Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second messenger signaling cascade that induces a broad, long-lasting signal. This modulation can last for hundreds of milliseconds to several minutes. Some of the effects of neuromodulators include: alter intrinsic firing activity, increase or decrease voltage-dependent currents, alter synaptic efficacy, increase bursting activity and reconfiguration of synaptic connectivity. Major neuromodulators in the central nervous system include: dopamine, serotonin, acetylcholine, histamine, norepinephrine, nitric oxide, and several neuropeptides. Cannabinoids can also be powerful CNS neuromodulators.Neuromodulators can be packaged into vesicles and released by neurons, secreted as hormones and delivered through the circulatory system. A neuromodulator can be conceptualized as a neurotransmitter that is not reabsorbed by the pre-synaptic neuron or broken down into a metabolite. Some neuromodulators end up spending a significant amount of time in the cerebrospinal fluid (CSF), influencing (or "modulating") the activity of several other neurons in the brain.