**3. GABAergic system and neurological disorders**

The main components of brain inhibitory circuits are networks of (GABAergic) interneurons in the amygdala [20]. This neurotransmitter is essential to maintain a balance between neuronal excitation and inhibition. Both glutamatergic neurons and the GABAergic interneurons compose of the basolateral nucleus (BLA). A relatively small group of GABAergic inhibitory neurons is closely regulated by Glutamatergic neurons. Devastation of GABAergic BLA inhibition, such as anxiety and depression, emotional dysregulation, and seizure actions, can cause hyperexcitability of the The central amygdala (CeA) consisting only of GABAergic neurons acts by converging inputs from the BLA as the primary output nucleus of the amygdala. In addition, the BLA, the central amygdala and all their associations play a key role in the regulation of the GABAergic system. As a result, these

#### *Natural Products Altering GABAergic Transmission DOI: http://dx.doi.org/10.5772/intechopen.99500*

GABAergic amygdala neurons are properly trained to perform a central role in the stress management. Nonetheless, even less is known about the association between the GABAergic amygdala inhibitory system and stress [21].

The sedative and hypnotic effects are mediated by α1 subunit of GABAA receptors, whereas the anxiolytic effect is exhibited by the positive regulation of α2 and (or) α3 subunit of GABAA receptors. Furthermore, in learning and memory, the α<sup>5</sup> subunits play an important role. The cause of side effects, such as muscle relaxation or anterograde amnesia, is because of benzodiazepines, which are widely used in the treatment of anxiety, insomnia and seizures, functioning on various subunits (α1, α2, α3 and α5). Such drawbacks include the growth of resistance and dependence. The development of new and safer drugs with, for example, an efficient anxiolytic yet low sedative potential is therefore urgently warranted. Various studies have recently been performed on natural products with GABAergic involvement, and various types of approaches have been used to clarify the findings. Consequently, the purpose of this analysis is to gather current evidence and generate the findings obtained, thereby promoting the discussion of structure activity relationships [9].

In knock-out mice special kind of GABAB receptors are being introduced in mice that lack subunits of the GABAB receptor. In addition to psychiatric conditions, the phenotype of these mice shows evidence of GABAB receptor activation in epilepsy, sensorimotor gating, nociception and temperature control [22]. With almost the same behavioral phenotype as GABAB1 Knockout mice whereas mice that lack the GABAB2 subunit are currently developed. Some data suggest that these phenotypes underlie the lack of heteromeric GABAB1 and GABAB2 receptors. In order to evaluate the anxiolytic ability of other positive GABAB receptor modulators, further studies are required, but current evidence suggests that they may be a new category of anxiolytics with a higher side effect profile than benzodiazepines. The mechanisms involved in the anxiety activity impact of GABAB receptors are not well known. Future research should also focus on behavioral and electrophysiological approaches to the activation of GABAB receptors in major anxiety-related brain regions [23].

#### **3.1 GABAergic system in schizophrenia**

In late adolescence or early adulthood, schizophrenia is a mental health condition that commonly occurs. Its impact on speech, thinking, emotions and other areas of life can affect the social interactions and daily activities of people. In the presynaptic neuron, the carrier protein is available in GAT-1 and is mainly responsible for GABA reuptake in synapse. It plays a significant role in both phasic and tonic inhibition which is regulated by GABA. The synaptic potential of GABA is terminated by GAT-1 and it is managed by the duration and adequacy of GABAergic neurotransmission therefore, decreased GAT-1 levels demonstrate enhanced accessibility of GABA. In schizophrenia, numerous studies show decreased levels of mRNA encoding for the GAT-1 protein along with the decreased expression of GAD 67 mRNA. GAT-1 mRNA delivery is decreased and generally unchanged in most GABAergic neurons. GAT-1 mRNA concentration fluctuations are recognized in chandelier neurons. In schizophrenia, the thickness of immunoreactive GAT-1 cartridges is reduced, although axon terminal marker in other populations remains unaltered. Relatively low GAT-1 immunoreactive cartridge thickness indicates a significantly reduced GAT-1 protein correlated with a reduced level of GAT-1 mRNA. Therefore, in individuals with schizophrenia, the amount of GAT-1 proteinenclosing chandelier neurons decreased whereas the number of neurons comprising parvalbumin remained consistent. This outcome infers that the decreased degrees of GAT-1 mRNA are restricted to chandelier neurons.

The decline of GAD67 mRNA coding in the prefrontal dorsolateral cortex is the most predictable post-mortem finding in schizophrenia, which led to decrease in GAD67 levels of protein, despite the fact that this has been less widely considered. The schizophrenia-influenced subset tends to incorporate GABAergic neurons comprising parvalbumin. Expression of parvalbumin mRNA in schizophrenia is diminished in layer 3 and 4 of the prefrontal cortex (PFC). In the prefrontal cortex (PFC), the recent discovery indicates that the decreased articulation of GAD67 mRNA is unique for the GABA neuron subgroup [24].

Adequate histopathological data also suggests that, the association of GABAergic neurotransmission impairment with pathologies and cognitive dysfunctions of schizophrenia. The primary motor cortex (PMC), primary visual cortex (VC), anterior cingulate cortex (ACC) is distinguished by the similar GABAergic gene expression deficits as shown in the Dorsolateral prefrontal cortex, which includes selective parvalbumin-containing GABA neuron involvement. The greatest decreases in mRNA encoding levels for parvalbumin have been reported. In serious case reduction in the α1 and δ subunits of GABA receptors, GAD67 mRNA, GAD65 mRNA and GAT-1 mRNA is displayed in the brain regions [10, 25].

#### **3.2 GABAergic system in anxiety and depression**

Both in animals and humans, depression and anxiety are most frequent causes of persistent stress. Two mechanisms are defined by anxiety models: fear processes are believed to be developed to allow us to change our emphasis on the first hint of risk and behavioral modification in order to prevent or eliminate an imminent or predicted overt danger [26].

The long-term potential activity strongly depends on the augmentation of GABA signaling which process through the GABAA receptors namely α1 and α2. The long-term potential response triggers are not only restricted to GABAA but also to the GABAB receptor. The GABAB receptor antagonists causing the long-term potential response on cortical along with thalamic centripetal synapses whereas the thalamic feed needs postsynaptic response from NMDA-receptor. The cortical actions controlled by pre-synaptic response on increased glutamate response by NMDA receptor independent activity, so activating GABA synapse thereby inducing GABAB receptor might help to arrest non associated long-term potential there by reducing agitation response [27].

By protruding to the central amygdala (CEA), CEA output neurons control the GABAergetic tone and form a spontaneous active neuron in lateral subdivisions. Aversive stimulus can reduce this inhibitory tone. CEA consists primarily of localized GABA neurons and the inhibition of GABA occurs through GABAA α2 receptor. Therefore, for benzodiazepine-induced anxiolysis and anti-panic activity, CEA considered to be a significant target [28].

#### **3.3 Epilepsy and GABAergic system**

Epilepsy can be the consequence of disturbances in the homeostasis involving other neurotransmitters and neuromodulators, for example, glutamate, adenosine, norepinephrine, and acetylcholine. GABA receptor or transporter function alteration can allow the occurrence of seizure in the presence of normal GABA levels. Some data indicates that low occipital lobe GABA concentration (remote from the seizure focus) is a risk factor for seizure recurrence. Low GABA levels predispose but may not be sufficient for seizures to become clinically effective [28, 29].

In case of adults, status epilepticus induces a complete re-organization of the networks, with cell death, axonal growth leading to an increased glutamatergic

*Natural Products Altering GABAergic Transmission DOI: http://dx.doi.org/10.5772/intechopen.99500*

drive. This, in turn, will decrease the threshold of seizure generation and thus contribute to seizure generation. Somatostatin innervates the dendrites of the principal cells in the hippocampus and triggers a chemical imbalance between excitatory and inhibitory neurotransmitters which leads to a reduction of the inhibitory strength that is necessary but not sufficient to generate ongoing seizures. An additional important factor is the persistent increase of the intracellular chloride concentration that leads to a long-lasting shift in the depolarizing direction of the actions of GABA that will also contribute to seizure generation [30, 31].
