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 altering intrinsic firing activity, increasing or decreasing voltage-dependent currents, altering synaptic efficacy, increasing bursting activity and reconfiguring 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.
Neuromodulator systems
The major neurotransmitter systems are the noradrenaline (norepinephrine) system, the dopamine system, the serotonin system, and the cholinergic system. Drugs targeting the neurotransmitter of such systems affect the whole system, which explains the mode of action of many drugs.
Most other neurotransmitters, on the other hand, e.g. glutamate, GABA and glycine, are used very generally throughout the central nervous system. +Neuromodulator systems System OriginUnless else specified in boxes, then ref is: Targets Effects Noradrenaline systemLocus coeruleusAdrenergic receptors in: spinal cord thalamus hypothalamus striatum neocortex cingulate gyrus cingulum hippocampus amygdala arousal (Arousal is a physiological and psychological state of being awake or reactive to stimuli) reward systemLateral tegmental field hypothalamus Dopamine systemDopamine pathways: mesocortical pathway mesolimbic pathway nigrostriatal pathway tuberoinfundibular pathwayDopamine receptors at pathway terminations. motor system reward system cognition endocrine nausea Serotonin system caudal dorsal raphe nucleusSerotonin receptors in: deep cerebellar nuclei cerebellar cortex spinal cordbehavior behavior mood satiety body temperature sleep decrease nociception rostral dorsal raphe nucleusSerotonin receptors in: thalamus striatum hypothalamus nucleus accumbens neocortex cingulate gyrus cingulum hippocampus amygdala Cholinergic systemPedunculopontine nucleus and dorsolateral tegmental nuclei (pontomesencephalotegmental complex) (mainly) M1 receptors in: brainstem deep cerebellar nuclei pontine nuclei locus ceruleus raphe nucleus lateral reticular nucleus inferior olive thalamus tectum basal ganglia basal forebrain muscle and motor control system learning short-term memory arousal rewardbasal optic nucleus of Meynert (mainly) M1 receptors in: neocortex medial septal nucleus (mainly) M1 receptors in: hippocampus neocortex
Noradrenaline system
The noradrenaline system consists of around 15,000 neurons, primarily in the locus coeruleus. This is diminutive compared to the more than 100 billion neurons in the brain. As with dopaminergic neurons in the substantia nigra, neurons in the locus coeruleus tend to be melanin-pigmented. Noradrenaline is released from the neurons, and acts on adrenergic receptors. Noradrenaline is often released steadily so that it can prepare the supporting glial cells for calibrated responses. Despite containing a relatively small number of neurons, when activated, the noradrenaline system plays major roles in the brain including involvement in suppression of the neuroinflammatory response, stimulation of neuronal plasticity through LTP, regulation of glutamate uptake by astrocytes and LTD, and consolidation of memory.
Dopamine system
The dopamine or dopaminergic system consists of several pathways, originating from the ventral tegmentum or substantia nigra as examples. It acts on dopamine receptors.
Parkinson's disease is at least in part related to dropping out of dopaminergic cells in deep-brain nuclei, primarily the melanin-pigmented neurons in the substantia nigra but secondarily the noradrenergic neurons of the locus coeruleus. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success.
Dopamine pharmacology Cocaine, for example, blocks the reuptake of dopamine, leaving these neurotransmitters in the synaptic gap for longer. AMPT prevents the conversion of tyrosine to L-DOPA, the precursor to dopamine; reserpine prevents dopamine storage within vesicles; and deprenyl inhibits monoamine oxidase (MAO)-B and thus increases dopamine levels.
Serotonin system
The serotonin created by the brain comprises around 10% of total body serotonin. The majority (80-90%) is found in the gastrointestinal (GI) tract. It travels around the brain along the medial forebrain bundle and acts on serotonin receptors. In the peripheral nervous system (such as in the gut wall) serotonin regulates vascular tone.
Serotonin pharmacology Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are widely used antidepressants that specifically block the reuptake of serotonin with less effect on other transmitters. Tricyclic antidepressants also block reuptake of biogenic amines from the synapse, but may primarily affect serotonin or norepinephrine or both. They typically take four to six weeks to alleviate any symptoms of depression. They are considered to have immediate and long-term effects. Monoamine oxidase inhibitors allow reuptake of biogenic amine neurotransmitters from the synapse, but inhibit an enzyme which normally destroys (metabolizes) some of the transmitters after their reuptake. More of the neurotransmitters (especially serotonin, noradrenaline and dopamine) are available for release into synapses. MAOIs take several weeks to alleviate the symptoms of depression.
Although changes in neurochemistry are found immediately after taking these antidepressants, symptoms may not begin to improve until several weeks after administration. Increased transmitter levels in the synapse alone does not relieve the depression or anxiety.
Cholinergic system The cholinergic system consists of projection neurons from the pedunculopontine nucleus, laterodorsal tegmental nucleus, and basal forebrain and interneurons from the striatum and nucleus accumbens. It is not yet clear whether acetylcholine as a neuromodulator acts through volume transmission or classical synaptic transmission, as there is evidence to support both theories. Acetylcholine binds to both metabotropic muscarinic receptors (mAChR) and the ionotropic nicotinic receptors (nAChR). The cholinergic system has been found to be involved in responding to cues related to the reward pathway, enhancing signal detection and sensory attention, regulating homeostasis, mediating the stress response, and encoding the formation of memories.
GABA
Gamma-aminobutyric acid (GABA) has an inhibitory effect on brain and spinal cord activity. GABA is an amino acid that is the primary inhibitory neurotransmitter for the central nervous system (CNS). It reduces neuronal excitability by inhibiting nerve transmission. GABA has a multitude of different functions during development and influences the migration, proliferation, and proper morphological development of neurons. It also influences the timing of critical periods and potentially primes the earliest neuronal networks. There are two main types of GABA receptors: GABAa and GABAb. GABAa receptors inhibit neurotransmitter release and/or neuronal excitability and are a ligand-gated chloride channel. GABAb receptors are slower to react due to a GCPR that acts to inhibit neurons. GABA can be the culprit for many disorders ranging from schizophrenia to major depressive disorder because of its inhibitory characteristics being dampened.
Neuropeptides
Neuropeptides are small proteins used for communication in the nervous system. Neuropeptides represent the most diverse class of signaling molecules, and vary considerably between animals. There are 90 known genes that encode human neuropeptide precursors. In the fruit fly Drosophila there are ~50 known genes encoding precursors, and in the worm C. elegans 120 genes specify more than 250 neuropeptides. Most neuropeptides bind to G-protein coupled receptors, however some neuropeptides directly gate ion channels or act through kinase receptors. Opioid peptides – a large family of endogenous neuropeptides that are widely distributed throughout the central and peripheral nervous system. Opiate drugs such as heroin and morphine act at the receptors of these neurotransmitters.
Endorphins Enkephalins Dynorphins Vasopressin Oxytocin Gastrin Cholecystokinins Somatostatin Cortistatins RF-amides Neuropeptide FF Neuropeptide Y - Pancreatic Polypeptide Peptide YY Prolactin-releasing peptide Calcitonin Adrenomedullin Natriuretic Bombesin-like peptides Endothelin Glucagon Secretin Vasoactive Intestinal Peptide Growth Hormone Releasing Hormone Gastric Inhibitory Peptide Corticotropin Releasing Hormone Urocortin Urotensin Substance P Neuromedins Tensin Kinin Granin Nerve Growth Factor Motilin Ghrelin Galanin Neuropeptide B/W Neurexophilin Insulin Relaxin Agouti-related protein homolog gene Prolactin Apelin Metastasis-suppressor Diazepam-binding inhibitor Cerebellins Leptin Adiponectin Visfatin Resistin Nucleibindin Ubiquitin
Neuromuscular systems Neuromodulators may alter the output of a physiological system by acting on the associated inputs (for instance, central pattern generators). However, modeling work suggests that this alone is insufficient, because the neuromuscular transformation from neural input to muscular output may be tuned for particular ranges of input. Stern et al. (2007) suggest that neuromodulators must act not only on the input system but must change the transformation itself to produce the proper contractions of muscles as output.
Volume transmission Neurotransmitter systems are systems of neurons in the brain expressing certain types of neurotransmitters, and thus form distinct systems. Activation of the system causes effects in large volumes of the brain, called volume transmission. Volume transmission is the diffusion of neurotransmitters through the brain extracellular fluid released at points that may be remote from the target cells with the resulting activation of extra-synaptic receptors, and with a longer time course than for transmission at a single synapse. Such prolonged transmitter action is called tonic transmission, in contrast to the phasic transmission that occurs rapidly at single synapses.
Tonic Transmission There are three main components of tonic transmission: Continued release, sustained release, and baseline regulation. In the context of neuromodulation, continuous release is responsible for releasing neurotransmitters/neuromodulators at a constant low level from glial cells and tonic active neurons. Sustained Influence provides long-term stability to the entire process, and baseline regulation ensures that the neurons are in a continued state of readiness to respond to any signals. Acetylcholine, noradrenaline, dopamine, norepinephrine, and serotonin are some of the main components in tonic transmission to mediate arousal and attention.
Phasic Transmission