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.

Essays in Behavioral Personnel Economics

The thesis contemplates 4 papers and its main goal is to provide evidence on the prominent impact that behavioral analysis can play into the personnel economics domain.The research tool prevalently used in the thesis is the experimental analysis.The first paper provide laboratory evidence on how the standard screening model–based on the assumption that the pecuniary dimension represents the main workers’choice variable–fails when intrinsic motivation is introduced into the analysis.The second paper explores workers’ behavioral reactions when dealing with supervisors that may incur in errors in the assessment of their job performance.In particular,deserving agents that have exerted high effort may not be rewarded(Type-I errors)and undeserving agents that have exerted low effort may be rewarded(Type-II errors).Although a standard neoclassical model predicts both errors to be equally detrimental for effort provision,this prediction fails when tested through a laboratory experiment.Findings from this study suggest how failing to reward deserving agents is significantly more detrimental than rewarding undeserving agents.The third paper investigates the performance of two antithetic non-monetary incentive schemes on schooling achievement.The study is conducted through a field experiment.Students randomized to the main treatments have been incentivized to cooperate or to compete in order to earn additional exam points.Consistently with the theoretical model proposed in the paper,the level of effort in the competitive scheme proved to be higher than in the cooperative setting.Interestingly however,this result is characterized by a strong gender effect.The fourth paper exploits a natural experiment setting generated by the credit crunch occurred in the UK in the2007.The economic turmoil has negatively influenced the private sector,while public sector employees have not been directly hit by the crisis.This shock–through the rise of the unemployment rate and the increasing labor market uncertainty–has generated an exogenous variation in the opportunity cost of maternity leave in private sector labor force.This paper identifies the different responses.

Effect of loss of CDKL5 on brain development in a new Cdkl5 knockout mouse model

Rett's Syndrome (RTT) is a severe neurodevelopmental disorder, characterized by cognitive disability that appears in the first months/years of life. Recently, mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been detected in RTT patients characterized by early-onset seizures. CDKL5 is highly expressed in the brain starting from early postnatal stages to adulthood, suggesting the importance of this kinase for proper brain maturation and function. However, the role/s of CDKL5 in brain development and the molecular mechanisms whereby CDKL5 exerts its effects are still largely unknown. In order to characterize the role of CDKL5 on brain development, we created a mice carrying a targeted conditional knockout allele of Cdkl5. A first behavioral characterization shows that Cdkl5 knockout mice recapitulate several features that mimic the clinical features described in CDKL5 patients and are a useful tool to investigate phenotypic and functional aspects of Cdkl5 loss. We used the Cdkl5 knockout mouse model to dissect the role of CDKL5 on hippocampal development and to establish the mechanism/s underlying its actions. We found that Cdkl5 knockout mice showed increased precursor cell proliferation in the hippocampal dentate gyrus. Interestingly, this region was also characterized by an increased rate of apoptotic cell death that caused a reduction in the final neuron number in spite of the proliferation increase. Moreover, loss of Cdkl5 led to decreased dendritic development of new generated granule cells. Finally, we identified the Akt/GSK3-beta signaling as a target of Cdkl5 in the regulation of neuronal precursor proliferation, survival and maturation. Overall our findings highlight a critical role of CDKL5/AKT/GSK3-beta signaling in the control of neuron proliferation, survival and differentiation and suggest that CDKL5-related alterations of these processes during brain development underlie the neurological symptoms of the CDKL5 variant of RTT.

Social Welfare and Behavioral Public Policies

In this work I discuss several key aspects of welfare economics and policy analysis and I propose two original contributions to the growing field of behavioral public policymaking. After providing a historical perspective of welfare economics and an overview of policy analysis processes in the introductory chapter, in chapter 2 I discuss a debated issue of policymaking, the choice of the social welfare function. I contribute to this debate by proposing an original methodological contribution based on the analysis of the quantitative relationship among different social welfare functional forms commonly used by policy analysts. In chapter 3 I then discuss a behavioral policy to contrast indirect tax evasion based on the use of lotteries. I show that the predictions of my model based on non-expected utility are consistent with observed, and so far unexplained, empirical evidence of the policy success. Finally, in chapter 4 I investigate by mean of a laboratory experiment the effects of social influence on the individual likelihood to engage in altruistic punishment. I show that bystanders’ decision to engage in punishment is influenced by the punishment behavior of their peers and I suggest ways to enact behavioral policies that exploit this finding.

Behavioral Assessment of Core ADHD Symptoms Using the QbTest

Objective: Hyperactivity, one of the core symptoms of ADHD, has been mostly neglected in neuropsychological assessment of childhood ADHD. The neuropsychological Quantified behavior Test (QbTest) separately assesses all three core symptoms of ADHD on a behavioral level. Factor structure of the QbTest and its concurrent and discriminant validity are presented. Method: An exploratory factor analysis (n = 828 children) was performed. In a second sample (n = 102 children) a Multi-Trait-Multi-Method (MTMM) approach was used for validity analyses. Results: A three factorial model explained 76 % of the total variance, with the resulting QbTest factors significantly influenced by age and gender. The MTMM approach yielded promising results for discriminant, yet inconsistent findings for concurrent validity between the QbTest and another attention test as well as for Conners' Parent and Teacher Rating Scales. Conclusion: Results indicate that the QbTest may be helpful for the behavioral assessment of childhood ADHD, yet further studies on its psychometric quality and clinical utility are needed. (J. of Att. Dis. 2012; XX(X) 1-XX).

Rufinamide attenuates mechanical allodynia in a model of neuropathic pain in the mouse and stabilizes voltage-gated sodium channel inactivated state

Background: Voltage-gated sodium channels dysregulation is important for hyperexcitability leading to pain persistence. Sodium channel blockers currently used to treat neuropathic pain are poorly tolerated. Getting new molecules to clinical use is laborious. We here propose a drug already marketed as anticonvulsant, rufinamide. Methods: We compared the behavioral effect of rufinamide to amitriptyline using the Spared Nerve Injury neuropathic pain model in mice. We compared the effect of rufinamide on sodium currents using in vitro patch clamp in cells expressing the voltage-gated sodium channel Nav1.7 isoform and on dissociated dorsal root ganglion neurons to amitriptyline and mexiletine. Results: In naive mice, amitriptyline (20 mg/kg) increased withdrawal threshold to mechanical stimulation from 1.3 (0.6–1.9) (median [95% CI]) to 2.3 g (2.2–2.5) and latency of withdrawal to heat stimulation from 13.1 (10.4–15.5) to 30.0 s (21.8–31.9), whereas rufinamide had no effect. Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 ± 0.03 g (mean ± SD) to 1.99 ± 0.26 g for rufinamide and 0.25 ± 0.22 g to 1.92 ± 0.85 g for amitriptyline). All drugs reduced peak current and stabilized the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons. Conclusions: At doses alleviating neuropathic pain, amitriptyline showed alteration of behavioral response possibly related to either alteration of basal pain sensitivity or sedative effect or both. Side-effects and drug tolerance/compliance are major problems with drugs such as amitriptyline. Rufinamide seems to have a better tolerability profile and could be a new alternative to explore for the treatment of neuropathic pain.

A prediction model for personal radio frequency electromagnetic field exposure

Radio frequency electromagnetic fields (RF-EMF) in our daily life are caused by numerous sources such as fixed site transmitters (e.g. mobile phone base stations) or indoor devices (e.g. cordless phones). The objective of this study was to develop a prediction model which can be used to predict mean RF-EMF exposure from different sources for a large study population in epidemiological research. We collected personal RF-EMF exposure measurements of 166 volunteers from Basel, Switzerland, by means of portable exposure meters, which were carried during one week. For a validation study we repeated exposure measurements of 31 study participants 21 weeks after the measurements of the first week on average. These second measurements were not used for the model development. We used two data sources as exposure predictors: 1) a questionnaire on potentially exposure relevant characteristics and behaviors and 2) modeled RF-EMF from fixed site transmitters (mobile phone base stations, broadcast transmitters) at the participants' place of residence using a geospatial propagation model. Relevant exposure predictors, which were identified by means of multiple regression analysis, were the modeled RF-EMF at the participants' home from the propagation model, housing characteristics, ownership of communication devices (wireless LAN, mobile and cordless phones) and behavioral aspects such as amount of time spent in public transports. The proportion of variance explained (R2) by the final model was 0.52. The analysis of the agreement between calculated and measured RF-EMF showed a sensitivity of 0.56 and a specificity of 0.95 (cut-off: 90th percentile). In the validation study, the sensitivity and specificity of the model were 0.67 and 0.96, respectively. We could demonstrate that it is feasible to model personal RF-EMF exposure. Most importantly, our validation study suggests that the model can be used to assess average exposure over several months.

Traumatization and chronic pain: a further model of interaction.

Up to 80% of patients with severe posttraumatic stress disorder are suffering from "unexplained" chronic pain. Theories about the links between traumatization and chronic pain have become the subject of increased interest over the last several years. We will give a short summary about the existing interaction models that emphasize particularly psychological and behavioral aspects of this interaction. After a synopsis of the most important psychoneurobiological mechanisms of pain in the context of traumatization, we introduce the hypermnesia-hyperarousal model, which focuses on two psychoneurobiological aspects of the physiology of learning. This hypothesis provides an answer to the hitherto open question about the origin of pain persistence and pain sensitization following a traumatic event and also provides a straightforward explanatory model for educational purposes.

Long-term injury induced plasticity in {\it Aplysia\/} neurons: Behavioral, electrophysiological, and morphological studies

Nerve injury is known to produce a variety of electrophysiological and morphological neuronal alterations (reviewed by Titmus and Faber, 1990; Bulloch and Ridgeway, 1989; Walters, 1994). Determining if these alterations are adaptive and how they are activated and maintained could provide important insight into basic cellular mechanisms of injury-induced plasticity. Furthermore, characterization of injury-induced plasticity provides a useful assay system for the identification of possible induction signals underlying these neuronal changes. Understanding fundamental mechanisms and underlying induction signals of injury-induced neuronal plasticity could facilitate development of treatment strategies for neural injury and neuropathic pain in humans.^ This dissertation characterizes long-lasting, injury-induced neuronal alterations using the nervous system of Aplysia californica as a model. These changes are examined at the behavioral, electrophysiological, and morphological levels. Injury-induced changes in the electrophysiological properties of neurons were found that increased the signaling effectiveness of the injured neurons. This increase in signalling effectiveness could act to compensate for partial destruction of the injured neuron's peripheral processes. Recovery of a defensive behavioral response which serves to protect the animal from further injury was found within 2 weeks of injury. For the behavioral recovery to occur, new neural pathways must have been formed between the denervated area and the CNS. This was found to be mediated at least in part by new axonal growth which extended from the injured cell back along the original pathway (i.e. into the injured nerve). In addition, injury produced central axonal sprouting into different nerves that do not usually contain the injured neuron's axons. This could be important for (i) finding alternative pathways to the periphery when the original pathways are impassable and (ii) the formation of additional synaptic connections with post-synaptic targets which would further enhance the signalling effectiveness of the injured cell. ^

Quantitative MRI of spinal cord injury in a rat model: Correlative studies

Serial quantitative and correlative studies of experimental spinal cord injury (SCI) in rats were conducted using three-dimensional magnetic resonance imaging (MRI). Correlative measures included morphological histopathology, neurobehavioral measures of functional deficit, and biochemical assays for N-acetyl-aspartate (NAA), lactate, pyruvate, and ATP. A spinal cord injury device was characterized and provided a reproducible injury severity. Injuries were moderate and consistent to within $\pm$20% (standard deviation). For MRI, a three-dimensional implementation of the single spin-echo FATE (Fast optimum angle, short TE) pulse sequence was used for rapid acquisition, with a 128 x 128 x 32 (x,y,z) matrix size and a 0.21 x 0.21 x 1.5 mm resolution. These serial studies revealed a bimodal characteristic in the evolution in MRI pathology with time. Early and late phases of SCI pathology were clearly visualized in $T\sb2$-weighted MRI, and these corresponded to specific histopathological changes in the spinal cord. Centralized hypointense MRI regions correlated with evidence of hemorrhagic and necrotic tissue, while surrounding hyperintense regions represented edema or myelomalacia. Unexpectedly, $T\sb2$-weighted MRI pathology contrast at 24 hours after injury appeared to subside before peaking at 72 hours after injury. This change is likely attributable to ongoing secondary injury processes, which may alter local $T\sb2$ values or reduce the natural anisotropy of the spinal cord. MRI, functional, and histological measures all indicated that 72 hours after injury was the temporal maximum for quantitative measures of spinal cord pathology. Thereafter, significant improvement was seen only in neurobehavioral scores. Significant correlations were found between quantitated MRI pathology and histopathology. Also, NAA and lactate levels correlated with behavioral measures of the level of function deficit. Asymmetric (rostral/caudal) changes in NAA and lactate due to injury indicate that rostral and caudal segments from the injury site are affected differently by the injury. These studies indicate that volumetric quantitation of MRI pathology from $T\sb2$-weighted images may play an important role in early prediction of neurologic deficit and spinal cord pathology. The loss of $T\sb2$ contrast at 24 hours suggests MR may be able to detect certain delayed mechanisms of secondary injury which are not resolved by histopathology or other radiological modalities. Furthermore, in vivo proton magnetic resonance spectroscopy (MRS) studies of SCI may provide a valuable addition source of information about changes in regional spinal cord lactate and NAA levels, which are indicative of local metabolic and pathological changes. ^

Behavioral and psychosocial factors associated with sexual risk in a population of crack cocaine users

The purpose of this dissertation was to examine the relationship between key psychosocial and behavioral components of the Transtheoretical Model and the Theory of Reasoned Action for sexual risk reduction in a population of crack cocaine smokers and sex workers, not in drug treatment. ^ The first study examined the results of an analysis of the association between two principal constructs in the Transtheoretical Model, the processes of change and the stages of change for condom use, in a high risk population. In the analysis of variance for all respondents, the overall F-test revealed that people in different stages have different levels of experiential process use, F(3,317) = 17.79, p = 0.0001 and different levels of behavioral process use, F(3,317) = 28.59, p = .0001. For the experiential processes, there was a significant difference between the precontemplation/contemplation stage, and both the action, and maintenance, stages.^ The second study explored the relationship between the Theory of Reasoned Action “beliefs” and the stages-of-change in the same population. In the analysis of variance for all participants, the results indicate that people in different stages did value the positive beliefs differently, F(3,502) = 15.38, p = .0001 but did not value the negative beliefs differently, F(3,502) = 2.08, p = .10. ^ The third study explored differences in stage-of-change by gender, partner type drug use, and HIV status. Three discriminant functions emerged, with a combined χ2(12) = 139.57, p = <.0001. The loading matrix of correlations between predictors and discriminant functions demonstrate that the strongest predictor for distinguishing between the precontemplation/contemplation stage and the preparation, action, and maintenance stages (first function) is partner type (.962). The loadings on the second discriminant function suggest that once partner type has been accounted for, ever having HIV/AIDS (.935) was the best predictor for distinguishing between the first three stages and the maintenance stage. ^ These studies demonstrate that behavioral change theories can contribute important insight to researchers and program planners attempting to alter HIV risk behavior in high-risk populations. ^

Behavioral effects of plasma tryptophan depletion in aggressive and nonaggressive men

Serotonin (5-HT) neurotransmission deficits have been implicated in impulsive aggression. A Trp-free beverage of amino acids competitively inhibits Trp uptake into the brain for 5-HT synthesis and also lowers endogenous plasma Trp for several hours. This has worsened mood and/or increased aggressive behavior, especially in hostile persons or those with histories of depression. In 24 community-recruited men (12 each with and without significant aggression histories), aggressive and impulsive behavior in the laboratory was assessed before and after plasma Trp depletion and Trp loading. In the aggression model, subjects were provoked by periodic subtractions of participation earnings, and these subtractions were blamed on a ficitious other participant. Aggression was measured as the responses the subject made to subtract money from his antagonist. Impulsiveness was operationalized as: (1) the choice of smaller reward after a shorter delay over having to wait longer to receive a larger reward, and (2) “false alarm” commission errors in a modified Continuous Performance Task, which represent a failure to inhibit responding to stimuli similar (but not identical) to target stimuli. Finally, plasma cortisol and Trp were measured under each condition immediately following a aggression testing session when subjects were highly provoked. I hypothesized that 5-HT may tonically modulate (inhibit) the hypothalmnic-pituitary-adrenal stress response, such that Trp depletion may enhance the cortisol response to high provocation in aggressive men. ^ Trp depletion had no effect in the laboratory tasks purported to measure impulsive behavior, and failed to cause increases in aggressive behavior under low provocation conditions. Under higher provocation, however, aggressive responses we re elevated under Trp-depleted conditions relative to Trp-loaded conditions in aggressive men, whereas the reverse was true in nonaggressive men. Cortisol levels nonsignificantly paralled the group differences in aggression under Trp-depleted and Trp-loaded conditions. Aggressive men achieved lower plasma Trp levels after Trp loading than did nonaggressive men, possibly due to heavy alcohol use histories. The high post-loading plasma Trp levels in nonaggressive men tended also to correlate with their aggressive responding rates, due perhaps to increases in other psychoactive Trp metabolites. ^

Do different anesthesia regimes affect hippocampal apoptosis and neurologic deficits in a rodent cardiac arrest model?

Background Different anesthesia regimes are commonly used in experimental models of cardiac arrest, but the effects of various anesthetics on clinical outcome parameters are unknown. We conducted a study in which we subjected rats to cardiac arrest under medetomidine/ketamine or sevoflurane/fentanyl anesthesia. Methods Asystolic cardiac arrest for 8 minutes was induced in 73 rats with a mixture of potassium chloride and esmolol. Daily behavioral and neurological examination included the open field test (OFT), the tape removal test (TRT) and a neurodeficit score (NDS). Animals were randomized for sacrifice on day 2 or day 5 and brains were harvested for histology in the hippocampus cornus ammonis segment CA1. The inflammatory markers IL-6, TNF-α, MCP-1 and MIP-1α were assessed in cerebrospinal fluid (CSF). Proportions of survival were tested with the Fisher’s exact test, repeated measurements were assessed with the Friedman’s test; the baseline values were tested using Mann–Whitney U test and the difference of results of repeated measures were compared. Results In 31 animals that survived beyond 24 hours neither OFT, TRT nor NDS differed between the groups; histology was similar on day 2. On day 5, significantly more apoptosis in the CA1 segment of the hippocampus was found in the sevoflurane/fentanyl group. MCP-1 was higher on day 5 in the sevoflurane/fentanyl group (p = 0.04). All other cyto- and chemokines were below detection threshold. Conclusion In our cardiac arrest model neurological function was not influenced by different anesthetic regimes; in contrast, anesthesia with sevoflurane/fentanyl results in increased CSF inflammation and histologic damage at day 5 post cardiac arrest.

Evidence of an association between sleep and levodopa-induced dyskinesia in an animal model of Parkinson's disease.

Levodopa-induced dyskinesia (LID) represents a major challenge for clinicians treating patients affected by Parkinson's disease (PD). Although levodopa is the most effective treatment for PD, the remodeling effects induced by disease progression and the pharmacologic treatment itself cause a narrowing of the therapeutic window because of the development of LID. Although animal models of PD provide strong evidence that striatal plasticity underlies the development of dyskinetic movements, the pathogenesis of LID is not entirely understood. In recent years, slow homeostatic adjustment of intrinsic excitability occurring during sleep has been considered fundamental for network stabilization by gradually modifying plasticity thresholds. So far, how sleep affects on LID has not been investigated. Therefore, we measured synaptic downscaling across sleep episodes in a parkinsonian animal model showing dyskinetic movements similar to LID. Our electrophysiological, molecular, and behavioral results are consistent with an impaired synaptic homeostasis during sleep in animals showing dyskinesia. Accordingly, sleep deprivation causes an anticipation and worsening of LID supporting a link between sleep and the development of LID.