The CNS is the best studied area of ECS function, and its receptors and components are present there in some of their highest concentrations of the body. Pain: Early studies showed CB1 activation in the brains of rats had an analgesic effect in specifically activating the dorsolateral periaqueductal gray matter and the dorsal raphe. Opiate tolerance in the PAG is also reversed by CB1 activation. The ECS also has analgesic effects in the ventromedial medulla, the basal ganglia, the amygdala, and the substantia nigra with inhibition of substance P release. AEA also prevented the release of CGRP both synaptically and postsynaptically to reduce neuropathic pain. Movement: ECS is involved in cerebellum-dependent learning. Excessive activation of the ECS can also disrupt cerebellar learning. Activation of CB1 receptors reduces neurotransmitter release from all Purkinje cell synapses. Spinocerebellar ataxias, including Huntington’s disease, have altered expression of CB1, CB2, FAAH, and MAGL in postmortem studies. The activation of the ECS in the globus pallidus results in reduced movement or catalepsy in mice studies. Memory: In the hippocampus where memories are generated via the process of long-term potentiation, CB1 receptors are extensively expressed, located primarily in GABAergic interneurons but also in glutamatergic, cholinergic and dopaminergic neurons as well as astrocytes. Cannabinoids have long been known to impair encoding by decreasing LTP in the CA1 region. Blockage of CB1 receptors, however, also impaired spatial memory, demonstrating that memory generation does still require some endocannabinoid activity. Administration of CB1 agonist also impaired memory consolidation and retrieval. Endocannabinoid function is, however, necessary in the amygdala for fear extinction. Posttraumatic stress disorder is characterized by slower or nonexistent extinction of fear responses. Elevations in ECS following a traumatic events are protective against PTSD.