Frederico Guilherme Graeff

Bio: Frederico Guilherme Graeff is an academic researcher from University of São Paulo. The author has contributed to research in topics: Anxiety & Panic disorder. The author has an hindex of 60, co-authored 183 publications receiving 12209 citations. Previous affiliations of Frederico Guilherme Graeff include Universidade de Mogi das Cruzes & Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto.

5-HT and mechanisms of defence.

Abstract: are concerned with adaptive responses to aversive events. Aversive stimuli can be defined as stimuli which motivate avoidance behaviour. This definition encompasses negative incentives and reinforcers and much of what passes under vaguer terms such as ’punishers’ and ’stresses’. Aversive stimuli can be considered in three groups and we suggest they bring different anatomical structures and 5-HT systems into play. Dysfunction in these central mechanisms of aversion results in different groups of psychological symptoms. The three forms of aversion are summarized below and they form the basis of this article.

Role of 5-HT in stress, anxiety, and depression

Abstract: There are conflicting results on the function of 5-HT in anxiety and depression. To reconcile this evidence, Deakin and Graeff have suggested that the ascending 5-HT pathway that originates in the dorsal raphe nucleus (DRN) and innervates the amygdala and frontal cortex facilitates conditioned fear, while the DRN-periventricular pathway innervating the periventricular and periaqueductal gray matter inhibits inborn fight/flight reactions to impending danger, pain, or asphyxia. To study the role of the DRN 5-HT system in anxiety, we microinjected 8-OH-DPAT into the DRN to inhibit 5-HT release. This treatment impaired inhibitory avoidance (conditioned fear) without affecting one-way escape (unconditioned fear) in the elevated T-maze, a new animal model of anxiety. We also applied three drug treatments that increase 5-HT release from DRN terminals: 1) intra-DRN microinjection of the benzodiazepine inverse agonist FG 4172, 2) intra-DRN microinjection of the excitatory amino acid kainic acid, and 3) intraperitoneal injection of the 5-HT releaser and uptake blocker D-fenfluramine. All treatments enhanced inhibitory avoidance in T-maze. D-Fenfluramine and intra-DRN kainate also decreased one-way escape. In healthy volunteers, D-fenfluramine and the 5-HT agonist mCPP (mainly 5-HT2C) increased, while the antagonists ritanserin (5-HT2A/2C) and SR 46349B (5-HT2A) decreased skin conductance responses to an aversively conditioned stimulus (tone). In addition, D-fenfluramine decreased, whereas ritanserin increased subjective anxiety induced by simulated public speaking, thought to represent unconditioned anxiety. Overall, these results are compatible with the above hypothesis. Deakin and Graeff have suggested that the pathway connecting the median raphe nucleus (MRN) to the dorsal hippocampus promotes resistance to chronic, unavoidable stress. In the present study, we found that 24 h after electrolytic lesion of the rat MRN glandular gastric ulcers occurred, and the immune response to the mitogen concanavalin A was depressed. Seven days after the same lesion, the ulcerogenic effect of restraint was enhanced. Microinjection of 8-OH-DPAT, the nonselective agonist 5-MeO-DMT, or the 5-HT uptake inhibitor zimelidine into the dorsal hippocampus immediately after 2 h of restraint reversed the deficits of open arm exploration in the elevated plus-maze, measured 24 h after restraint. The effect of the two last drugs was antagonized by WAY-100135, a selective 5-HT1A receptor antagonist. These results are compatible with the hypothesis that the MRN-dorsal hippocampus 5-HT system attenuates stress by facilitation of hippocampal 5-HT1A-mediated neurotransmission. Clinical implications of these results are discussed, especially with regard to panic disorder and depression.

Ethopharmacological analysis of rat behavior on the elevated plus-maze

Abstract: Behavioral categories were measured in rats left on an elevated plus-maze for 5 min, in addition to the traditional measures. Four independent factors emerged from a factor analysis. The variables that loaded highly and positively on Factor 1, seemingly related with anxiety, were: number of entries onto open arms, time spent on open arms, percentage of open/total arm entries, percentage of time on open arms, scanning over the edge of an open arm, and open arm end-exploring. The time spent on enclosed arms loaded highly, but negatively on the same factor. Risk-assessment from an enclosed arm also loaded negatively on Factor 1. Number of enclosed arm entries, total number of arm entries and rearing loaded highly on Factor 2, probably related to motor activity. However, the total number of entries also loaded on Factor 1, being thus a mixed index. Similarly, the number of open arm entries loaded on both Factors 1 and 2. As expected, the variables having high loads on Factor 1 were changed to one direction by administration of two anxiolytics (nitrazepam and midazolam) and to the opposite direction by two anxiogenic drugs (pentylenetetrazol and FG 7142). Such pattern of drug effects was not observed with the remaining variables.

Antianxiety effect of cannabidiol in the elevated plus-maze

Abstract: In order to assess the presence of anxiolytic properties in cannabidiol (CBD) the drug was tested in an elevated plus-maze model of anxiety, in rats. Doses of 2.5, 5.0 and 10.0 mg/kg significantly increased the entry ratio (open/total number of entries), an anxiolytic-like effect. CBD at a dose of 20.0 mg/kg was no longer effective. None of the doses of CBD used changed total number of entries, a measure of total exploratory activity. Diazepam (2.0 mg/kg) also caused an anxiolytic-like effect in this model. These results indicate that CBD causes a selective anxiolytic effect in the elevated plus-maze, within a limited range of doses.

I and i

Abstract: There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality. Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

Précis of The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-Hippocampal System..

Abstract: A model of the neuropsychology of anxiety is proposed. The model is based in the first instance upon an analysis of the behavioural effects of the antianxiety drugs (benzodiazepines, barbiturates, and alcohol) in animals. From such psychopharmacologi-cal experiments the concept of a “behavioural inhibition system” (BIS) has been developed. This system responds to novel stimuli or to those associated with punishment or nonreward by inhibiting ongoing behaviour and increasing arousal and attention to the environment. It is activity in the BIS that constitutes anxiety and that is reduced by antianxiety drugs. The effects of the antianxiety drugs in the brain also suggest hypotheses concerning the neural substrate of anxiety. Although the benzodiazepines and barbiturates facilitate the effects of γ-aminobutyrate, this is insufficient to explain their highly specific behavioural effects. Because of similarities between the behavioural effects of certain lesions and those of the antianxiety drugs, it is proposed that these drugs reduce anxiety by impairing the functioning of a widespread neural system including the septo-hippocampal system (SHS), the Papez circuit, the prefrontal cortex, and ascending monoaminergic and cholinergic pathways which innervate these forebrain structures. Analysis of the functions of this system (based on anatomical, physiological, and behavioural data) suggests that it acts as a comparator: it compares predicted to actual sensory events and activates the outputs of the BIS when there is a mismatch or when the predicted event is aversive. Suggestions are made as to the functions of particular pathways within this overall brain system. The resulting theory is applied to the symptoms and treatment of anxiety in man, its relations to depression, and the personality of individuals who are susceptible to anxiety or depression.

The use of the elevated plus maze as an assay of anxiety-related behavior in rodents

Abstract: The elevated plus maze is a widely used behavioral assay for rodents and it has been validated to assess the anti-anxiety effects of pharmacological agents and steroid hormones, and to define brain regions and mechanisms underlying anxiety-related behavior. Briefly, rats or mice are placed at the junction of the four arms of the maze, facing an open arm, and entries/duration in each arm are recorded by a video-tracking system and observer simultaneously for 5 min. Other ethological parameters (i.e., rears, head dips and stretched-attend postures) can also be observed. An increase in open arm activity (duration and/or entries) reflects anti-anxiety behavior. In our laboratory, rats or mice are exposed to the plus maze on one occasion; thus, results can be obtained in 5 min per rodent.