As an important contributor to such a wide variety of psychopathology, the dysregulation of human fear constitutes a major burden to public health and well-being. With respect to pharmacologic strategies for the treatment of anxiety, the most commonly used drugs include selective serotonin reuptake inhibitors (SSRIs)1C3 as well as agents that act to enhance the actions of -aminobutyric acid (GABA), usually through agonist-like activity at central GABAA receptors. 4 Benzodiazepines and barbiturates, which act to enhance GABAergic neurotransmission, have been widely used Daptomycin and are generally recognized to be effective at reducing the expression of fear and anxiety in treated humans as well as most animal models of anxiety. and anxiety are defining features of many devastating Daptomycin psychiatric illnesses, including posttraumatic stress disorder and specific phobias, and are major contributors to the morbidity associated with many other common psychiatric illnesses, ranging from depression to schizophrenia. As an important contributor to such a wide variety of psychopathology, the dysregulation of human fear constitutes a major burden to public health and well-being. With respect to pharmacologic strategies for Daptomycin the treatment of anxiety, the most commonly used drugs include selective serotonin reuptake inhibitors (SSRIs)1C3 as well as agents that act to enhance the actions of -aminobutyric acid (GABA), usually through agonist-like activity at central GABAA receptors.4 Benzodiazepines and barbiturates, which act to enhance GABAergic neurotransmission, have been widely used and are generally recognized to be effective at reducing the expression of fear and anxiety in treated humans as well as most animal models of anxiety. Indeed, many animal models of anxiety are designed and validated using benzodiazepine-mediated anxiolysis as a readout. This being said, very little is known about the effect of benzodiazepines on extinction, with some research5 suggesting that benzodiazepines may even impair extinction of clinical fear. While effective, available anxiolytics often engender a number of undesirable side effects, including impaired arousal, amnestic effects, tolerance, dependence, and abuse liabilities. Recently, a more detailed understanding of the neural circuitry involved in the formation, expression, and experience-dependent inhibition of mammalian fear responses has yielded a number of potentially Rabbit Polyclonal to EXO1 useful therapeutic targets.6,7 It is hoped that new treatments aimed at these new drug targets will allow the development of anxiolytics with fewer side effects. This review will briefly discuss the literature examining the role of the endocannabinoid system in the learning, expression, and learned inhibition of the mammalian fear response. Furthermore, as agonists, antagonists, and reuptake inhibitors of the endocannabinoid neurotransmitter system are all being pursued for clinical use,8C15 we will briefly comment on how currently available studies from the animal literature may inform future clinical directions. FEAR, ANXIETY, AND THE AMYGDALA The neural mechanisms controlling fear and anxiety have been intensively studied in laboratory and clinical settings. These studies have elucidated several structures within the limbic system as key players in the production of both normal and pathologic fear, including the hippocampus, prefrontal cortex, and the amygdala. Among these structures, the amygdala has the most well-established role in the production of fear states in a variety of different animal species, ranging from mice to humans.16,17 The amygdala is an almond-shaped nuclear structure located within the temporal lobe. It can be subdivided into three major nuclei: the basolateral nuclear complex, the central nucleus, and the medial nucleus. Notably, these nuclei of the amygdala can be differentiated on the basis of their connectivity, the types of neurons they contain, and, finally on their roles in the production of behavioral states. Work in a variety of animal models has identified the central nucleus of the amygdala (CeA) as the major output of the amygdalar circuit, on the basis of its robust connectivity to other brain regions involved in the production of fear responses and on the basis of animal behavior following lesions of the CeA.16C19 In contrast, the basolateral complex of the amygdala (BLA) seems to be critical component in the learning of conditioned fear responses, and accordingly receives a wide array of sensory input, both from subcortical and cortical structures. From a behavioral perspective, it has been widely observed16C19 that animals with lesions to the BLA (especially dorsal lesions including the lateral nucleus) can express fear normally, but have profound deficits in learning new fear responses in a number of different conditioning tasks. This has led to the view that experience-dependent alterations in the neural circuitry of the BLA allow an animal to learn which sensory information should lead to the production of a fear response. More recent studies have implicated the BLA in the extinction of a fear response through the repeated presentation of the conditioned stimulus in the absence of the unconditioned stimulus in previously fear conditioned animals. Additionally, these studies strongly suggest that extinction learning, while it also seems to rely on the BLA, is a form of learning that is distinct and parallel to fear learning.20C22 Organization of the Endocannabinoid Neurotransmitter System At the current time, there are two known cannabinoid receptor subtypes: cannabinoid-type 1.