Gabriel Esquivel

An environmental analysis of genes associated with schizophrenia: hypoxia and vascular factors as interacting elements in the neurodevelopmental model

Investigating and understanding gene–environment interaction (G × E) in a neurodevelopmentally and biologically plausible manner is a major challenge for schizophrenia research. Hypoxia during neurodevelopment is one of several environmental factors related to the risk of schizophrenia, and links between schizophrenia candidate genes and hypoxia regulation or vascular expression have been proposed. Given the availability of a wealth of complex genetic information on schizophrenia in the literature without knowledge on the connections to environmental factors, we now systematically collected genes from candidate studies (using SzGene), genome-wide association studies (GWAS) and copy number variation (CNV) analyses, and then applied four criteria to test for a (theoretical) link to ischemia–hypoxia and/or vascular factors. In all, 55% of the schizophrenia candidate genes (n=42 genes) met the criteria for a link to ischemia–hypoxia and/or vascular factors. Genes associated with schizophrenia showed a significant, threefold enrichment among genes that were derived from microarray studies of the ischemia–hypoxia response (IHR) in the brain. Thus, the finding of a considerable match between genes associated with the risk of schizophrenia and IHR and/or vascular factors is reproducible. An additional survey of genes identified by GWAS and CNV analyses suggested novel genes that match the criteria. Findings for interactions between specific variants of genes proposed to be IHR and/or vascular factors with obstetric complications in patients with schizophrenia have been reported in the literature. Therefore, the extended gene set defined here may form a reasonable and evidence-based starting point for hypothesis-based testing of G × E interactions in clinical genetic and translational neuroscience studies.

Acids in the brain: a factor in panic?

Several methods to experimentally induce panic cause profound acid-base disturbances. Evidence suggests that CO2 inhalations, lactate infusions and, to a certain extent, voluntary hyperventilation can conceivably lead to a common scenario of brain acidosis in the face of disparate intravascular pH alterations. The importance of this event is reflected in data that support a model in which experimental panic attacks, as proxy to those occurring spontaneously, constitute a response to acute brain acidosis. Given that central CO2/H+ chemoreception is an important drive for ventilation, and many chemosensitive neurons are related to respiration and arousal, this model can explain much of the connection between panic and respiration. We propose that the shared characteristics of CO2/H+ sensing neurons overlap to a point where threatening disturbances in brain pH homeostasis, such as those produced by CO2 inhalations, elicit a primal emotion that can range from breathlessness to panic.

Genetic moderation of CO2-induced fear by 5-HTTLPR genotype

Inhalation of an increased concentration of carbon dioxide (CO2) has been shown to induce a state of negative affect in healthy subjects that is closely related to the clinical phenomenon of panic. It has been suggested that the vulnerability to CO2 is moderated by differences in serotonin (5-HT) activity, caused by a functional polymorphism in the promoter region of the 5-HT transporter (5-HTTLPR) gene. Our aim was to examine the relationship between bi- and tri-allelic 5-HTTLPR genotype and the affective response to different dosages of inhaled CO2 in healthy volunteers. Ninety-six subjects performed a double inhalation of four mixtures containing, respectively, 0%, 9%, 17.5% and 35% CO2, following a double-blind, cross-over, randomized design. Affective responses were measured with a visual analogue scale for fear and the Panic Symptom List. 5-HTTLPR genotype was expressed as LL, SL and SS. Subjects with the SL and SS genotype reported less fear than LL subjects. A significant interaction effect was found between genotype and CO2 dosage: the SS genotype showed lower fear scores than the LL genotype, particularly in the 17.5% CO2 dose condition. The present study suggests that the dose-dependent fear reaction to CO2 is moderated by a polymorphism in the 5-HT transporter gene, particularly at intermediate CO2 dosages. It also underscores the usefulness of the introduction of an intermediate phenotype related to panic to reveal an underlying genetic vulnerability otherwise staying elusive. These results are in line with current theories on the role of 5-HT in both panic and respiration.

The effects of acute exercise and high lactate levels on 35% CO2 challenge in healthy volunteers

Objective:  To test the possible antipanic effects of acute exercise in healthy volunteers exposed to an inhalation of 35% CO2 challenge.

Brainstem response to hypercapnia: A symptom provocation study into the pathophysiology of panic disorder

Background: The biological basis of uncued panic attacks is not yet understood. An important theory concerning the nature and cause of panic disorder is the ‘suffocation false alarm theory’. This alarm is supposed to be over-sensitive in panic disorder patients and can be triggered by CO2. No neurobiological substrate has been identified for such an alarm. The present study investigates differences in brain activation in panic patients, healthy individuals and experienced divers in response to CO2, representing three groups with descending sensitivity to CO2. Method: Brain activation was measured with functional magnetic resonance imaging. Subjects breathed through a mouthpiece delivering a continuous flow of 100% oxygen for two minutes, followed by a hypercapnic gas mixture (7% CO2) for the next two minutes. Statistical analysis was performed using SPM8. Results: There was a significant main effect of group in response to the CO2. Patients show increased brainstem activation in response to hypercapnia compared to controls and divers. Subjective feelings of breathing discomfort were positively correlated with brain activation in the anterior insula in all groups. Conclusion: This is the first study showing that the behavioural response to CO2 that characterises panic disorder patients is likely due to increased neural sensitivity to CO2 at brainstem level.

Effect of buspirone on the behavioral regulation of rats in low versus high anxiety conditions

INTRODUCTION Buspirone (CAS 33386-08-2) is reported to have anxiolytic effects in humans and is mostly described for mild anxiety. To further explore the effects of buspirone on different levels of anxiety, the effect of buspirone was evaluated in two different conditions of the open field which were distinguished as low and high anxiety (enclosed and exposed open field, respectively). MATERIALS AND METHODS Twenty-eight albino Wistar rats (350-400 g) were tested in two different arena settings, an enclosed and an exposed open field. Fourteen animals were initially injected with 1 ml saline while the others (n = 14) received buspirone 3 mg/kg. RESULTS The data showed clear differences in the two open-field settings, suggesting a higher anxiety level in the exposed open field. In addition, correlation analysis showed that the two anxiety tests measure different aspects of anxiety. Buspirone treatment reduced the behavioral activity in both the enclosed and exposed open-field, which is generally interpreted as an anxiogenic effect. However, buspirone increased the time in the center areas and decreased the frequencies in the outer regions. These behavioral changes are generally seen as an anxiolytic effect. Correlation analysis showed that buspirone treatment disrupted the relation between indices of anxiety. CONCLUSION These results showed that in an open-field setting buspirone appears to have a dual effect. The reduced activity and increase in time spent in the center areas are indicative of both an anxiogenic and an anxiolytic effect, respectively. This was found in both open-field settings, suggesting that the effects of buspirone are independent of the anxiety level.

Tradução e adaptação transcultural do Questionário de Atividade Física Habitual

CONTEXTO: Atualmente ha na literatura um crescente interesse na interface entre exercicio fisico e transtornos psiquiatricos. Apesar disso, ainda ha uma deficiencia de instrumentos de autorrelato para medir os niveis de atividade fisica dos pacientes. OBJETIVO: A traducao, a afericao da equivalencia semântica e uma aplicacao piloto (n = 30), sem pretensao psicometrica, do Questionario de Atividade Fisica Habitual, visando sua utilizacao na populacao brasileira de diferentes niveis de escolaridade. METODOS: O processo envolveu duas traducoes e retrotraducoes realizadas por avaliadores independentes, avaliacao das versoes seguida da elaboracao de uma versao sintese e pre-teste comentado. RESULTADOS: A maioria dos participantes (91%) nao apresentou dificuldades de compreensao com o questionario. Para cada item do instrumento, apresentam-se os resultados das quatro etapas. Mais estudos sao necessarios para determinar a adequacao para populacoes de baixa escolaridade. Os autores recomendam que sujeitos menos instruidos sejam supervisionados ao preencher o questionario. CONCLUSOES: A utilizacao de duas versoes de traducao e retrotraducao, a discussao sobre a versao sintese e a interlocucao com a populacao-alvo proporcionam maior seguranca ao processo de equivalencia semântica.

On the Psychotropic Effects of Carbon Dioxide

It has been well established that the inhalation of Carbon Dioxide (CO2) can induce in humans an emotion closely replicating spontaneous panic attacks, as defined by current psychiatry nosology. The purpose of this review is to provide a critical summary of the data regarding CO2s psychopharmacological properties and underlying mechanisms. The authors review the literature on the human and animal response for the exposure of exogenous CO2 focusing on five points of interest: 1) the early history of the use of CO2 as an anesthetic and therapeutic agent, 2) the subjective effects of breathing CO2 at different concentrations in humans, 3) the use of CO2 in experimental psychiatric research as an experimental model of panic, 4) the pharmacological modulation of CO2-induced responses, and 5) the putative neurobiological mechanisms underlying the affective state induced by CO2. The authors conclude with an evolutionary-inspired notion that CO2 might act as an agent of a primal emotion serving a homeostatic function, in the control of respiration and acid-base balance.

The effects of opioid receptor blockade on experimental panic provocation with CO2

Several reports have linked, among other aspects, the role of an opioid system in respiratory physiology with underlying mechanisms of panic attacks. The involvement of the opioid system in experimental panic is to be further probed. This study aimed to determine whether opioid blockade would increase panic-related symptomatology on provocation with 35% CO2 inhaled by healthy volunteers. Participants in a double-blind, randomised crossover design orally received either 50 mg of naltrexone or placebo. Most subjects undertook a double inhalation of 35% CO2 one hour after pre-medication, and a separate group did so after five hours. The reactivity to CO2 and the symptoms elicited by naltrexone alone were measured. Among other findings, naltrexone pre-medication alone elicited significant increments in panic-related symptoms. Responses to CO2 were not significantly different between conditions in either group. These preliminary findings suggest that exposure to opioid blockade alone can potentially elicit symptoms that resemble panic, however, without modifying the response to experimental panic provocation with 35% CO2.

Therapygenetics: 5-HTTLPR genotype predicts the response to exposure therapy for agoraphobia

This study was intended to assess the extent to which the low-expression allele of the serotonin transporter gene promoter predicts better response to exposure-based behavior therapy in patients with panic disorder with agoraphobia (PDA). Ninety-nine patients with PDA underwent a 1-week in vivo exposure-based behavior therapy program and provided saliva samples to extract genomic DNA and classify individuals according to four allelic forms (SA, SG, LA, LG) of the 5-HTT-linked polymorphic region (5-HTTLPR). We determined whether the 5-HTTLPR genotype predicted change in avoidance behavior in PDA following treatment. After controlling for pre-treatment avoidance behavior, the 5-HTTLPR low-expression genotypes showed a more favorable response to exposure therapy two weeks following treatment, compared to the other patients. This study suggests a genetic contribution to treatment outcome following behavior therapy and implicates the serotonergic system in response to exposure-based treatments in PDA.