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Review ? 2008 Nature Publishing Group http://www.nature.com/naturemedicine Endocannabinoid signaling as a synaptic circuit breaker in neurological disease IPTV?n Katina & Tam’s F Freud Cannabis

How is the endocannabinoid system involved in brain development, brain function, and drug abuse? Endocannabinoids are compounds released by cells that regulate neurotransmitter release, including serotonin, dopamine, and opioid systems (1). The system is also involved in synaptic plasticity, synapse formation, and neurotransmitter metabolism (1,2,3). It is believed that endocannabinoids play important roles in neuronal development, plasticity, and synaptic function (1,2,3). For example, in the developing human brain, endocannabinoids act on CB1 receptors to regulate synaptic formation (4). The CB1 receptor also regulates the release of endocannabinoids in the hippocampus with enhanced synthesis of the CB1 cannabinoid receptor agonist AEA during development (5). AEA enhances synaptic plasticity, such as long-term depression and long-term potentiating, leading to memory formation (5). The same CB1 receptor mechanism is also responsible for the increased anxiety-like state produced by ? 9-tetrahydrocannabinol, the primary psychoactive component of marijuana, in mice (6). The endocannabinoid system is highly organized and is composed of different types of receptors in the nervous system, called cannabinoid receptors. The most well-known nonneuronal type of cannabinoid receptor is the CB 1 receptor. CB 1 receptors primarily respond to the plant psychoactive constituent THC in humans, but also respond to other cannabinoids, with the highest concentration of CB 1 receptors being found in the brain (in the hippocampus and prefrontal cortex) and spinal cord (7). CB 1 receptors are found on nerve cells in the midbrain, spinal cord, and in neurons in the hippocampus and prefrontal cortex, and are highly concentrated in the amygdala. Other types of cannabinoid receptors are also present in this system, such as the CB 2 receptor, which has been shown to play a role in several important physiological processes, such as anxiety and depression (4,8–11). The majority of research examining the endocannabinoid system in relation to brain disorders has focused on the potential role of CB 1 receptor agonists in the pathophysiology of stress-related illness, such as depression or Parkinson's disease (13–44). However, studies in rodents have also identified that the endocannabinoid system is a key mediator of anxiety and depression (13–35).

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