**Abstract**

Anxiety is one of the most common psychopathologies in the general population that often begin early in life; however, research on this disorder during early developmental stages has been poorly explored compared to adults. A better understanding of the anxiety disorder through childhood is essential to develop more effective treatments. This chapter provides a general overview of the usefulness of animal models of childhood anxiety and its neurobiological bases to discuss how the studies on animals meet the several criteria of validity to discover pathophysiological mechanisms of human disorders and new treatments for these conditions. The research methodology for this chapter consisted in using a thesaurus system such as Medical Subject Headings (MeSH) terms of the National Library of Medicine to find original articles in databases as PubMed or Web of Science about preclinical findings related to the neuropharmacology of anxiety before adulthood. The contribution of this chapter is to provide data from preclinical studies which are encouraged to a better comprehension of anxiety at young age.

**Keywords:** adolescent, anxiety, anxiolytics, animal model, child, rats

## **1. Introduction**

Anxiety is a disorder that can be developed in offspring as a result of aversive life conditions. Some factors in the childhood and adolescence that predispose the development of anxiety disorders include sexual abuse [1], social isolation [2], maternal separation [3], physical abuse, emotional abuse, negligence, and exposure to partner violence [4]. In addition, children who experience multiple types of abuse can suffer exacerbate symptoms of anxiety and comorbidity with depression compared to those who are only exposed to one type of abuse [1, 5, 6].

Although researchers have tried to probe the heritability of anxiety with studies of twin pairs, first-degree relatives, or big samples of anxiety-diagnosed patients,

findings are inconsistent and could not be replicated [7–9], so there is no clear evidence to suggest a genetic component in the development of anxiety.

The assessment and treatment of childhood disorders are challenging because this population should not be compared to adults. Children and adolescent have their own features (e.g., difficulty to concentrate in school tasks, decreased academic or athletic performance, avoidance, "clinging" behavior, and tantrum [10]) which are in complex interaction with social and physiological environment.

In the similar way in young rats, anxiety has particular characteristics, and manifestation differs with age, e.g., in the elevated plus maze, young rodents (males and females) have high anxiety levels that increase with age [11]. However, adolescent females with food deprivation have lower anxiety level compared to adult rats [12]; these findings suggest that infantile and juvenile stages constitute a period of transition toward adulthood.

Therefore, the objective of this chapter is to review preclinical findings of experimental anxiety with pharmacological manipulations in young rats. This chapter will provide data from preclinical studies which are encouraged to a better comprehension of anxiety before adulthood.

#### **2. Neurobiology of anxiety**

Anxiety is a disorder of complex etiology, which includes stressful, environmental, epigenetic, social, and psychological factors that modify neurotransmission systems such as serotonergic, noradrenergic, dopaminergic, and glutamatergic [13–16]. The most studied neurobiological mechanism is the monoaminergic hypothesis, since clinically effective anxiolytic drugs have their place of action on various monoamines, such as serotonin (5-HT), noradrenaline (NE), and dopamine (DA), neurotransmitters involved in the pathogenesis of anxiety [13, 17]. However, in recent years attention has focused on alterations of the hypothalamic-pituitaryadrenal axis (HPA), neuroplasticity, neurogenesis, and inflammatory response [18], opening a new paradigm for the study of the biological bases of anxiety.

The amygdala is the main brain region involved in the processing of fear information by integrating prior learning and incoming sensory information from cortical and subcortical regions [19]. In anxiety disorders it is common to observe a decreased inhibitory neurotransmission mediated by gamma-aminobutyric acid (GABA), an increase in excitatory neurotransmission mediated by glutamate [20], as well as the interruption of fight-or-flight response mechanism regulated by the HPA axis with participation of emotional processing structures including the amygdala, hypothalamus, periaqueductal gray substance, and hippocampus and chemical mediators such as corticotropin-releasing factor, glutamate, and neuropeptides (substance P, neuropeptide Y, oxytocin, orexin, and galanin) [18, 20].

Unpredictable chronic mild stress increases glutamatergic neurotransmission and decreases prefrontal cortex (PFC) function in rats which display anxiety-like behavior [20], and the imbalance between neuronal excitation and inhibition in the medial prefrontal cortex, hippocampus, and amygdala contributes to the development of emotional disorders such as anxiety [21]. Chronic dexamethasone produces deficient learning and decreased pyramidal neurons in CA3 of the hippocampus in rats [22]. These findings lead to improper process of the cognitive responses to face aversive situations.

Glucocorticoids like corticosterone in rats can also alter the functional brain connections responsible for the emotional processing; for example, chronic stress decreases cognitive function due to loss of projections from the basolateral amygdala to the medial prefrontal cortex [23]. These data together indicate that if the

**127**

**Table 1.**

stress

*Neuropharmacology of Anxiety Disorders at Young Age: A Perspective from Preclinical Research*

organism remains in a state that deteriorates its homeostasis with alterations in the functionality of the HPA axis, responsible for regulating the response to stress, it leads to the development of diseases such as anxiety [21]. Thus, the secretion of hormones, such as glucocorticoids, catecholamines, growth hormone, and prolactin, promotes adaptive responses, but physiopathological processes are triggered

On the other hand, glutamate is an excitatory neurotransmitter that acts through different types of N-methyl-D-aspartate (NMDA) and non-NMDA receptors. This neurotransmitter has been associated with anxiety since the increase of brain glutamate/glutamine levels induced by monosodium glutamate produces anxiety-like behavior measured in two models of anxiety, the open field test and the elevated plus maze [26]. In consistency the antagonism of NMDA receptors promotes anxiolytic-like behavior in experimental animal models of open field and

Animal models help to understand the physiopathology of some human diseases, the development of new therapeutic options, as well as the evaluation of the existing ones to identify other relevant effects [27]. Additionally, animals are relatively easy to obtain, maintain, and manipulate. They have broad reproducibil-

Our interest is situated in animal models of mental disorders associated to altered emotions. In the book *The Expression of the Emotions in Man and Animals*, Darwin makes it clear that through behavioral patterns, animals have the capacity to express their emotions [28]. Based on this capacity, a wide range of animal models have been developed, which allow us to understand some aspects of various psychiatric disorders as anxiety. Although it is not possible to fully model the complexity of human psychopathology, the physiological, anatomical, and genetic similarities allow us to understand, with limitations, the neurobiological basis of

Animal models are very useful approaches at preclinical research to study anxiety and the closest possible to the anxiety disorders described in the DSM-5 which could occur at childhood and adolescence and not only in adults. **Table 1** shows

The animal models mentioned in **Table 1** are used to study anxiety disorders and the effectiveness of several pharmacological treatments. These models evaluate conditioned or unconditioned responses to novel or stressful stimuli, measuring

**Human condition Rodent model Reference**

board

Selective mutism Social interaction test (with measure of pup

*Anxiety disorders and their experimental model used at young age.*

Separation anxiety disorder Maternal separation [34] Panic disorder T-maze [31–33]

Elevated plus maze, defensive burying test, marble burying, open field test, T-maze

Light–dark box, social interaction test, hole

ultrasound vocalizations during the test)

[29–33]

[35, 36]

[33]

some human anxiety disorders that can be studied in laboratory rats.

ity and involve less investment compared with clinical studies.

*DOI: http://dx.doi.org/10.5772/intechopen.90486*

when the response is excessive [24, 25].

marble burying [16].

**3. Anxiety animal models**

human diseases, as anxiety.

Generalized anxiety, posttraumatic

Specific phobia: Photophobia, Social

phobia, Agoraphobia

#### *Neuropharmacology of Anxiety Disorders at Young Age: A Perspective from Preclinical Research DOI: http://dx.doi.org/10.5772/intechopen.90486*

organism remains in a state that deteriorates its homeostasis with alterations in the functionality of the HPA axis, responsible for regulating the response to stress, it leads to the development of diseases such as anxiety [21]. Thus, the secretion of hormones, such as glucocorticoids, catecholamines, growth hormone, and prolactin, promotes adaptive responses, but physiopathological processes are triggered when the response is excessive [24, 25].

On the other hand, glutamate is an excitatory neurotransmitter that acts through different types of N-methyl-D-aspartate (NMDA) and non-NMDA receptors. This neurotransmitter has been associated with anxiety since the increase of brain glutamate/glutamine levels induced by monosodium glutamate produces anxiety-like behavior measured in two models of anxiety, the open field test and the elevated plus maze [26]. In consistency the antagonism of NMDA receptors promotes anxiolytic-like behavior in experimental animal models of open field and marble burying [16].
