphobia, and compulsive buying disorder were independently related to post-traumatic OCD. In contrast, earlier age at OCD onset, alcohol-related disorders, contamination-washing symptoms, and self-mutilation disorder were all independently associated with pre-traumatic OCD. In addition, patients with post-traumatic OCD without a previous history of obsessive-compulsive symptoms (OCS) showed lower educational levels, greater rates of contamination-washing symptoms, and more severe miscellaneous symptoms as compared to post-traumatic OCD patients with a history of OCS. (C) 2011 Elsevier Ltd. All rights reserved.

Role of common mental and physical disorders in partial disability around the world

Background Mental and physical disorders are associated with total disability, but their effects on days with partial disability (i.e. the ability to perform some, but not full-role, functioning in daily life) are not well understood. Aims To estimate individual (i.e. the consequences for an individual with a disorder) and societal effects (i.e. the avoidable partial disability in the society due to disorders) of mental and physical disorders on days with partial disability around the world. Method Respondents from 26 nationally representative samples (n=61 259, age 18+) were interviewed regarding mental and physical disorders, and day-to-day functioning. The Composite International Diagnostic Interview, version 3.0 (CIDI 3.0) was used to assess mental disorders; partial disability (expressed in full day equivalents) was assessed with the World Health Organization Disability Assessment Schedule in the CIDI 3.0. Results Respondents with disorders reported about 1.58 additional disability days per month compared with respondents without disorders. At the individual level, mental disorders (especially post-traumatic stress disorder, depression and bipolar disorder) yielded a higher number of days with disability than physical disorders. At the societal level, the population attributable risk proportion due to physical and mental disorders was 49% and 15% respectively. Conclusions Mental and physical disorders have a considerable impact on partial disability, at both the individual and at the societal level. Physical disorders yielded higher effects on partial disability than mental disorders.

Clinical features of tic-related obsessive-compulsive disorder: results from a large multicenter study

Objective. To evaluate the clinical features of obsessive-compulsive disorder (OCD) patients with comorbid tic disorders (TD) in a large, multicenter, clinical sample. Method. A cross-sectional study was conducted that included 813 consecutive OCD outpatients from the Brazilian OCD Research Consortium and used several instruments of assessment, including the Yale-Brown Obsessive-Compulsive Scale, the Dimensional Yale-Brown Obsessive-Compulsive Scale, the Yale Global Tic Severity Scale (YGTSS), the USP Sensory Phenomena Scale, and the Structured Clinical Interview for DSM-IV Axis I Disorders. Results. The sample mean current age was 34.9 years old (SE 0.54), and the mean age at obsessive-compulsive symptoms (OCS) onset was 12.8 years old (SE 0.27). Sensory phenomena were reported by 585 individuals (72% of the sample). The general lifetime prevalence of TD was 29.0% (n=236), with 8.9% (n=72) presenting Tourette syndrome, 17.3% (n=5141) chronic motor tic disorder, and 2.8% (n=523) chronic vocal tic disorder. The mean tic severity score, according to the YGTSS, was 27.2 (SE 1.4) in the OCD1TD group. Compared to OCD patients without comorbid TD, those with TD (OCD1TD group, n=236) were more likely to be males (49.2% vs. 38.5%, p<005) and to present sensory phenomena and comorbidity with anxiety disorders in general: separation anxiety disorder, social phobia, specific phobia, generalized anxiety disorder, post-traumatic stress disorder, attention-deficit hyperactivity disorder, impulse control disorders in general, and skin picking. Also, the "aggressive," "sexual/religious," and "hoarding" symptom dimensions were more severe in the OCD+TD group. Conclusion. Tic-related OCD may constitute a particular subgroup of the disorder with specific phenotypical characteristics, but its neurobiological underpinnings remain to be fully disentangled.

Should Psychotherapy Consider Reincarnation?

There is increasing recognition of the need to take into account the cultural environment and belief systems of psychotherapy patients because these values reflect basic assumptions about man's nature and the cognitive references used to cope with psychological difficulties. Currently accepted psychotherapeutic approaches take no account of the belief in life after death held by most of the world's population. The World Values Survey (http://www.worldvaluessurvey.org) showed that there are large numbers of reincarnationists around the world, and whatever the reasons for believing in reincarnation, psychotherapeutic approaches should not ignore this significant group of people. Respect for patient opinions and subjective realities is a therapeutic need and an ethical duty, even though therapists may not share the same beliefs. Guidelines are suggested for professionals to develop collaborative models that help patients mobilize their intrinsic intelligence to find solutions to their complaints.

Clinical correlates of social adjustment in patients with obsessive-compulsive disorder

Background: Patients with obsessive-compulsive disorder (OCD) frequently show poor social adjustment, which has been associated with OCD severity. Little is known about the effects that age at symptom onset, specific OCD symptoms, and psychiatric comorbidities have on social adjustment. The objective of this study was to investigate the clinical correlates of social functioning in OCD patients. Methods: Cross-sectional study involving 815 adults with a primary DSM-IV diagnosis of OCD participating in the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders. Patients were assessed with the Social Adjustment Scale, the Medical Outcomes Study 36-item Short-Form Health Survey, the Yale-Brown Obsessive-Compulsive Scale, the Dimensional Yale-Brown Obsessive-Compulsive Scale, and the Structured Clinical Interview for DSM-IV Axis I Disorders. Clinical correlates of social adjustment were assessed with generalized linear models with gamma distribution. Results: Poor overall social functioning was associated with greater OCD severity (p = 0.02); hoarding symptoms (p = 0.004); sexual/religious obsessions (p = 0.005); current major depressive disorder (p = 0.004); current post-traumatic stress disorder (p = 0.002); and current eating disorders (p = 0.02). Poor social adjustment was also associated with impaired quality of life. Conclusions: Patients with OCD have poor social functioning in domains related to personal relationships and professional performance. Hoarding symptoms and sexual/religious obsessions seem to have the strongest negative effects on social functioning. Early age at OCD symptom onset seems to be associated with professional and academic underachievement and impairment within the family unit, whereas current psychiatric comorbidity worsen overall social functioning. In comparison with quality of life, social adjustment measures seem to provide a more comprehensive overview of the OCD-related burden. (C) 2012 Elsevier Ltd. All rights reserved.

The Dorsolateral Periaqueductal Gray and Its Role in Mediating Fear Learning to Life Threatening Events

The dorsolateral column of the periaqueductal gray (dlPAG) integrates aversive emotional experiences and represents an important site responding to life threatening situations, such as hypoxia, cardiac pain and predator threats. Previous studies have shown that the dorsal PAG also supports fear learning; and we have currently explored how the dlPAG influences associative learning. We have first shown that N-methyl-D-aspartate (NMDA) 100 pmol injection in the dlPAG works as a valuable unconditioned stimulus (US) for the acquisition of olfactory fear conditioning (OFC) using amyl acetate odor as conditioned stimulus (CS). Next, we revisited the ascending projections of the dlPAG to the thalamus and hypothalamus to reveal potential paths that could mediate associative learning during OFC. Accordingly, the most important ascending target of the dlPAG is the hypothalamic defensive circuit, and we were able to show that pharmacological inactivation using beta-adrenoceptor blockade of the dorsal premammillary nucleus, the main exit way for the hypothalamic defensive circuit to thalamo-cortical circuits involved in fear learning, impaired the acquisition of the OFC promoted by NMDA stimulation of the dlPAG. Moreover, our tracing study revealed multiple parallel paths from the dlPAG to several thalamic targets linked to cortical-hippocampal-amygdalar circuits involved in fear learning. Overall, the results point to a major role of the dlPAG in the mediation of aversive associative learning via ascending projections to the medial hypothalamic defensive circuit, and perhaps, to other thalamic targets, as well. These results provide interesting perspectives to understand how life threatening events impact on fear learning, and should be useful to understand pathological fear memory encoding in anxiety disorders.

On Disruption of Fear Memory by Reconsolidation Blockade: Evidence from Cannabidiol Treatment

The search for reconsolidation blockers may uncover clinically relevant drugs for disrupting memories of significant stressful life experiences, such as those underlying the posttraumatic stress disorder. Considering the safety of systemically administered cannabidiol (CBD), the major non-psychotomimetic component of Cannabis sativa, to animals and humans, the present study sought to investigate whether and how this phytocannabinoid (3-30 mg/kg intraperitoneally; i.p.) could mitigate an established memory, by blockade of its reconsolidation, evaluated in a contextual fear-conditioning paradigm in rats. We report that CBD is able to disrupt 1- and 7-days-old memories when administered immediately, but not 6 h, after their retrieval for 3 min, with the dose of 10 mg/kg being the most effective. This effect persists in either case for at least 1 week, but is prevented when memory reactivation was omitted, or when the cannabinoid type-1 receptors were antagonized selectively with AM251 (1.0 mg/kg). Pretreatment with the serotonin type-1A receptor antagonist WAY100635, however, failed to block CBD effects. These results highlight that recent and older fear memories are equally vulnerable to disruption induced by CBD through reconsolidation blockade, with a consequent long-lasting relief in contextual fear-induced freezing. Importantly, this CBD effect is dependent on memory reactivation, restricted to time window of <6h, and is possibly dependent on cannabinoid type-1 receptor-mediated signaling mechanisms. We also observed that the fear memories disrupted by CBD treatment do not show reinstatement or spontaneous recovery over 22 days. These findings support the view that reconsolidation blockade, rather than facilitated extinction, accounts for the aforementioned CBD results in our experimental conditions. Neuropsychopharmacology (2012) 37, 2132-2142; doi:10.1038/npp.2012.63; published online 2 May 2012

Does anti-obsessional pharmacotherapy treat so-called comorbid depressive and anxiety states?

Background: Obsessive-compulsive disorder (OCD) is a chronic condition that normally presents high rates of psychiatric comorbidity. Depression, tic disorders and other anxiety disorders are among the most common comorbidities in OCD adult patients. There is evidence that the higher the number of psychiatric comorbidities, the worse the OCD treatment response. However, little is known about the impact of OCD treatment on the outcome of the psychiatric comorbidities usually present in OCD patients. The aim of this study was to investigate the impact of exclusive, conventional treatments for OCD on the outcome of additional psychiatric disorders of OCD patients, detected at baseline. Methods: Seventy-six patients with primary OCD admitted to the treatment protocols of the Obsessive-Compulsive Spectrum Disorders Program between July 2007 and December 2009 were evaluated at pre-treatment and after 12 months. Data were analyzed to verify possible associations between,OCD treatment response and the outcome of psychiatric comorbidities. Results: Results showed a significant association between OCD treatment response and improvement of major depression and dysthymia (p-value = 0.002), other anxiety disorders (generalized anxiety disorder, social phobia, specific phobia, posttraumatic stress disorder, panic disorder, agoraphobia and anxiety disorder not otherwise specified) (p-value = 0.054) and tic disorders (p-value = 0.043). Limitations: This is an open, non-blinded study, without rating scales for comorbid conditions. Further research is necessary focusing on the possible mechanisms by which OCD treatment could improve these specific disorders. Conclusions: Our results suggest that certain comorbid disorders may benefit from OCD-targeted treatment. (C) 2012 Elsevier B.V. All rights reserved.

Effects of cryogenic and stress relief treatments on temper carbide precipitation in AISI D2 tool steel

The effects of cryogenic and stress relief treatments on temper carbide precipitation in the cold work tool steel AISI D2 were studied. For the cryogenic treatment the temperature was −196°C and the holding time was 2, 24 or 30 h. The stress relief heat treatment was carried at 130°C/90 min, when applied. All specimens were compared to a standard thermal cycle. Specimens were studied using metallographic characterisation, X-ray diffraction and thermoelectric power measurements. The metallographic characterisation used SEM (scanning electron microscopy) and SEM-FEG (SEM with field emission gun), besides OM (optical microscopy). No variation in the secondary carbides (micrometre sized) precipitation was found. The temper secondary carbides (nanosized) were found to be more finely dispersed in the matrix of the specimens with cryogenic treatment and without stress relief. The refinement of the temper secondary carbides was attributed to a possible in situ carbide precipitation during tempering.