Fear-induced Avoidance Research Articles

Histamine in the brain.

Brain histamine promotes wakefulness and orchestrates disparate behaviors and homeostatic functions. Recent evidence suggests that aberrant histamine signaling in the brain may also be a key factor in addictive behaviors and degenerative disease such as Parkinson's diseases and multiple sclerosis. The intent of this research Topic is to provide an overview of the recent advances in the understanding of the many functions of brain histamine and to propose neurobiological substrates and mechanisms of action that might explain the reasons why the histaminergic system is a potential target for therapeutic interventions. This may justify the search for new histaminergic compounds. The authors that contributed to this e-book offered several approaches to the study of brain histamine function. Tomasch et al. (2012) synthesized a novel fluorescent ligand of the human histamine H3 receptor with potential to be used as pharmacological tools for visualization in different tissues. Shibuya et al. (2012) by using positron emission tomography (PET) in the human brain examined whether the levels of neuronal release of histamine might change binding of [(11)C]doxepin to the H1 receptors (a standard method for measuring H1 distribution) under the influence of physiological stimuli. Histamine acts as a modulator of several neurotransmitters in the brain and its role in promoting wakefulness has for long overshadowed other important functions. In fact, histamine signaling controls feeding behavior in a complex fashion and it has been considered for long a satiety system as brain histamine decreases the drive to consume food. In their paper, Ishizuka and Yamatodani (2012) demonstrated the fine regulation of histamine release during feeding and in taste perception. Furthermore, they showed that histamine neurons respond to both mechanical and chemical sensory input from the oral cavity, as may be expected for a danger detection system. Brain histamine is crucial for motivation and goal-directed behaviors as reviewed by Torrealba et al. (2012). The authors evaluated recent works demonstrating that histamine is differentially involved in the appetitive, food anticipatory responses, and in food consumption, suggesting that it may have an important role in abnormal appetites not only for food but also for substances of abuse. Indeed, preclinical studies on both rats and mice are hinting at a possible role of the histaminergic system in alcohol consumption, as blockade of the H3 receptor (which regulates histamine and other neurotransmitters' release), decreases alcohol drinking in several behavioral tasks, like operant alcohol administration and “drinking in the dark” paradigm (Nuutinen et al., 2012). However, the authors caution that despite the evidence that the H3 receptor is a key element in alcohol drinking and place preference, the role of histamine in these behaviors is poorly understood and deserves further investigation. The importance of H3 receptor signaling in the brain to acquire and store short- and long- term memories has been documented extensively. However a limited number of studies have investigated the role of the H3 receptor in anxiety. By using novel behavioral test, Abuhamdah et al. (2012) present their results with selective agonist and antagonist for the H3 receptor providing new evidence that the H3R may have a role in fear-induced avoidance responses, but not in anxiety. In addition, Vohora and Bhowmik (2012) provided comprehensive neurobiological/neurochemical evidence of the role of histaminergic H3 receptor antagonists in the physiopathology of cognitive dysfunction and motor impairments. Dysfunctions of the histaminergic system may also contribute to the pathogenesis of multiple sclerosis and its murine model of experimental autoimmune encephalomyelitis, although the role of the different histamine receptors is complex and still controversial (Passani and Ballerini, 2012). Histaminergic neurons are sensitive to CO2, Yanovsky et al. (2012) showed the complex mechanism of histaminergic neuron activation by acidification in murine brain slices. Their results contribute to understand the neuronal mechanisms controling acid/CO2-induced arousal in hepatic encephalopathy and obstructive sleep apnoea. Recent evidence summarized by Blandina et al. (2012) suggest that such a complexity of the brain histamine system may be served by different neuronal subpopulations that are recruited at different times during the unfolding of a specific behavior. Histamine neurons send broad projections within the CNS that are organized in functionally distinct circuits impinging on different brain regions. This implies independent functions of subsets of histamine neurons according to their terminal projections and their selective participation in different aspects of behavioral responses. In conclusion, we believe that this Research Topic offered an inter-disciplinary forum that improved our current knowledge of the role of brain histamine. It also provided the necessary drive to stimulate innovation in clinical practice to manage and treat neurological disorders.

Anxiolytic-like effects of the selective 5-HT 1A receptor antagonist WAY 100635 in non-human primates

Non-human primates provide important insights into the potential use of 5-HT 1A receptor antagonists in treating human anxiety disorders and as research tools, given the existent inconsistencies in rodent tests. This study investigated the effects of the selective silent 5-HT 1A receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}- N-(2-pyridinyl)cyclohexane-carboxamide trihydrochloride (WAY 100635), administered systemically, in an ethologically based fear/anxiety test in marmoset monkeys ( Callithrix penicillata). Subjects were tested using a figure-eight maze and a taxidermized wild cat as ‘predator’ stimulus. After seven 30-min maze habituations in the absence of the ‘predator’, each animal was submitted to four pseudo-randomly assigned 30-min treatment trials in the presence of the ‘predator’: three WAY 100635 (0.2, 0.4 and 0.8 mg/kg, i.p.) sessions and a saline control trial. The ‘predator’ stimulus caused a significant fear-induced avoidance of the maze sections closest to where it was presented, indicating an anxiogenic effect. However, WAY 100635 treatment reversed, significantly and dose-dependently, this fear-induced avoidance behavior, while increasing maze exploration. Sedation was not observed. This is the first study to suggest an anxiolytic-like effect of the selective silent 5-HT 1A receptor antagonist WAY 100635 in non-human primates, indicating its potential use as a therapeutic agent.

Anxiolytic-like effects of substance P fragment (SP 1–7) in non-human primates ( Callithrix penicillata)

The behavioral effects of the amino (N)-terminal fragment of substance P (SP 1–7) on the marmoset ( Callithrix penicillata) predator confrontation test of fear/anxiety were investigated. The test apparatus consisted of a figure-eight maze with three parallel arms interconnected at each extremity to a perpendicular arm. A taxidermized oncilla cat ( Felis tigrina) was placed outside the maze facing one of its corners. Subjects were submitted to seven 30 min maze habituation trials (HTs), in the absence of the ‘predator’, and then to six 30 min treatment trials (TTs), in the presence of the ‘predator’, consisting of four doses of SP 1–7 (5, 50, 250 and 500 μg/kg; IP), saline and sham injection. SP 1–7 treatment reversed, in a dose-dependent way, the fear-induced avoidance behavior due to the predator’s presence and increased the frequency of exploratory behaviors. Locomotor activity decreased during successive HTs, yet increased after all SP 1–7 treatments. These results indicate that systemic administration of SP 1–7 produces anxiolytic-like effects in marmosets tested in the predator confrontation model of fear/anxiety.

Behavioral effects of buspirone in the marmoset employing a predator confrontation test of fear and anxiety

In order to further validate the recently developed marmoset ( Callithrix penicillata) predator confrontation model of fear and anxiety, we investigated the behavioral effects of buspirone with this method. The apparatus consisted of three parallel arms connected at each end to a perpendicular arm, forming a figure-eight continuous maze. A taxidermized wild oncilla cat ( Felis tigrina) was positioned facing a corner of the parallel arms, alternating between the left or right side of the maze among animals tested. All subjects were first submitted to seven 30-min maze habituation trials (HTs) in the absence of the predator, and then to five randomly assigned treatment trials (TTs) in the presence of the predator: three buspirone sessions (0.1, 0.5 and 1.0 mg/kg), saline and sham injection controls. Twenty minutes after treatment administration, the animal was released into the maze and had free access to the apparatus for 30 min. All trials were taped for later behavioral analysis. Buspirone significantly decreased the frequency of scent marking, while increasing the time spent in proximity to the ‘predator’ stimulus, indicating an anxiolytic effect. Neither locomotor activity, exposure to a novel environment, stimulus location and habituation, nor gender influenced the effects of the drug treatments. These results further validate this method and demonstrate the potential usefulness of this ethologically based paradigm to test anxiety and fear-induced avoidance in nonhuman primates and its susceptibility to anxiolytic pharmacological manipulations.

Measuring fear and anxiety in the marmoset ( Callithrixpenicillata) with a novel predator confrontation model: effects of diazepam

This report describes a new experimental method for measuring fear and anxiety in Cerrado marmosets ( Callithrix penicillata). In order to test the sensitivity of the behavioral parameters to an anxiolytic substance, the effects of the benzodiazepine diazepam on the anxiety measures were examined. The strategy was to use a naturally occurring stimulus known to elicit anxiety and fear in this species. A taxidermized predator (the wild cat Felis tigrina) was chosen as the stimulus to induce anxiety-related behaviors on the basis of a preceding study in which various stimuli were systematically compared in their effectiviness to induce fear responses. The apparatus consisted of three parallel arms of equal dimensions, joining two perpendicular arms at each end, thus comprising a figure eight-like or five-arm continuous rectangular maze. The wild-cat was placed outside of one corner of the maze’s outer parallel arms. Each subject was submitted to six treatments given in random order: three drug sessions (diazepam 1, 2 and 3 mg/kg, IM), saline, sham (injection control), and a control session, involving neither manipulation nor injection. Subjects were placed into the back of the chamber, out of sight of the ‘predator’, 20 min after a treatment and given free access to the maze for 30 min. The behavioral repertoire was recorded via videocamera. The following behaviors were considered to be possible indices of emotionality relevant to exposure to the predator in the paradigm used: scratching, scent marking, exploration, frequency and time spent in each of 13 defined sections of the maze. Administration of diazepam induced a significant reduction in scratching and an increase in the time spent in the vicinity of the ‘predator’, as well as in the frequency of exploratory behaviors, indicative of an anxiolytic effect. Gender did not influence the effect of treatment. These results suggest that this new ethologically-based test may be a useful method for studying anxiety and fear-induced avoidance in non-human primates and for pre-clinical research on psychoactive drugs.