**1. Introduction**

In humans, the appropriate and measured behavioral responses to environmental cues are under control of the limbic nervous system which is composed primarily of the amygdala, hippocampus, thalamus, and hypothalamus [1]. In order for

sensory inputs to the cerebral cortex to result in the appropriate responses in the body, sensory inputs relay from the cerebrum, to the limbic system and then from the limbic system to the body either through the brainstem or through the pituitary gland. It is when relaying sensory inputs from the cerebral cortex to the body that the limbic system also assigns emotional value to sensory input and sets or fixes that value by learning and remembering the rewards and punishments associated with specific environmental cues. The amygdala is known for assigning a scaled value to negative threats and stressors which the amygdala then communicates to learning and memory centers in the hippocampus so that human behavioral responses to negative cues can be consistent and appropriate. The amygdala also stimulates the hypothalamus to secrete corticotrophin-releasing hormone (CRH) which in turn stimulates the pituitary to release adrenocorticotropin hormone (ACTH), which in turn stimulates the adrenal cortex to secrete glucocorticoids including primarily, cortisol in what is known as the HPA-axis [2–4]. The hypothalamus can also send signals through the brainstem and activate the adrenal medulla to secrete epinephrine and norepinephrine. Cortisol, epinephrine and norepinephrine are hormones that can signal body wide changes in metabolic rates, breathing, heart rate, blood pressure and a variety of other appropriate body responses to the presence of an environmental threat or stressor [2, 3]. Anxiety is the feeling of fear or worry that arises from the neurochemistry of the amygdala in response to negative environmental cues and the activation of the HPA-axis and the overall preparation of the body to meet the challenges of a threat or stressor and while anxiety is a negative feeling, when it is in proportion to the actual threat a stressor presents, anxiety can be a normal and even healthy part of an adequate response to the stressor [5–7]. However, excessive and prolonged anxiety that is unwarranted by the environmental cue and exaggerated in proportion to the actual threat level leads to inappropriate and prolonged activation of the HPA-axis and cortisol release which is associated with inflammatory damage and other pathophysiologies that further stresses the human body system [2–4]. In these cases anxiety interferes with normal and health everyday life and is considered an anxiety disorder [8, 9].

People suffer from five different types of anxiety disorders; generalized anxiety disorder (GAD, obsessive compulsive disorder (OCD), panic disorder (PD), social anxiety disorder (SAD), and posttraumatic stress disorder (PTSD) [8, 9]. Each of these anxiety disorders can be described by the level of synaptic neurotransmitters and cell surface neurotransmitter receptors in the amygdala [1, 8, 9]. For example, GAD is associated with decreased activity of the inhibitory neurotransmitter, GABA. GABA acts on GABAA receptors on neurons within the amygdala to inhibit signals and help to assign lower threat values to certain stressor. Down regulation of the GABAA receptor and the subsequent reduction of GABA signaling in the amygdala leads GAD through elevated valuation of threats [10]. Similarly, PD is also associated with decreased GABAnergic transmission and subsequent over stimulation of neural pathways, however in PD the decrease GABAnergic signaling may be due to reduced level of the GABA neurotransmitter itself and not due to decreased GABAA receptors as seen in GAD [9, 11, 12]. While GABAnergic pathways in the amygdala are inhibitory and stress reducing, glutamate, the major stimulatory neurotransmitter, when over active in the amygdala enhances stress and can lead to OCD. Pharmacological enhancement of glutaminergic signals in the frontolimbic regions of the brain enhance anxiety and imaging studies have shown increased glutaminergic activity in various structures of the limbic system in the brain [13–15]. PTSD and SAD also appear involve increased glutaminergic activity in the amygdala [9, 16]. GABA and glutamate influence the feeling of anxiety be reducing and enhancing the perceived threats, while the neurotransmitters, serotonin and dopamine are associated with the reward and pleasure pathways of the limbic

#### *Physiological and Cellular Targets of Neurotrophic Anxiolytic Phytochemicals in Food… DOI: http://dx.doi.org/10.5772/intechopen.97565*

system and can influence the overall perception of environmental stressors generally reducing anxiety. For example, SAD is associated with both decreased activity at serotonin receptors and also decreased dopamine levels in limbic neurocircuitry [9, 16, 17]. Taken together, anxiety disorders involve irregularities in the levels of neurotransmitters and neurotransmitter receptors in the neurocircuitry of the limbic system. The inappropriate levels of neurotransmitters and their receptors can lead to hyper activity in regions of the limbic system such as the amygdale and lead to incorrect and unhealthy assessment of the risks and threats associated with stressors or lack of stressors and lead to anxiety and fear potentially even in the absence of threat. Activation of the HPA-axis can contribute to both the clinical signs and symptoms of anxiety and also lead to chronic glucocorticoid induced pathologies which serve and further internal stressors and add to anxiety. Treatments for anxiety disorders have therefore focused on developing drugs that correct and manage the levels of neurotransmitters and neurotransmitters receptors and signaling in the limbic system pathways and particularly in the amygdala.

GABAnergic benzodiazepines are the favored class of anxiolytic medications [10, 11, 18]. The diazepine ring is a seven membered ring structure containing two nitrogens and this diazepine ring and when fuses with a benzene ring forms a benzodiazepine that can bind to GABAA receptors on neurons in the brain [18]. Benzodiazepines are favored due to their lesser side-effects compared to other anxiolytic drugs, although side effects are still concerns [18]. The mechanism of benzodiazepine signaling is binding to either GABAA or GABAB receptors and allowing either chlorine ions into the cell at the synapse or stimulating the release of potassium from the cell into the synapse respectively [10, 11, 18]. In the cells of the amygdala, the chlorine influx inhibits the signaling of the pathway and diminishes the level of potential threat assigned to a sensory input or any external or internal stressor. People with GAD and PD express low levels of GABAA and produce less GABA respectively thereby limiting the patient's ability diminish the signals from stressors is associate with a heightened sense of fear and worry. By being GABAnergic the benzodiazepines help to restore or boost the GABAnergic pathway and the therefore the reduction of anxiety. Alternatively to drugs that act in a GABAnergic fashion, serotonin and dopamine uptake inhibitors, often used for depression, reduce anxiety and fear by increasing levels of these "feel good" neurotransmitters in the limbic neurocircuitry. Low synaptic serotonin and dopamine in the amygdale and nucleus accumbens is associated SAD. Serotonin uptake inhibitors (SSRIs) and noradrenalin and dopamine reuptake inhibitors (NDRIs) increased the level of serotonin and dopamine in the synapse and have been used to treat depression and also provide relief from anxiety and anxiety disorders. [18–22].

In addition to the development of new drugs that interact with the amygdala and HPA-axis, anxiety can also be addressed by diet. The diet can be associated with anxiety in two main ways. First, if a diet is deficient in nutrients such as selenium, lysine, magnesium and inositol, changes in food consumptions or dietary supplementation can replace the deficient nutrient, balance the diet and alleviate anxiety [23]. Further, dietary deficiencies in antioxidants can lead to the buildup of reactive oxygen species (ROSs) that form as a part of normal metabolism and are reactive chemicals that can bind to DNA, lipids and proteins leading to DNA and membrane damage and cellular toxicity. This cellular damage serves as a stress signal and is associated with anxiety [24, 25]. Therefore, increasing dietary antioxidant intake can help with anxiety. Second, food nutrients can directly affect the neurochemistry of the limbic system by either directly boosting GABA or Serotonin levels or by binding to neurotransmitter receptors. For example, GABA is an amino acid is available directly in the diet. Further the amino acid,

5-hydroxytryptophan is a serotonin precursor and is a popular dietary supplement taken to easy feelings of anxiety and stress. While it is not clear if increasing oral consumption of GABA and 5-hydroxytrptophan can increase brain GABA and serotonin levels, clinical studies have shown and relaxing effect of GABA and 5-HTP supplementation [23]. The neurochemistry of the brain can also be altered by food chemicals eaten from bacteria, fungi and plants that have nutraceutical effects by acting in a drug-like fashion as cell signaling molecules and alerting cellular behavior. In this chapter we focus on food nutraceuticals that are anxiolytic in humans and alter the neurochemistry and the amygdala and other limbic structures in the brain. Of particular interest are anxiolytic phytochemicals that in addition to changing the brain neurotransmitter physiology also stimulate neuronal plasticity through the activation and or potentiating of neurotrophin receptors and signal transduction pathways.

Recent studies have revealed that numerous anxiolytic substances, including endogenous neurotransmitters, anxiolytic drugs, and nutraceuticals, are also neurotrophic in that they also activate the brain derived neurotrophic factor (BDNF) pathway, the neurotrophin-3 (NT-3) pathways and the nerve growth factor (NGF) pathway by binding to or potentiating the TRKA – C neurotrophin receptors and directly activating the ERK1/2 signaling pathway leading to neuroplasticity [26–37]. This is important because neurotrophins can regulate neuroplasticity not only during development but also during learning and the establishment of memories [35–37]. Neurotrophins are small soluble signaling molecules that can diffuse between cells to play a role in cell–cell communication [35–37]. These neurotrophic factors include BDNF, NGF and NT3 bind to cell surface molecules on neuronal cells known as the tropomyosin receptor kinases (TRK) A – C respectively [35–37]. Neurotrophin signaling is associated with neuritogenesis or new neurite formation in neuronal cells. The changes in cell shape associated with the establishment of new neurites and therefore potentially new connections is known as neuroplasticity [35–37]. Recent attention has been brought to the idea that in so far as anxiety is related to the memories of trauma and the establishment of a learned threat level in the perception of stressors through neuroplasticity, perhaps anxiolytic phytochemicals with neurotrophic activity can be used to reduce anxiety not only through changes neurotransmitter activity, but also by providing the plasticity required to relearn and reduce the emotional value ascribed to a stressor thereby also facilitating the reduction in anxiety [26–34]. Therefore anxiolytic phytochemical neurotrophins are important because they offer a new area of research into not simply adjusting neurotransmitter activity, but to the development of natural treatments and drugs that can actually reverse the neurocircuitry associated with anxiety through neuroplasticity and relearning. It is important to note however, not all anxiolytic phytochemicals are capable of stimulating neuroplasticity. The following section of this chapter will present all nutraceutical phytochemicals that are anxiolytic in human clinical trials that also show potential for stimulating neuroplasticity either by directly stimulating neuritogenesis or neurite outgrowth neuronal cells or by binding to the TRKA-C neurotrophin receptors and or by the activation of the neurotrophin ERK1/2 signal transduction pathway and others associated with neurite formation.
