After studying this chapter, the student should be able to:
Diagram the synthesis, packaging, and transport of the monoamine neurotransmitters (NTs) dopamine, norepinephrine (NE), epinephrine (EP), serotonin, and histamine.
Identify the localization of monoaminergic neuron cell bodies in the brainstem or hypothalamus and their projections in the brain and spinal cord.
Describe the functions of the monoamine NTs.
Distinguish the types of purine NTs and their metabolism, receptors, and functions.
Illustrate the synthesis, packaging, and removal of neuropeptides (NPs).
Identify the main categories of NPs and outline their general functions.
Define unconventional NTs, gasotransmitters, and endocannabinoids.
Diagram the synthesis and targets of unconventional NTs.
Monoamine neurotransmitters (NTs) are a subgroup of biogenic amines that contain an amino and aromatic group and function as NTs. The 3 categories of monoamine NTs are the catecholamines, which include dopamine (DA), norepinephrine (NE), and epinephrine (EP); the indolamine serotonin (abbreviated by its chemical name 5-hydroxytryptamine [5-HT]); and the imidazolamine histamine (HA) (Figure 9–1). Monoamine neuron cell bodies are located in the brainstem or hypothalamus, with their axons projecting throughout the brain and spinal cord. Although they represent only a small percentage of the total number of neurons in the brain, monoaminergic neurons function in important processes, including emotion, arousal, mood, reward, sleep, and memory. Therapeutic drugs that modulate monoamine transmission are used to treat depression, bipolar disorder, attention deficit hyperactivity disorder (ADHD), anxiety disorders, posttraumatic stress disorder (PTSD), schizophrenia, and Parkinson disease (PD). Several addictive drugs of abuse, including cocaine and methamphetamine, lead to alteration of neuronal circuits involving monoamines. In the peripheral nervous system (PNS), monoamines are synthesized and released by postganglionic sympathetic neurons, adrenal chromaffin cells, and neurons in the gastrointestinal (GI) tract. All monoamines function via specific metabotropic G-protein–coupled receptors (GPCRs); 5-HT also employs an ionotropic receptor (Figure 9–2). Given their mechanisms of action through G proteins and second messenger pathways, monoamines function in slow synaptic transmission and neuromodulation.
Schematic of a presynaptic monoaminergic neuron. All monoamines are transported into synaptic vesicles by a vesicular monoamine transporter (VMAT1 or VMAT2). Following release into the synaptic cleft, monoamines are transported back into the presynaptic neuron or nearby astrocytes by the selective transporters for dopamine (DAT), norepinephrine (NET) or serotonin (SERT).
Monoamines function through metabotropic G-protein–coupled receptors. A. Under basal conditions, the α subunit is bound to GDP and the G protein exists in a heterotrimer complex composed of a single α, β, and γ subunit. B. After the receptor (R) is activated by its ligand (e.g., a monoamine), R associates with the α subunit, causing the α subunit to release the bound GDP. Subsequently GTP (present in higher concentrations than GDP) binds to the α subunit. C. GTP binding causes the dissociation of the α subunit from its βγ subunits and from the receptor. Free α subunit, bound to GTP, directly regulates effector proteins, such as adenylyl cyclase and phospholipase. Free βγ subunits can also directly regulate some of the same effector proteins as well as ion channels. D. Intrinsic GTPase activity in the α subunit hydrolyzes GTP to GDP and causes reassociation of the α and βγ subunits, restoring the basal state. (Reproduced with permission from Nestler EJ, Hyman SE, Holtzman DM, et al: Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3rd ed. New York, NY: McGraw Hill; 2015.)
Catecholamines are defined by containing an amino group and the aromatic catechol group. All 3 catecholamine NTs are derived from the amino acid tyrosine, which is obtained from the diet or synthesized in the liver from phenylalanine by the enzyme phenylalanine hydroxylase. The first step in catecholamine NT biosynthesis involves the conversion of tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA) by tyrosine hydroxylase (Figure 9–3). L-DOPA is then converted to DA by aromatic L-amino acid decarboxylase (AAAD). After synthesis in dopaminergic neurons, DA is transported into synaptic vesicles by the vesicular monoamine transporter (VMAT) isoform VMAT2.
Steps in the biosynthesis of catecholamines. Dopamine, norepinephrine, and epinephrine are derived from the multistep processing of tyrosine, a dietary amino acid that is actively transported across the blood–brain barrier and concentrated in catecholaminergic neurons. Neuron-specific expression of the enzymes shown here determines which neurotransmitters are synthesized in a given neuron.
Dopaminergic neurons are located in the midbrain region of the brainstem in the substantia nigra (SN) and ventral tegmental area (VTA) and in the hypothalamus. The SN derives its name from the expression of melanin, which produces a dark bluish-black pigmentation in neurons. Dopaminergic neurons project to nearly every region of the brain (Figure 9–4). DA is involved in executive functions, motivation, arousal, reward, and motor control, as well as lower level functions including lactation, sexual gratification, and nausea.
Localization of dopaminergic neurons in the brain. Dopaminergic neuron cell bodies are located in the midbrain in the substantia nigra and ventral tegmental area, and in the hypothalamus (not illustrated). Axons from dopaminergic neurons project to cortical, subcortical, brainstem, and spinal cord regions.
Projection of dopaminergic neurons from the SN pars compacta to the dorsal striatum (the caudate nucleus and putamen), termed the nigrostriatal pathway, plays significant roles in the regulation of motor control and in learning motor skills. These SN neurons are especially vulnerable to damage, and when a large number degenerate, the result is PD. The nigrostriatal pathway is also partially involved in reward and procedural memory. VTA dopaminergic neurons project to the prefrontal cortex via the mesocortical pathway, which is involved in cognitive control, executive functions, motivation, and emotional responses. Another smaller group from the VTA projects to the nucleus accumbens (NA) via the mesolimbic pathway. Sometimes referred to as the reward pathway, the mesolimbic pathway is involved in motivation, incentive salience (an increased motivation for rewarding stimuli), reinforcement and reward-related motor function learning, and fear. The VTA also sends dopaminergic projections to the amygdala, cingulate gyrus, hippocampus, and olfactory bulb. The fourth dopaminergic pathway is the tuberoinfundibular system, which originates in the arcuate nucleus of the hypothalamus, projects to the median eminence, and controls secretion of prolactin by the pituitary.
DA receptors are metabotropic GPCRs. Five subtypes of DA receptors (D1R to D5R) have been identified, which can be divided into the D1-like and D2-like families. D1-like receptors (D1R and D5R) are predominantly expressed postsynaptically where they couple through Gαs to stimulation of adenylyl cyclase, which synthesizes cyclic adenosine monophosphate (cAMP), leading to activation of protein kinase A (PKA). D1-like effects can be excitatory or inhibitory. D2-like receptors (D2R, D3R, and D4R) are located both presynaptically and postsynaptically, where they couple through Gαi/o to inhibition of adenylyl cyclase and decreased cAMP and PKA activity. Activation of D2-like receptors usually produces inhibition. The signaling pathways downstream of DA receptors can be complex, with effects on several mitogen-activated protein (MAP) kinase pathways reported.
D1Rs are the most abundantly expressed DA receptors in humans, with highest levels in the striatum, NA, SN, olfactory bulb, amygdala, and frontal cortex, and lower levels in the hippocampus, cerebellum, thalamus, and hypothalamus. D5Rs are expressed in the prefrontal cortex, hippocampus, SN, and hypothalamus. D2R expression occurs in the striatum, NA, olfactory tubercle, SN, NA, VTA, hypothalamus, cortex, septum, amygdala, and hippocampus. Consistent with the proposal that dysregulation of DA signaling contributes to symptoms in schizophrenia and bipolar disorder, D2-like receptor antagonists are the main receptor targets for antipsychotic drugs. In addition, some typical and atypical antipsychotics are antagonists of D1-like, 5-HT, and HA receptors as well.
DA is synthesized by neurons and nonneuronal cells in the periphery, where it exerts many local effects. In the GI tract, dopaminergic neurons reduce GI motility and protect intestinal mucosa. DA inhibits insulin synthesis in the pancreas and increases Na+ excretion and urinary output by the kidneys. In the immune system, DA reduces activity of lymphocytes. A substantial amount of DA circulates in the bloodstream in the conjugated form DA sulfate, with low levels of free DA. In blood vessels, DA inhibits NE release and acts as a vasodilator.
DA is removed from the synapse by uptake via the specific DA transporter (DAT) or the nonselective plasma membrane monoamine transporter (PMAT). Dysfunction of DAT is implicated in a number of disorders, including ADHD, bipolar disorder, clinical depression, and alcoholism. DAT is a target for addictive drugs of abuse and therapeutic drugs, which are predicted to enhance dopaminergic signaling by increasing DA levels at the synapse. Cocaine, methylphenidate (Ritalin) prescribed for ADHD, and bupropion prescribed for depression block DAT by binding directly and reducing the rate of DA transport. Amphetamine and methamphetamine work by a less direct mechanism. They enter the presynaptic neuron, compete for reuptake with DA, and stimulate the reverse transport (efflux) of intracellular DA. Within the presynaptic neuron, DA is degraded by the sequential activity of monoamine oxidase (MAO), catechol-O-methyltransferase (COMT), and aldehyde dehydrogenase (ALDH). Drugs that block these enzymes are used to treat depression and PD, but are nonselective, with some diet and drug interactions and significant side effects. The other important drugs, including L-DOPA, used in the treatment of PD are described in Chapter 28.
NE is synthesized from DA by the enzyme DA β-hydroxylase (DBH). Both soluble and membrane-associated DBH isoforms exist. After synthesis by soluble DBH, NE is transported into synaptic vesicles in the central nervous system (CNS) by VMAT2. In neurosecretory cells such as chromaffin cells in the PNS, NE is transported by VMAT1 into a specialized type of secretory vesicle called a dense core vesicle, which is larger than a synaptic vesicle and contains adenosine triphosphate (ATP) and the protein chromogranin. NE can also be synthesized from DA by DBH located inside synaptic or dense core vesicles. NE is also called noradrenaline, and neurons that synthesize and release NE are called noradrenergic neurons. In the CNS, noradrenergic neurons are located in 3 brainstem areas and project throughout the CNS. The largest population of noradrenergic neurons is located is the locus coeruleus (LC) in the pons, which send projections to every major part of the brain and spinal cord (Figure 9–5). Noradrenergic neurons located in the caudal ventrolateral part of the medulla play a role in the control of body fluid metabolism. Noradrenergic neurons located in the nucleus tractus solitarius (NTS) in the medulla function in control of food intake and responses to stress.
Localization of noradrenergic neurons in the brain. Noradrenergic cell bodies are located in the pons in the locus coeruleus as illustrated, and project axons to many cortical and subcortical regions of the brain, the brainstem and to the spinal cord. Noradrenergic neuron cell bodies are also located in the medulla (not shown) where they contribute to autonomic control.
LC noradrenergic (LCN) neurons are involved in sleep and dreaming. During sleep, LCN activity is low and decreases even further during rapid eye movement (REM) sleep. During wakefulness, LCN neurons are involved in attentiveness, memory, and emotion. LCN activity increases transiently when presented with attention-drawing stimuli. NE enhances attention, processing of sensory inputs and perception, modulation of synaptic plasticity, and formation and retrieval of both long-term and working memory. Unpleasant stimuli, such as pain, difficulty breathing, bladder distension, or noxious temperature, or stimuli that produce fear generate larger increases in LCN activity. In general, situations that activate LCN neurons are similar to those that activate the sympathetic nervous system. Consequently, as the LCN system mobilizes the brain to respond, the sympathetic system mobilizes the body for action.
In the PNS, postganglionic sympathetic neurons (except those that innervate sweat glands and some blood vessels) are noradrenergic. Sympathetic neurons innervate tissues in most organ systems, providing regulation of a diversity of functions, including pupil constriction, gut motility, mobilization of energy, urinary system output, activity in the heart, and regulation of blood flow. Preganglionic sympathetic innervation of the adrenal medulla stimulates adrenal chromaffin cells to release NE and EP into the circulation, which causes blood vessel constriction to divert blood from nonessential organs and increases in heart rate.
EP (also known as adrenaline) is synthesized from NE by the enzyme phenylethanolamine N-methyltransferase (PNMT). Similar to NE, EP is transported into synaptic vesicles by VMAT2 or into dense core vesicles by VMAT1. Adrenergic neurons identified in the CNS by the expression of PNMT are located in several nuclei in the medulla oblongata, including the dorsal part of the NTS and dorsomedial reticular formation. Adrenergic neurons in the brain are involved in sexual arousal and sexual behavior, control of appetite, and metabolic control, and may contribute to some functions ascribed to NE, including attentiveness, arousal, cognition, and mental focus. In the periphery, adrenal chromaffin cells are the major source of EP. In response to sympathetic activation, EP and NE are released into the circulation and act as adrenal stress hormones.
Both NE and EP function through metabotropic GPCRs called α- and β-adrenergic receptors. The α1 receptor subtypes (α1A, α1B, and α1D) are Gαq/11-coupled receptors that activate phospholipase C (PLC), resulting in increases in inositol triphosphate, Ca2+, and diacylglycerol. The α2 receptors (α2A to α2C) are Gαi/o-coupled receptors that inhibit adenylyl cyclase, reducing levels of cAMP and decreasing PKA activity. Phenylephrine is a selective agonist of the α1 receptor, whereas clonidine is a nonselective α2 receptor agonist. Three subtypes of β receptors (β1, β2, and β3) are linked to the Gαs proteins that activate adenylyl cyclase, which increase cAMP and PKA activity. The β2 isoform can also couple to Gαi/o. Isoproterenol is a nonselective β receptor agonist, whereas propranolol, one of the “β-blockers,” is a β receptor antagonist.
Both α- and β-adrenergic receptors are expressed in many brain regions including the cerebral cortex, hippocampus, brainstem, thalamus, and cerebellum, where they produce a variety of neuromodulatory effects. Coexpressed in most brain regions, β1 receptors predominate in the cerebral cortex, whereas β2 receptors predominate in the cerebellum. α2 receptors are located postsynaptically and presynaptically, where they mediate inhibition of NT release (Figure 9–6). In the periphery, responses to postganglionic sympathetic neurons involve α- or β-adrenergic receptors. For example, α receptors mediate smooth muscle contraction, whereas β receptors mediate heart muscle contraction, smooth muscle relaxation, and gluconeogenesis. A large number of important therapeutic drugs exert their effects by interacting with adrenergic systems in the brain or body, including treatment of cardiovascular disorders, shock, and a variety of psychiatric conditions. For CNS disorders, the α2-adrenergic agonist clonidine is used to treat ADHD and anxiety disorder. Recently, α1-adrenergic antagonists have emerged in treatment of PTSD, dementia-related agitation, and alcohol, cocaine, and nicotine dependence.
Illustration of a synapse between a sympathetic neuron and its target blood vessel, called a neurovascular junction. The presynaptic sympathetic neuron releases norepinephrine, which can bind to α-adrenergic receptors localized at the postsynaptic (α1) and presynaptic (α2) regions.
In the CNS, NE is taken up by the NE transporter (NET). Although NET expression appears to be restricted to noradrenergic neurons, NETs can also take up DA. NETs are targets of many antidepressant drugs, including 5-HT–NE reuptake inhibitors (SNRIs), NE-DA reuptake inhibitors (NDRIs), NE reuptake inhibitors (NRIs or NERIs), and the tricyclic antidepressants (TCAs). Moreover, although originally thought to be selective DAT modulators, cocaine, amphetamine, methylphenidate, and bupropion are also inhibitors of reuptake by NETs and 5-HT transporters as well. Consequently, NETs are also the target of addictive drugs of abuse and therapeutic drugs. Polymorphisms in NETs have been implicated in several clinical disorders, including ADHD, postural tachycardia, and orthostatic intolerance. A selective EP transporter has yet to be identified, and EP transport may involve PMAT and/or the organic cation transporter 3 (OCT3).
The indolamine 5-HT is synthesized from the amino acid tryptophan by the enzymes tryptophan hydroxylase and AAAD (Figure 9–7). 5-HT is one of the oldest NTs in evolution. In the presynaptic neuron, 5-HT is transported into synaptic vesicles via VMAT2. In the brain, serotonergic neurons are localized in 9 nuclei in the median and dorsal raphe nuclei in the reticular formation (Figure 9–8). From this brainstem region, serotonergic neurons project to nearly every region of the CNS, including the hippocampus, amygdala, hypothalamus, thalamus, neocortex, brainstem, and basal ganglia.
Biosynthetic pathway of serotonin. Serotonin, also known as 5-hydroxytryptamine (5-HT), is derived from the multistep processing of the dietary amino acid tryptophan.
Localization of serotonergic neurons in the brain. Serotonergic neuron cell bodies are located in the raphe nuclei in the reticular formation. Serotonergic axons project to the majority of regions in the brain and spinal cord.
Serotonergic neurons are involved in the regulation of mood, reward, anger, aggression, anxiety, sleep, nausea, sexuality, sensorimotor functions including pain processing, and cognition including learning and memory. Dysregulation of serotonergic systems has been implicated in the pathogenesis of depression, bipolar disorder, anxiety disorders, neuropathic pain, and schizophrenia. 5-HT is also involved in homeostatic mechanisms including appetite, thermoregulation, modulation of energy balance, and the hypothalamic-pituitary-adrenal axis. In addition, roles for 5-HT in the control of breathing and respiratory drive have been revealed by studies showing serotonergic abnormalities in roughly half of infants who have died from sudden infant death syndrome. In nonhuman primates, levels of 5-HT are correlated with social hierarchy and with risk-sensitive decision making.
The 2 main categories of 5-HT receptors (5HTRs) are the ionotropic 5HTRs and metabotropic GPCR 5HTRs. A total of 15 5HTR genes grouped into 7 families (5HT1-7R) have been identified, with numerous subtypes within each family. The 5HT3R genes encode the ionotropic receptors. All the rest are GPCRs. 5HTRs are expressed throughout the CNS, including the cerebral cortex, amygdala, basal ganglia, thalamus, hypothalamus, hippocampus, brainstem, cerebellum, and spinal cord. Located both postsynaptically and presynaptically, many effects of 5HTRs are mediated through effects on the release of other NTs, including glutamate (Glu), γ-aminobutyric acid (GABA), DA, EP, NE, and acetylcholine (ACh), and neurohormones.
As an ionotropic receptor, the 5HT3R consists of 5 subunits, which forms a nonselective cation channel permeable to Na+, K+, and Ca2+. Binding of 5-HT to the 5HT3R opens the channel and leads to a fast excitatory postsynaptic potential (EPSP). 5HT3Rs are localized to brainstem regions that control the vomiting reflex. Accordingly, 5HT3Rs antagonists are the current gold standard for treatment of postoperative, chemotherapy-induced, and radiation-induced nausea and vomiting. 5HT3Rs are expressed in many other brain regions, including the neocortex and amygdala. Mutations in 5HT3R subunits have been associated with bipolar disorder, depression, anxiety, anorexia, and irritable bowel syndrome (IBS). Postsynaptic 5HT3Rs are preferentially expressed on interneurons where they may play a role in the formation and function of cortical circuits. Consistent with this, 5HT3Rs have also been implicated in susceptibility to seizures.
5HT1R and 5HT5R inhibit adenylyl cyclase through Gαi/o, and as neuromodulators, 5HT1R and 5HT5R generally produce inhibitory effects. 5HT1ARs are expressed in high densities in the cerebral cortex, hippocampus, septum, amygdala, and raphe nucleus, whereas lower levels are located in the medulla, basal ganglia, and thalamus. 5HT1ARs have been implicated in the central control of blood pressure and heart rate and have been demonstrated to affect specific aspects of memory, probably through their modulation of other NT levels. 5HT1AR agonists such as buspirone have shown efficacy in relieving anxiety, depression, and migraine and cluster headaches. Some atypical antipsychotics such as aripiprazole are partial agonists at the 5HT1AR and are sometimes used in combination with 5-HT reuptake inhibitors to treat depression.
5HT2Rs activate PLC through Gαq/11 and generally mediate excitatory effects. However, because an important target of 5HTRs is NT release, enhancing GABA release can produce inhibitory effects. The 5HT2Rs were first noted for their importance as targets for the psychedelic drugs lysergic acid diethylamide (LSD) and mescaline, which are 5HT2R agonists. 5HT2ARs are widely distributed in the brain, including the neocortex and cerebellum. 5HT2AR antagonists have antipsychotic, antidepressant, and anxiolytic properties and may be useful in treating drug addiction and disorders that affect memory. 5HT2CRs are distributed throughout the brain and regulate anxiety, reward processing, locomotion, appetite, and energy balance.
5HT4Rs and 5HT6Rs activate adenylyl cyclase through Gαs. 5HT4Rs are expressed throughout the brain, with the highest levels in the basal ganglia. Evidence supports a role for 5HT4R s in the pathogenesis of depression, and other studies on animal models show that modulation of 5HT4Rs produces effects on memory and feeding. Based on its abundance in extrapyramidal, limbic, and cortical regions, it has been suggested that 5HT6R plays a role in motor control, emotion, cognition, and memory. Recent studies report cognitive enhancing properties of a 5HT6R antagonist in patients with moderate Alzheimer disease (AD).
Several lines of evidence indicate that 5-HT and 5HTRs are involved in cognition and memory. Serotonergic neurons project to, and 5HTRs are robustly expressed in, brain regions and neuronal populations essential for learning and memory. Reductions in brain 5-HT concentrations impair contextual fear memory and object memory in rodents and declarative memory in humans. Decreased expression of 5HTRs has been observed in postmortem AD brains. Polymorphisms in the human 5HT2AR gene are associated with altered memory processes. Agonists of 5HT2Rs and 5HT4Rs, and antagonists of 5HT1Rs and 5HT3Rs prevent memory impairment and facilitate learning in situations involving a high cognitive demand. Likewise, antagonists for 5HT2R and 5HT4R or agonists for 5HT1R or 5HT3R have the expected opposite effects on learning and memory.
After release, 5-HT is transported back into the presynaptic neuron by the specific 5-HT transporter (SERT) and possibly via PMAT, reducing the levels of 5-HT at the synapse. Inhibition of 5-HT reuptake at synapses is the target of therapeutic drugs including selective 5-HT reuptake inhibitors (SSRIs) and TCAs. SSRIs are usually the first-line treatment option for depression and some of the most widely prescribed antidepressants. SSRIs are also frequently prescribed for anxiety disorders, such as social anxiety disorder, panic disorders, obsessive-compulsive disorder, eating disorders, chronic pain, and, occasionally, PTSD. Several addictive drugs of abuse, including cocaine, amphetamine, and dextromethorphan, also modulate 5-HT levels at the synapse by effects on SERT.
The highest concentrations of 5-HT are found in the body, produced by enterochromaffin cells of the GI tract, where 5-HT regulates intestinal movements, and by platelets in the blood. 5HT3R and 5HT4R antagonists are used to treat symptoms in IBS. The effects of 5-HT are also prominent in the cardiovascular system, with additional effects on the peripheral respiratory and genitourinary system. 5-HT can cause either vasoconstriction or vasodilation of blood vessels, depending on which subtypes of receptors are involved.
The imidazolamine histamine (HA) functions as an NT in the CNS and as a mediator released by cells in the immune system and GI tract. HA is synthesized from the amino acid histidine by the enzyme L-histidine decarboxylase and is transported into synaptic vesicles by VMAT. The cell bodies of histaminergic neurons are found in the tuberomammillary nuclei in the posterior hypothalamus (Figure 9–9). Passing through the medial forebrain bundle, histaminergic neurons project to several regions throughout the brain, including the cortex. In the periphery, mast cells and basophils of the immune system and enterochromaffin-like cells of the GI system are the major HA-producing cells.
Localization of histaminergic neurons in the brain. Histaminergic neuron cell bodies are located in the tuberomammillary nuclei in the hypothalamus. Histaminergic axons project to regions in the forebrain, brainstem, and spinal cord.
Four HA receptors, identified as H1R, H2R, H3R, and H4R, are metabotropic GPCRs. Expressed in the CNS in the tuberomammillary nucleus and in many peripheral tissues, H1R is coupled to Gαq/11 and activation of PLC (Figure 9–10). In their central action, the H1Rs participate in modulation of the circadian cycle and sleep. H2R is coupled to Gαs and increased cAMP and is expressed in the brain. The H3R protein is coupled to a Gαi/o and PLC. Expression of the HRH3 gene occurs predominantly in the basal ganglia, cortex, hippocampus, and striatum, where it decreases ACh, 5-HT, and NE production and release. HA neurons increase wakefulness and prevent sleep. Antihistamines (H1R receptor antagonists), which cross the blood–brain barrier, produce drowsiness and impair the ability to maintain vigilance. Histaminergic neurons have a wakefulness-related firing pattern. They fire rapidly during waking, fire slowly during periods of relaxation/tiredness, and completely stop firing during REM and non-REM sleep. They also have possible roles in learning and memory. After release, HA can be metabolized by oxidation involving diamine oxidase or by methylation via HA N-methyltransferase, producing N-methylhistamine that is further metabolized by MAO. HA can also be taken up via the transporters PMAT and OCT3.
Different histamine receptor types couple to different G protein signal transduction pathways. H1 receptors activate phosphatidylinositol turnover via Gq/11. The other receptors couple either positively (H2 receptor) or negatively (H3 and H4 receptor) to adenylyl cyclase activity via Gs and Gi/o, respectively. Signaling pathways affected by histamine provide both immediate and long-term regulation of cell function. (Reproduced with permission from Brunton LL, Hilal-Dandan R, Knollmann BC: Goodman & Gilman’s the Pharmacological Basis of Therapeutics, 13th ed. New York, NY: McGraw Hill; 2018.)
By numerous criteria, purines are considered NTs and have emerged as important neuromodulators in the CNS and PNS. Purine NTs contain an adenine group and include ATP, adenosine diphosphate (ADP), and adenosine (Ado). ATP is released from synaptic vesicles and often functions as a cotransmitter. In contrast, ADP and Ado are not released from synaptic vesicles but are derived from ATP. At the synapse and extracellular fluid, ATP is rapidly metabolized by ectonucleoside triphosphate diphosphohydrolases to ADP and AMP, which is further metabolized by ecto-5′-nucleotidase to form Ado. Extracellular Ado can be removed by a nucleoside transporter or by metabolism by Ado deaminase and Ado kinase. Purines act through specific purinergic receptors, which are expressed in neurons, glial cells, and PNS targets.
Two main categories of receptors are activated by purines, the ionotropic receptors and metabotropic GPCRs. The P2X receptors (P2XRs) are ionotropic receptors that are considered ATP receptors because P2XRs exhibit a much higher affinity for ATP compared with other purines (Figure 9–11). Seven P2XR isoform genes have been cloned, and they likely form heterotrimer channels. P2XRs are nonselective cation channels with high Ca2+ permeability that are expressed in neurons both presynaptically and postsynaptically and in glial cells throughout the CNS and PNS.
Ionotropic purinoreceptor (P2X). P2X is an ATP-gated cation channel that is similar in structure to the epithelial Na+ channel (ENAC). It binds ATP in the extracellular ligand binding domain and is permeable to Na+, K+, and Ca2+. Separate genes coding for P2X subunits have been identified, named P2X1 through P2X7.
P2Y receptors (P2YRs) and P1 receptors (P1Rs) are metabotropic GPCRs. The P2Ys have high affinity for ATP, ADP, or uridine-5′-triphosphate (UTP). Eight different P2YRs have been identified. P2Y1R, P2Y2R, P2Y4R, P2Y6R, and P2Y11R couple through Gαq/11 proteins to activation of PLC. P2Y12R, P2Y13R, and P2Y14R couple through Gαi/o to inhibition of adenylyl cyclase. P2YR signaling may be complex because P2Y11R can also couple to Gαs and P2Y14R may couple to Gαq. P2YRs are expressed throughout the CNS by neurons, astrocytes, oligodendrocytes, and microglia. Localized both presynaptically and postsynaptically in neurons, P2YRs are anticipated to modulate synaptic transmission and plasticity by effects on a number of ion channels, receptors, and gene expression.
P1Rs have a high affinity for Ado compared with other purines and are considered Ado receptors. Four Ado receptor subtypes (A1R, A2AR, A2BR, and A3R) have been identified. The A1Rs and A3Rs couple to Gαi/o to inhibition of adenylyl cyclase, inhibit Ca2+ conductance, and activate K+ channels. A2ARs and A2BRs couple to Gαs, which stimulates adenylyl cyclase (Figure 9–12). A2BRs and A3Rs may also couple to Gαq/11 to activation of PLC activity. A1Rs are highly expressed by neurons in many brain regions including the neocortex, hippocampus, cerebellum, and brainstem. Expressed by both neurons and glial cells and displaying a more restricted localization, A2ARs are highly expressed in the striatum and olfactory bulb but show lower expression in other brain regions. Both presynaptic A1R and A2ARs are linked to modulation of NT release. Low levels of A2BR and A3R expression occur in most CNS areas.
Diagram of a purinergic synapse. Adenosine triphosphate (ATP) is typically colocalized with a small molecule neurotransmitter and is released into the synaptic cleft in a Ca2+-dependent manner. After release, ATP can directly activate P2Y and P2X receptors. P2Y receptors are coupled to G proteins and activate second messenger systems. Most are coupled to Gq/11 and activate phospholipase C (PLC) and the phosphatidylinositol pathway. P2X receptors are ligand-gated cation channels that depolarize the postsynaptic membrane and increase Ca2+ levels. ATP remaining in the synapse is rapidly converted into adenosine (Ado) by the actions of an ectodiphosphohydrolase and an ecto-5´-nucleotidase. Subsequently, Ado can activate presynaptic and postsynaptic G-protein–coupled P1 receptors (A1 and A2) and regulate adenylyl cyclase (AC) and the cAMP pathway, and in turn can be recycled into the presynaptic cell by means of a Na+-dependent transporter (N1). (Reproduced with permission from Nestler EJ, Hyman SE, Holtzman DM, et al: Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3rd ed. New York, NY: McGraw Hill; 2015.)
ATP functions as an NT in both the CNS and PNS. In postganglionic sympathetic and parasympathetic neurons, ATP is coreleased with NA and ACh, respectively. In both neuronal types, ATP acts at postjunctional P2X1Rs to enhance smooth muscle contraction, often synergizing with NA or ACh. ATP is also coreleased with ACh from motor neurons at the neuromuscular junction, where it may function in regulating postjunctional gene expression and nicotinic ACh receptor clustering. In the periphery, nonneuronal cells release ATP after tissue damage in response to pressure, heat, or chemicals. Released ATP can activate purinergic receptors on receptor regions of somatosensory neurons and transmit nociceptive responses. Sensory axons also release ATP at terminals in the dorsal horn of the spinal cord. In the GI tract, ATP is released from enteric neurons where it acts as an inhibitory NT, mediating descending muscle relaxation during peristalsis.
In the gustatory system, ATP is released by taste receptor cells in response to tastants, most likely through a nonvesicular mechanism involving ATP release channels. The released ATP activates purinergic receptors on second-order taste neurons to mediate sensory transmission. In the CNS, although a few small populations of neurons in the hippocampus, brainstem, and cortex may use ATP in fast excitatory synaptic transmission, in general, ATP is a cotransmitter and neuromodulatory in its effects, through both P2X and P2Y receptors. Disruption of purine-regulated responses has been linked to a variety of disorders, including anxiety, stroke, and epilepsy, and has prompted the development of new therapies to target specific purinergic receptors.
As a neuromodulator, Ado plays an important role in neuronal excitability, with a general inhibitory effect and a central role in sleep. Activation of presynaptic A1Rs inhibits the release of the majority of NTs including Glu, ACh, NE, 5-HT, and DA, whereas stimulation of A2ARs facilitates the release of Glu and ACh and inhibits release of GABA. The concentration of Ado in the brain, most notably in the basal forebrain, increases during waking periods and decreases during sleep. The Ado antagonists caffeine and theophylline are stimulants that act through A1R and A2AR to increase wakefulness and decrease sleep. Ado is involved in regulation of slow wave activity expressed during slow wave sleep. A population of cells in the brainstem and basal forebrain arousal centers has been identified that have activity that is both tightly coupled to thalamocortical activation and under tonic inhibitory control by Ado. Ado regulates numerous NT systems involved in sleep and wakefulness. A1Rs and A2ARs are thought to act in various areas of the brain to decrease neural activity and facilitate sleep. Ado receptors have also been implicated in neuroprotection following brain injury, cognition, and memory.
Neuropeptides (NPs) are small polypeptides containing between 3 and 40 amino acids that are neuromodulatory NTs. NPs represent the most diverse class of signaling molecules in the brain. The human genome contains about 90 genes that encode precursors of NPs, which can be processed to form about 100 identified NPs, although estimates of the total number of candidate NPs are much greater. Most neurons synthesize both a small-molecule NT, such as Glu or GABA, and 1 or more NP, which together function as cotransmitters (Figure 9–13). NPs are similar to peptide hormones released by endocrine cells and neurohormones released by neuroendocrine cells but are released into the synapse or extracellular fluid rather than into the blood. In fact, a number of NPs that function at synapses also function as hormones or neurohormones in the periphery. NPs are involved in a wide range of brain functions including neuroendocrine regulation, analgesia, food and water intake, thermoregulation, circadian rhythms, energy homeostasis and metabolism, sleep-wake states, sexual and reproductive behaviors, social behaviors, mood, reward and motivation, and learning and memory.
Comparison between small molecule neurotransmitter and neuropeptide synthesis and localization at the same synapse. Here dopamine represents the small molecule neurotransmitter. Although some dopamine is synthesized in the cell body, the majority of dopamine is synthesized in the presynaptic terminals where it is transported into small clear synaptic vesicles which are located closer to the active zones. In contrast, neuropeptide synthesis occurs in the cell body in the rough ER, and neuropeptides are packaged into large dense core vesicles at the trans Golgi network, transported down the axon and are located further away from the active zone. Both dopamine and the neuropeptides can be degraded at the synapse, but only dopamine is transported back into the nerve terminal. Note that MAO is also located in the presynaptic terminus. AADC, aromatic amino acid decarboxylase; COMT, catechol-O-methyltransferase; DA, dopamine; ER, endoplasmic reticulum; HVA, homovanillic acid; MAO, monoamine oxidase; TH, tyrosine hydroxylase. (Reproduced with permission from Nestler EJ, Hyman SE, Holtzman DM, et al: Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3rd ed. New York, NY: McGraw Hill; 2015.)
In the neuronal soma, NPs are synthesized and packaged as precursor peptides in the rough endoplasmic reticulum and traffic to the Golgi where they are sorted and packaged into secretory vesicles that then travel along the axon. NP precursors undergo maturation as they are transported down the axon via fast axonal transport to the presynaptic terminus. Inside the secretory vesicles, prohormone convertases and carboxypeptidases selectively cleave the NP precursors to generate bioactive NPs, in some cases giving rise to several NPs with distinct functions. Secretory vesicles containing NPs are distinguishable as 100- to 200-nm dense core vesicles (DCVs) that are so named for their electron-dense appearance by electron microscopy. In contrast, synaptic vesicles containing small-molecule NTs are smaller (40 to 50 nm) and are electron lucent.
NP-containing DCVs coexist in the presynaptic neuron with synaptic vesicles but in different locations, with important consequences. Whereas synaptic vesicles are localized close to the presynaptic active zone near the voltage-gated Ca2+ channels, DCVs are often located far away from the active zone. Thus, DCVs require a higher rate of presynaptic APs for their Ca2+-dependent fusion and release of NP. NPs can be released near the synapse, but also outside the synapse where they can diffuse some distance. Hence, released NPs tend to be found in lower concentrations but can have access to receptors located extrasynaptically and even on nearby neurons. Once released, NPs are not recycled back to the presynaptic neuron but are cleaved by extracellular peptidases that either inactivate the NP or produce modified NPs with different receptor properties. Therefore, NPs may have more prolonged actions than small-molecule NTs.
Many NPs were originally discovered in the context of regulation of hormone release, and their NP name may reflect that functional link. For example, somatostatin (SS) released by the hypothalamus acts on the anterior pituitary to decrease growth hormone release into the circulation, but SS released by cortical or hippocampal neurons is not involved in hormone regulation. Likewise, vasopressin released by the posterior pituitary into the circulation acts in the kidney as an antidiuretic hormone and on blood vessels to regulate blood pressure, but within the CNS, vasopressin has different functions, including regulation of social behaviors. NPs can be categorized based on different criteria, including their functions, or where the NP is also used as a hormone in the periphery (Table 9–1). Some NPs are synthesized by small populations of neurons, whereas other NPs are synthesized throughout the brain. For several NPs, neurons that use NPs in one brain region may have no anatomic or functional connection with neurons that use that NP in another brain region.
TABLE 9–1Examples of neuropeptides.
NPs function via the activation of metabotropic GPCRs and are neuromodulatory in their action. Depending on which G protein is involved, NPs can produce different modulatory effects. In addition, because NPs usually act as cotransmitters, NP modulation is intricately linked with fast or slow synaptic transmission mediated by small-molecule NTs. NPs can exert effects on the membrane potential or neuronal excitability within seconds to minutes, but can also modulate gene expression over the course of hours to days. NP receptors are expressed heterogeneously throughout the brain and can be localized to neuronal cell bodies, dendrites, and axon terminals. Numerous NP receptors have been identified, and some NPs act on several different isoforms, suggesting that hundreds of NP receptors may be encoded in the genome. Adding to their complexity, NP receptors can interact by heteromerization, with mosaic formation between different subtypes and subfamilies of NP GPCRs.
The release of NPs outside of the synapse raises an important question about the distances over which NPs work and has sparked debates about whether NPs function as local and/or long-distance neuromodulators. Complicating this debate, DCVs are also found in and released by the soma and dendrites. In many CNS regions, the expression patterns of NP-containing axons and their NP receptors correspond, consistent with a local action ascribed to NPs, meaning that the activity of an NP would be exerted on its synaptic partner and nearby cells. For some NPs, anatomic expression of the NP and its receptors may occur in different regions of the brain. Perhaps this mismatch represents a vestigial feature that was important during evolution but is no longer relevant. Alternately, a robust coordinated release of NP by a group of neurons could elevate the extracellular NP to a level that NPs could diffuse and act far away from the release site. This type of longer distance signaling has been proposed for oxytocin. Thus, there is evidence that most NPs function locally, but in a few cases, NPs may act in longer distance signaling.
NPs have been most extensively characterized in the hypothalamus, an ancient and conserved forebrain area. However, recent studies have also focused on the role of NPs in the neocortex and hippocampus, where GABAergic inhibitory interneurons differentially express NP cotransmitters, including SS, vasoactive intestinal peptide, cholecystokinin, neuropeptide Y (NPY), and substance P. Inhibitory interneurons also differentially express Ca2+ binding proteins such as parvalbumin and the 5HT3AR, which are used to distinguish inhibitory neuronal subtypes. Because local GABAergic inhibitory interneurons are proposed to play fundamental roles in shaping neocortical circuits, specific interneuron subtypes that differ in their NPs and responses may contribute to dynamic alterations in brain states and behavioral context. Moreover, given the importance of the excitation/inhibition ratio, dysregulation of specific subtypes of inhibitory interneurons has been examined for its contribution to disorders, including epilepsy, schizophrenia, and autism.
NPY & THE OPIOID PEPTIDES
One of the most abundant NPs, NPY is a 36–amino acid NP that functions in both the CNS and PNS. In the PNS, NPY is produced by sympathetic neurons and, together with NE, serves as a strong vasoconstrictor; it also enhances growth of fat tissue and affects immune cells. In the CNS, NPY is produced at highest levels in the hypothalamus and at lower levels in the pituitary, retina, hippocampus, neocortex, thalamus, amygdala, basal ganglia, and brainstem. Five NPY receptors (Y1R to Y5R) have been identified. All NPY receptors are GPCRs that couple through Gαi/o protein to inhibition of adenylyl cyclase and decreased cAMP production, depressed Ca2+ channel, or enhanced GIRK currents. NPY has numerous functions. It is a potent orexigenic hypothalamic NP that increases food intake and storage of energy as fat. NPY is also involved in anxiety and stress reduction, pain perception reduction, and memory processing and cognition; it also affects the circadian rhythm and has central effects on blood pressure. Dysregulation of NPY has also been implicated in several human disorders including obesity, alcoholism, and depression.
Three well-characterized families of endogenous opioid peptides are the endorphins, enkephalins, and dynorphins, produced by proteolytic cleavage of precursor proteins (proopiomelanocortin, proenkephalin, or prodynorphin). Opioid peptides are so named because they bind the opioid receptors, the same receptors that bind the opiates morphine and heroin, which mimic the effects of endogenous opioid peptides. Opioid peptides play a central role in pain processing and regulate many other aspects of behavior, including stress responses, mood, motivation and reward, emotion, and control of food intake, as well as functions in the endocrine, respiratory, GI, and immune systems.
Neurons that produce opioid peptides are found in specific populations of projection neurons in the hypothalamus, which project to limbic forebrain and midbrain areas, and in the medulla, which project to other areas of the brainstem and spinal cord. Opioid peptides are synthesized and released by local neurons distributed throughout the CNS, including the neocortex, hippocampus, thalamus, basal ganglia, brainstem, and spinal cord. In many neurons, opioid peptides are coexpressed with small-molecule NTs. Opioid peptides colocalize with GABAergic, glutamatergic, dopaminergic, and serotonergic neurons in several CNS regions.
The opioid receptor family includes µ, δ, and κ opioid receptors, which are GPCRs defined pharmacologically by their blockade by naloxone and differential affinities for different opioid peptides. Activation of opioid receptors leads to coupling through Gαi/o to inhibition of adenylyl cyclase, inhibition of presynaptic voltage-gated Ca2+ channels, activation of GIRK channels, and regulation of several MAP kinase pathways. Opioids exert a variety of neuromodulatory effects, depending on whether they act on presynaptic or postsynaptic receptors and in projection neurons or local neurons. Opioid receptors often lead to inhibition of NT release, postsynaptic inhibition, and decreased neuronal excitability. Although generally inhibitory, opioid peptides can also produce excitatory effects by inhibition of GABA release. Opioid receptors are widely but differentially expressed throughout the CNS, including the cerebral cortex, thalamus, limbic system, basal ganglia, brainstem, and dorsal horn, and in the PNS in the dorsal root ganglion and enteric nervous system.
The endogenous opioid systems are fundamental components of the central pain-modulatory network and potentially in peripheral mechanisms of analgesia. Events or stimuli that are perceived as traumatic, painful, and/or stressful often induce release of endogenous opioid peptides. Networks that involve endogenous opioid peptides are also involved in reward systems, mood control, and drug addiction. Endogenous opioids have been implicated in the pathophysiology of PD and seizures and may have roles in neuroprotection and immune modulation. The opiate drugs, including morphine, heroin, and oxycontin/oxycodone, produce potent analgesic and euphoric effects via their actions on opiate receptors. However, because opioids are major addictive drugs of abuse, opiate use represents a major public health problem worldwide. Hence, intense efforts are focused on developing selective drugs that target specific opioid receptors in order to enhance therapeutic efficacy, especially as analgesics, while reducing side effects, including addiction.
Unconventional NTs include gasotransmitters and endocannabinoids, which are not synthesized, stored, or released from the presynaptic neuron. Rather, they are hydrophobic molecules that are synthesized in response to conventional NT activity and diffuse directly across membranes to regulate their targets in the presynaptic, postsynaptic, and/or adjacent neurons. Gasotransmitters are small molecules of gas that are freely permeable to membranes, endogenously and enzymatically generated in a regulated manner, with specific functions at physiologic concentrations that can be mimicked by exogenous application of the gas. With specific molecular targets, the cellular effects of gasotransmitters may or may not be mediated by second messengers and can be endocrine, paracrine, and/or autocrine. Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulphide (H2S) have been proposed to function as gasotransmitters.
The best-characterized gasotransmitter, NO is synthesized from arginine by the enzyme nitric oxide synthase (NOS) (Figure 9–14). NOS is localized to the postsynaptic regions, chaperoned there by scaffolding proteins. NOS is activated by Ca2+/calmodulin following Glu activation of N-methyl-D-aspartic acid (NMDA) receptors. NO can diffuse into the cytoplasm and across the membrane to the presynaptic cell and nearby neurons, where it modifies its targets. Presynaptic NOS has also been identified. One well-studied target of NO is guanylyl cyclase (GC). NO binds to the heme at the active site of GC, enhancing its activity. GC synthesizes cyclic guanosine monophosphate (cGMP), a messenger that regulates cGMP-dependent protein kinase G (PKG) and the opening of the cyclic nucleotide–gated channel. Similar to PKA, PKG phosphorylates and regulates a myriad of neuronal substrates involved in synaptic transmission.
Nitric oxide can function as a gasotransmitter. Activation of NMDA receptors leads to the production of nitric oxide (NO) that can function as a retrograde messenger. The entry of Ca2+ via NMDA glutamate receptors activates neuronal nitric oxide synthase (nNOS) that converts L-arginine to NO. nNOS is localized next to NMDA receptors by the scaffolding protein PSD-95. Since it is a small gas, NO can diffuse directly from the postsynaptic cell into the presynaptic terminus and activate soluble guanylyl cyclase (sGC) that produces cGMP, a second messenger that modulates several presynaptic targets. (Reproduced with permission from Nestler EJ, Hyman SE, Holtzman DM, et al: Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3rd ed. New York, NY: McGraw Hill; 2015.)
In a redox-mediated reaction, NO can be covalently attached to sulfhydryl residues of proteins, called S-nitrosylation, with numerous potential neuronal targets, including ion channels and receptors, scaffolding proteins, cytoskeletal proteins, metabolic enzymes, and transcriptional regulators. Depending on the target, S-nitrosylation can induce conformational changes, activate or inhibit protein activity, modulate protein–protein interactions, or affect protein localization, or do a combination of these. In the CNS, NO has been implicated in synaptic plasticity, including long-term potentiation and long-term depression, learning, memory, neurogenesis, the central regulation of blood pressure, and the homeostatic regulation of sleep. In the periphery, many smooth muscle tissues are innervated by nitrergic nerves that generate and release NO. NO can also react with reactive oxygen species such as superoxide to form peroxynitrite, which can lead to protein nitration and lipid peroxidation. Abnormal NO signaling may contribute to neurodegenerative pathologies such as those that occur in excitotoxicity following stroke or epilepsy, and in multiple sclerosis, AD, and PD. CO is generated in neurons by the enzyme heme oxygenase (HO). Similar to NO, CO stimulates GC and increases cGMP second messenger pathways.
The endocannabinoids (ECs) anandamide and 2-arachidonoylglycerol (2-AG) are lipids produced in the postsynaptic neuron in response to NTs that increase postsynaptic Ca2+ levels. Anandamide synthesis involves conversion of the membrane phospholipid phosphatidylethanolamine by transacylase into N-acyl-phosphatidylethanolamine, followed by phospholipase D cleavage to yield anandamide. The mechanism of 2-AG synthesis is not as well characterized. ECs are released into the extracellular space by a putative EC transporter (Figure 9–15).
Endocannabinoids can function as retrograde messengers. Activation of voltage-dependent Ca2+ channels, metabotropic glutamate receptors (mGluR), or muscarinic acetylcholine receptors (mAChR) in the postsynaptic cell can increase the synthesis of endocannabinoids from a lipid precursor. Endocannabinoids diffuse or are transported out of the postsynaptic cell and activate presynaptic CB1 receptors, which inhibit neurotransmitter release. (Reproduced with permission from Nestler EJ, Hyman SE, Holtzman DM, et al: Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3rd ed. New York, NY: McGraw Hill; 2015.)
ECs and tetrahydrocannabinol (THC), the psychoactive component in cannabis, bind to cannabinoid receptors, which are metabotropic GPCRs. Two cannabinoid receptor isoforms have been identified; CB1 receptors are expressed in the CNS, whereas CB2 receptors are expressed in the PNS. CB1 activation couples through Gαi/o to inhibition of adenylyl cyclase and also activation of several MAP kinase and phosphoinositide 3-kinase pathways. A well-studied function for CB1 receptors at presynaptic membranes is inhibition of NT release. CB2 receptors also function in the immune system.
Anandamide, 2-AG, and THC have been implicated in the regulation of appetite, eating and feeding behavior, sleep, pain relief, motivation, and pleasure. Anandamide and THC have been shown to impair memory and enhance adult neurogenesis in the hippocampus in rodent models. ECs are taken up by a transporter on glial cells and possibly neurons and are degraded by hydrolases or lipases to arachidonic acid and other products. Arachidonic acid is a substrate for leukotriene and prostaglandin synthesis, although it has not been determined whether this product has a role in cannabinoid signaling.
Monoamines, purines, and NPs are NTs that function predominantly in slow synaptic transmission and neuromodulation.
Monoamine NTs include the catecholamines dopamine, NE, and EP; the indolamine serotonin; and the imidazolamine histamine.
Monoamines are synthesized from amino acids and are packaged into synaptic vesicles or dense core vesicles by the vesicular monoamine transporter.
Monoamine cell bodies are located in the brainstem or hypothalamus, and they project throughout the brain and spinal cord.
Dopamine functions in reward-motivated behavior and motor control.
NE and EP are involved in arousal and alertness.
Serotonin acts in mood, appetite, and sleep, whereas histamine is involved in wakefulness and sleep.
Monoamine NTs also play roles in cognitive functions including learning and memory.
Monoamines are removed from the synapse by specific plasma membrane NT transporters, which are targets of therapeutic drugs and addictive drugs of abuse.
As a purine NT, ATP is released from synaptic vesicles, whereas the purine NTs ADP and adenosine are derived from ATP by metabolism at the synapse.
Purine NTs function via ionotropic and metabotropic receptors in the CNS and PNS.
Adenosine plays an important role in sleep.
NPs are released from dense core or secretory granules at and around synapses and act via metabotropic receptors in neuromodulation.
At many synapses, small-molecule NTs and NPs are often coreleased and act as cotransmitters.
Unconventional NTs include the gasotransmitters, which are small gases, and the endocannabinoids, which are phospholipid derivatives.
Synthesized in response to conventional NTs, unconventional NTs diffuse or are transported across membranes and regulate targets in the postsynaptic, presynaptic, and adjacent neurons.