Transmitters and receptors

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8 Transmitters and receptors

Electrical Synapses

Electrical synapses are scarce in the mammalian nervous system. As seen in Figure 8.1, they consist of gap junctions (nexuses) between dendrites or somas of contiguous neurons, where there is cytoplasmic continuity through 1.5-nm channels. No transmitter is involved, and there is no synaptic delay.

The gap junctions are bridged by tightly packed ion channels, each comprising mirror image pairs of connexons, which are transmembrane protein groups (connexins) disposed in hexagonal format around an ion pore. Wedge-shaped connexin subunits bordering each ion pore are closely apposed when the neurons are inactive. Action potentials passing along the cell membrane cause the subunits to rotate individually, creating a pore large enough to permit free diffusion of ions and small molecules down their concentration gradients.

The overall function of these gap junctions is to ensure synchronous activity of neurons having a common action. An example is the inspiratory center in the medulla oblongata, where all the cells exhibit synchronous discharge during inspiration. A second example is among neuronal circuits controlling saccades, where the gaze darts from one object of interest to another.

Chemical Synapses

Transmitter liberation (Table 8.1 and Figure 8.2)

At resting nerve terminals, synaptic vesicles accumulate in the active zones, where they are tethered to the presynaptic densities by strands of docking proteins including actin. With the arrival of action potentials, myriads of voltage-gated calcium channels located in the presynaptic membrane are opened, leading to instant flooding of the active zone with Ca2+ ions. These ions cause contraction of actin filaments to bring the nearest vesicles into direct contact with the presynaptic membrane.

Table 8.1 Some named proteins involved in transmitter transport and vesicle recycling

Named protein Function
Actin Brings vesicle into contact with presynaptic membrane
Synaptophysin Creates the membrane fusion pore
Calmodulin Expels vesicle content into synaptic cleft
Clathrin Withdraws vesicle membrane from synaptic cleft
Dynamin Pinches the neck of the developing vesicle to complete its separation
Ligand Receptor protein that binds with the transmitter molecule

When the vesicle protein synaptophysin contacts the vesicle membrane, it becomes embedded in it and hollows out to create a fusion pore through which the vesicle discharges its contents into the synaptic cleft. The act of expulsion appears to be a function of another vesicle protein, calmodulin, activated by Ca2+ ions. These and other local protein responses to calcium entry are extremely rapid, the time elapsing between calcium entry and transmitter expulsion being less than 1 ms. In the case of small synaptic vesicles such as those containing glutamate or γ-aminobutyric acid (GABA), single spikes are sufficient to yield some transmitter release. In the case of peptidergic neurons, impulse frequencies of 10 Hz or more are required to induce typically slow (delay of 50 ms or more) transmitter release from the large, dense-cored vesicles.

Target cell receptor binding

Transmitter molecules bind with receptor protein molecules in the postsynaptic membrane. The two great categories of receptor are known as ionotropic and metabotropic. Each category contains some receptors whose activation leads to opening of ion pores and others whose activation leads to closure.

Ionotropic receptors

Ionotropic receptors are characterized by the presence of an ion channel within each receptor macromolecule (Figure 8.2). The transmitter binds with its specific receptor facing the synaptic cleft, causing it to change its conformation so as to open or close its ion pore. Ionotropic receptor channels are said to be transmitter-gated, or ligand-gated (from the Latin ligandum, ‘binding’), signifying their capacity to bind a transmitter molecule or a drug substitute.

In Figure 8.3A, the excitatory channel has been opened by the transmitter, causing a major influx of sodium and a minor efflux of potassium; the excitatory postsynaptic potential (EPSP) has depolarized the cell membrane almost to firing point. In Figure 8.3B, the membrane can be hyperpolarized only to −70 mV, the chloride equilibrium potential. A greater level of depolarization requires a second messenger system (see below).

Ionotropic receptors are called fast receptors on account of their immediate and brief effects on ion channels.

Metabotropic receptors

Metabotropic receptors are so called because many are capable of generating multiple metabolic effects within the cytoplasm of the neuron. The receptor macromolecule is an intrinsic membrane protein devoid of an ion channel. Its function is initiated by one or other of two subunits (α subunit, β subunit) that detaches in response to transmitter activation and moves along the inner surface of the membrane. The subunits are called G proteins, because most bind with guanine nucleotides such as guanine triphosphate (GTP) or guanine diphosphate. Their action on ion channels is usually indirect, via a second messenger system. However, some G proteins do not bind with nucleotides; instead, they activate ion channels directly (see later).

A G protein having a stimulatory effect is known as a Gs protein; a Gi protein is one with an inhibitory effect.

Three second messenger systems are well recognized.

Phosphoinositol system

In the example shown in Figure 8.5, activation of another kind of Gs protein alpha subunit causes the effector enzyme phospholipase C to split a membrane phospholipid (PIP2) into a pair of second messengers: diacylglycerol (DAG) and inositol phosphate (IP3). DAG activates protein kinase C, which initiates protein phosphorylation. IP3 diffuses into the cytosol, where it opens calcium-gated channels, mainly in nearby membranes of smooth endoplasmic reticulum. The Ca2+ ions activate certain calcium-dependent enzymes downstream, and may open calcium-gated K+ (outward) and Cl (inward) channels with excitatory effect.

Transmitters and Modulators

Several criteria should be fulfilled for a substance to be accepted as a neurotransmitter.

Many transmitters limit their own rate of release by negative feedback activation of autoreceptors in the presynaptic membrane, having the effect of inhibiting further release. Ideally, the existence of specific inhibitory autoreceptors should be established.

The term neuromodulator (L. modulare, to regulate) has been subject to several interpretations. The most satisfactory appears to derive from the terms amplitude modulation and frequency modulation in electrical engineering, signifying superimposition of one wave or signal onto another. Figure 8.6 represents a sympathetic and a parasympathetic nerve ending, close to a pacemaker cell (modified cardiac myocyte). This neighborly arrangement of nerve endings is common in the heart, and allows the respective transmitters to modulate each other’s activity. The sympathetic nerve ending liberates norepinephrine (noradrenaline), which has a stimulatory effect. The three modulators shown exert their effects via second messenger systems.

The figure caption also refers to autoreceptors and heteroreceptors. Receptors for a particular transmitter often occur in the presynaptic as well as in the postsynaptic membrane. They are called autoreceptors. These are activated by high transmitter concentration in the synaptic cleft, and they have a negative feedback effect, inhibiting further transmitter release from the synaptic bouton. Heteroreceptors occupy the plasma membrane of neurons that do not liberate the specific transmitter. In the example shown, activity at sympathetic nerve endings is accompanied by inhibition of parasympathetic activity through the medium of heteroreceptors located on parasympathetic nerve endings.

Fate of neurotransmitters

The ultimate fate of transmitters released into synaptic clefts is highly variable. Some transmitters are inactivated within the cleft, some diffuse away into the cerebrospinal fluid via the extracellular fluid, and some are recycled either by direct uptake or indirectly via glial cells.

The principal transmitters and modulators are shown in Table 8.2. Respective receptor types are in Table 8.3.

Table 8.2 Main types of transmitters and modulators, with examples of eacha The neuropeptides are modulators

Type Example(s)
Amino acids Glutamate
γ-Aminobutyric acid (GABA)
Glycine
Biogenic amines Acetylcholine
Monoamines
Catecholamines (dopamine, norepinephrine [noradrenaline], epinephrine [adrenaline])
Serotonin
Histamine
Neuropeptides Vasoactive intestinal polypeptide
Substance P
Enkephalin
Endorphins
Many others
Adenosine
Gaseous Nitric oxide

a The five monoamines contain a single amine group. Catecholamines also contain a catechol nucleus.

Table 8.3 Receptor types activated by different neurotransmitters

Ionotropic receptors Metabotropic receptors
Glutamate (AMPA/K) Glutamate (mGluR)
GABAA GABAA
Acetylcholine (nicotinic) Acetylcholine (muscarinic)
Glycine Dopamine (D1, D2)
Serotonin (5-HT3) Serotonin (5-HT1, 5-HT2)
  Norepinephrine (noradrenaline) (α1, α2), epinephrine (adrenaline)
  Histamine (H1, H2, H3)
  All neuropeptides
  Adenosine

Amino acid transmitters

The most prevalent excitatory transmitter in the brain and spinal cord is the amino acid l-glutamate (Figure 8.7). As an important example, all neurons projecting into the white matter from the cerebral cortex, regardless of their destinations in other areas of cortex or brainstem or spinal cord, are excitatory and use glutamate as transmitter. Glutamate is derived from α-ketoglutarate; it also provides the substrate for formation of the most common inhibitory transmitter, GABA.

GABA is widely distributed in the brain and spinal cord, being the transmitter in approximately one-third of all synapses. Millions of GABAergic neurons form the bulk of the caudate and lentiform nuclei, and they are also concentrated in the hypothalamus, periaqueductal gray matter, and hippocampus. Moreover, GABA is the transmitter for the large Purkinje cells, which are the only output cells of the cerebellar cortex, projecting to the dentate and other cerebellar nuclei.

GABA is synthesized from glutamate by the enzyme glutamic acid decarboxylase.

A third amino acid transmitter, glycine, is the same molecule that is used in the synthesis of proteins in all tissues. It is the simplest of the amino acids, being synthesized from glucose via serine. It is an inhibitory transmitter largely confined to internuncial neurons of the brainstem and spinal cord.

Glutamate

Glutamate acts on specific receptors of both ionotropic and metabotropic kinds. The three ionotropic ones, named after synthetic agonists that activate them, are known as AMPA, kainate, and NMDA (referring to amino-methylisoxazole propionic acid, kainate, and N-methyl-d-aspartate, respectively). Kainate receptors are scarce; they occur in company with AMPA, hence the common use of either AMPA–K or non-NMDA to include both.

Ionotropic glutamate receptors

Activation of AMPA–K receptor channels in the postsynaptic membrane allows an immediate inrush of Na+ together with a small outward movement of K+ ions (Figure 8.8), generating the early component of the EPSP in the target neuron. Should this component depolarize the target cell membrane from −65 mV to −50 mV, this will suffice to generate electrostatic repulsion of Mg2+ cations that plug the NMDA receptor ion pore at rest. Na+ ions enter via the pore and generate action potentials. Significantly, Ca2+ ions also enter, and the extended period of depolarization (up to 500 ms from a single action potential) allows activation of calcium-dependent enzymes with knock-on capacity to modify the structure and even the number of synaptic contacts in the target cell. The phenomenon of activity-dependent synaptic modification is especially detectable in experimental studies of cultured slices of rat hippocampus, and is likely to be important in the generation of short-term memory traces. (For example, the anesthetic drug ketamine, which blocks the NMDA channel, also blocks memory formation.) A characteristic effect of repetitive activation of the NMDA receptor is long-term potentiation, represented by above-normal EPSP responses even some days after ‘training’. (See long-term depression, later.)

The role of NMDA receptors in the phenomenon called glutamate excitotoxicity has been demonstrated in vascular strokes produced in experimental animals. The mass death of neurons in this kind of experiment is thought to be the result of degradation caused by excess calcium influx in accordance with the following sequence: ischemia > excess calcium influx > activation of calcium-dependent proteases and lipases > degradation of proteins and lipids > cell death. Ischemic damage may be less severe if an NMDA antagonist drug is administered soon after the initial insult.

GABA

Two major classes of GABA receptor are recognized, one being ionotropic and the other metabotropic.

Ionotropic GABA receptors

Termed GABAA, these are especially abundant in the limbic lobe of the brain. Each is directly linked to a chloride ion channel (Figure 8.9). Following activation of GABAA receptors, channel pores are opened and Cl ions diffuse down their concentration gradient from synaptic cleft to cytosol. Hyperpolarization up to −80 mV or more is brought about by summation of successive inhibitory postsynaptic potentials (IPSPs) (Figure 8.10).

The sedative, hypnotic barbiturates and benzodiazepines, for example diazepam (Valium), exert their effects by activating the natural receptor. So, too, does ethanol. (Loss of social control under the influence of ethanol may follow the release of target excitatory neurons normally held in check by tonic GABAergic activity.) Some volatile anesthetics also bind with the natural receptor, prolonging the open state of the ion channel.

The chief antagonist at the receptor site is the convulsant drug bicuculline. Another convulsant is picrotoxin, which binds with protein subunits that choke the ion pore when activated.

Metabotropic GABA receptors

Termed GABAB, these are relatively uniformly distributed throughout the brain. They are also found within peripheral autonomic nerve plexuses. Although most of their G proteins operate via second messengers, a significant number act directly, on a special class of postsynaptic K+ channels known as GIRK channels (G protein inwardly rectifying K+ channels). As shown in Figure 8.11, transmitter-binding releases the βγ subunit, which expels K+ ions through the GIRK channel, thereby producing an IPSP.

The response properties of the target neuronal receptors are slower and weaker than those of GABAA ionophores, requiring higher-frequency stimulation to be activated. This has led to the belief that they may be extrasynaptic in position rather than facing the synaptic cleft. This is indicated in Figure 8.12, where the belief is supported by the existence of another type of G-direct channel in extrasynaptic locations. This is a calcium channel that is also voltage-gated, and therefore participates in provision of the calcium ions needed to draw synaptic vesicles against the presynaptic membrane. Activation of a G–Ca2+ ligand site closes Ca2+ channels, thereby reducing the effectiveness of action potentials, with inhibitory effect on the parent neuron and on any nearby glutamatergic neurons.

In clinical disorders that involve excessive tonic muscle reflex responses (the state of spasticity, Ch. 16), the muscle relaxant baclofen is sometimes injected into the subarachnoid space surrounding the spinal cord. The drug seeps into the cord and inhibits release of glutamate from the terminals of muscle afferents, mainly by diminishing the massive calcium entry associated with excessively frequent action potentials.

Recycling of glutamate and GABA

The two routes for recycling are indicated for glutamate in Figure 8.13 and for GABA in Figure 8.14. On the left of each diagram, some transmitter molecules are retrieved from the synaptic cleft by a membrane transporter protein and reincorporated into a synaptic vesicle. On the right, transmitter molecules are being recycled through an adjacent astrocyte. Glutamate is converted to glutamine by glutamine synthetase during transit through astrocytes. Following intercellular transport into the bouton, glutamate is reassembled by glutaminase and then repacked into a synaptic vesicle. GABA is converted to glutamate by GABA transaminase during transit. Following return to the bouton, glutamate is converted (by glutamate decarboxylase) to GABA prior to storage in vesicles.

The remarkable autoimmune disorder known as stiff person syndrome, caused by blockade of glutamate decarboxylase, is described in Chapter 29.

Glycine

Glycine is synthesized from glucose via serine. Its main function as a transmitter is to provide tonic negative feedback on to motor neurons in the brainstem and spinal cord. Inactivation of glycine, for example by strychnine poisoning, results in agonizing convulsions (Clinical Panel 8.1).

Clinical Panel 8.1 Strychnine poisoning

Strychnine is a glycine receptor blocker. The victim of strychnine poisoning suffers agonizing convulsions because of liberation of α motor neurons from the tonic inhibitory control of Renshaw cells (Figure CP 8.1.1). The convulsions resemble those induced by the tetanus toxin, described in Chapter 6. This is no surprise, because tetanus toxin prevents the release of glycine from Renshaw cells. Postmortem studies of normal human brain, using radiolabeled strychnine, have shown glycine receptors to be especially abundant on internuncial neurons in the nucleus of the trigeminal nerve supplying the jaw muscles, and in the nucleus of the facial nerve supplying the muscles of facial expression. These two muscle groups are especially affected in both types of convulsive attack.

Biogenic amine transmitters

Acetylcholine

Acetylcholine (ACh) is a highly significant transmitter. In the central nervous system (CNS), activity of cholinergic neurons projecting from the basal region of the forebrain to the hippocampus is essential for learning and memory; degeneration of these neurons is consistently associated with the onset of Alzheimer disease. In the peripheral nervous system (PNS), all motor neurons to skeletal muscle are cholinergic; all preganglionic neurons supplying the ganglia of the sympathetic and parasympathetic systems are cholinergic, as is the postganglionic nerve supply of the parasympathetic system to cardiac muscle, the smooth muscle of the intestine and bladder, and the smooth muscles of the eye involved in accommodation for close-up vision.

Acetylcholine is formed when an acetyl group is transferred to choline from acetyl coenzyme A (acetyl CoA) by the enzyme choline acetyltransferase (Figure 8.15), which is unique to cholinergic neurons. The choline is actively transported into the neuron from the extracellular space. Acetyl CoA is synthesized in mitochondria that are concentrated in the nerve terminal and also provide the enzyme. Following release, ACh is degraded in the synaptic cleft by acetylcholinesterase (AChE), yielding choline and acetic acid. These molecules are largely recaptured and recycled to form fresh transmitter.

Some steps in synthesis, degradation, and recycling of ACh are also shown in Figure 8.16.

Both ligand-gated and G protein-coupled ACh receptors are recognized. The former are called nicotinic, because they were first discovered to be activated by nicotine extracted from the tobacco plant. The latter are called muscarinic because activated by muscarine extracted from the poisonous mushroom Amanita muscaria.

Monoamines

Catecholamines

As indicated in Table 8.2, the catecholamines comprise dopamine, norepinephrine, and epinephrine (adrenaline). As shown in Figure 8.17, all three are derived from the amino acid tyrosine.

The transmitters are synthesized in the nerve terminals, the requisite tyrosine and enzymes having been sent there by rapid transport. Newly synthesized transmitter must be packaged immediately into a synaptic vesicle by a monoamine transporter protein lodged in the vesicular membrane, because the catabolic enzyme monoamine oxidase (MAO) permeates the cytosol. On release, most of the transmitter binds with one or more specific receptors in the postsynaptic membrane and (where present) with an autoreceptor in the presynaptic membrane. Of the remainder, some is inactivated by catechol-O-methyl transferase (COMT), an enzyme liberated from the postsynaptic membrane into the synaptic cleft (Figure 8.18). The rest is taken up by a specific uptake transporter, and is either collected by a vesicular protein transporter or is inactivated by MAO.

Dopamine

Dopamine is of particular interest in the clinical contexts of Parkinson disease, drug addiction, and schizophrenia. It is synthesized from tyrosine in two steps (Figure 8.17), being converted to DOPA (dihydroxyphenylalanine) by amino acid hydroxylase, and from DOPA to dopamine by dopa decarboxylase, an enzyme restricted to catecholaminergic neurons. The two main sets of dopaminergic neurons are located in the midbrain. They are the substantia nigra and the ventral part of the tegmentum called the ventral tegmental area (VTA).

The substantia nigra belongs functionally to the basal ganglia (Ch. 28). A dopaminergic nigrostrial pathway projects from substantia nigra to striatum (caudate nucleus and putamen). This pathway controls a motor loop of neurons feeding forward to the motor cortex. Degeneration of neurons in the substantia nigra is a classic feature of Parkinson disease, in which normal movements are disrupted by rigidity of the musculature and/or tremor.

The VTA projects groups of dopaminergic neurons into the forebrain. One group, called mesocortical, projects to the prefrontal cortex; overactivity of this system has been invoked to explain some clinical features of schizophrenia (Ch. 29). The other, called mesolimbic, projects to several limbic nuclei including the nucleus accumbens (bedded in the ventral striatum); dopamine liberation within the nucleus accumbens appears to be the basis of the dopamine rush, or dopamine high, associated with several kinds of drug addiction (Ch. 34).

Catecholamine recycling

Recycling of dopamine and norepinephrine occurs via specific reuptake transporters, as indicated in Figure 8.18. The figure indicates that not all the molecules are recycled into synaptic vesicles within the parent neuron. Any of three other fates are possible: some are metabolized in or near the synaptic cleft by the enzyme COMT; others are carried for up to 100 µm by the extracellular fluid, perhaps bonding to isolated specific membrane heteroreceptors on other neurons as depicted in Figure 6.6 (‘volume transmission’); and others achieve reuptake only to be metabolized by the enzyme MAO liberated by nearby mitochondria.

Epinephrine

Neuronal production of epinephrine in the CNS appears to be confined to a group of cells in the upper lateral part of the medulla oblongata. Only these contain the enzyme (phentolamine N-methyltransferase) that provides the final link in the catecholamine chain (Figure 8.17). Some of these neurons project upward to the hypothalamus, others to the lateral gray horn of the spinal cord. Their functions are not yet clear.

In the PNS, the chromaffin cells of the adrenal medulla liberate epinephrine as a hormone into the capillary bed. The epinephrine augments sympathetic effects on the circulatory and other systems during the alarm response to danger. As shown in Figure 13.6, the chromaffin cells are modified sympathetic ganglion cells receiving synaptic contacts from preganglionic cholinergic neurons. One function of circulating epinephrine, illustrated in Figure 13.5, is to boost norepinephrine output at sympathetic nerve terminals by activating β2 heteroreceptors there.

Serotonin

In the medical literature, more has been written about serotonin than about any other neurotransmitter. Depletion of serotonin has a well-established connection with depression. Abnormalities of serotonin metabolism have been implicated in other behavioral disorders, including anxiety states, obsessive-compulsive disorders, and bulimia.

As indicated in Figures 21.2 and 21.5 Figure 21.2 Figure 21.5, serotonergic cell bodies occupy the midregion or raphe (seam) of the brainstem. Their axonal ramifications are quite prodigious, penetrating to every region of the gray matter of brain and spinal cord.

Serotonin, commonly referred to as 5-HT because it is 5-hydroxytryptamine, is derived from the dietary amino acid tryptophan, present in the circulation. It is actively transported across the blood–brain barrier into the brain extracellular fluid, then transported into serotonergic neurons. Formation of serotonin from tryptophan is a two-step process (Figure 8.19). Tryptophan is converted to 5-hydroxytryptophan by the enzyme tryptophan hydroxylase, and this is converted to serotonin by 5-hydroxytrytophan decarboxylase.

Histamine

Histamine is synthesized from histidine by histidine decaboxylase, as shown in Figure 8.22. The somas of histaminergic neurons appear to be confined to the posterior part of the hypothalamus, where they occupy the small tuberomammillary nucleus shown in Figure 26.1. However, their axons extend widely, mainly to all parts of the cerebral cortex. The main function of histaminergic neurons is to participate with cholinergic and serotonergic neurons in maintaining the awake state. These neurons are active in the awake state and silent during sleep (see Ch. 24). Activation is a function of the peptide orexin locally produced by lateral hypothalamic neurons. The compulsive daytime sleep disorder known as narcolepsy (Ch. 30) appears to result from failure of orexin production.

Acknowledgment

The assistance of Professor Brian Leonard, Department of Pharmacology, National University of Ireland, Galway, is gratefully acknowledged.

Core Information

Electrical synapses are gap junctions designed to ensure synchronous activity of groups of neurons. The gaps are bridged by tightly packed ion channels. Protein subunits surrounding the individual ion channels are apposed when the neurons are silent. In response to passage of action potentials along the cell membrane, they separate instant diffusion of ions from one cytosol to another.

At chemical synapses, transmitter molecules are expelled into the synaptic cleft and united with their specific target receptors in the manner already summarized in Table 8.1.

Ionotropic receptors are ligand-gated. Each is either excitatory through admission of Na+ ions or inhibitory through admission of Cl ions. Metabotropic receptors have no ion pore. Their receptor macromolecule responds to transmitter activation by detaching a G-protein subunit that usually binds to guanine triphosphate or guanine diphosphate, which in turn activates the cyclic AMP, phosphoinositol, or arachidonic acid system.

Amino acid transmitters include glutamate, GABA, and glycine. Biogenic amine transmitters and modulators include acetylcholine (ACh) and the monoamines, i.e. catecholamines (dopamine, norepinephrine, epinephrine), serotonin, and histamine. Neuropeptides include vasoactive intestinal polypeptide (VIP), substance P, enkephalin, and endorphins. Also prevalent are adenosine and nitric oxide.

Glutamate activation of target AMPA–K receptors produces the early component of the excitatory postsynaptic potential, which in turn opens NMDA receptors, producing action potentials through entry of Na+, and long-term potentiation through entry of Ca2+. Excitotoxicity caused by excessive Ca2+ influx may cause target cell necrosis.

GABA activation of target GABAA (ionotropic) receptors generates inhibitory postsynaptic potentials by causing Cl influx. These receptors are also activated by barbiturates, benzodiazepines, alcohol, and some volatile anesthetics. Activation of GABAB (metabotropic) receptors leads to hyperpolarization indirectly by depressing cyclic AMP formation, and directly by expelling K+ ions through GIRK channels.

Glycine released by Renshaw cells provides tonic negative feedback on to motor neurons. Strychnine and tetanus convulsions are caused by inactivation of glycine.

Acetylcholine target receptors are either nicotinic (causing entry of Na+ and Ca2+) or muscarinic. The latter include excitatory M1, M3 and M5 receptors, and inhibitory M2 and M4 autoreceptors.

Dopamine is relevant to Parkinson disease by the nigrostriatal pathway, to drug addiction and to schizophrenia by mesocortical and mesolimbic pathways. Target receptors are all G protein-coupled. D1 receptors are excitatory via cyclic AMP activation. D2 receptors are inhibitory via cyclic AMP or Ca2+ channel inactivation and/or activation of GIRK channels.

Norepinephrine is liberated by noradrenergic neurons. Main source within the central nervous system (CNS) is the cerulean nucleus; in the peripheral nervous system, postganglionic sympathetic fibers. Target receptors are all G protein-gated and are grouped into α and β subtypes, some of each being excitatory and others inhibitory.

Serotonin is highly relevant to clinical psychology and psychiatry. It is synthesized mainly in the raphe nuclei of the brainstem. Seven groups of receptors have been identified. 5-HT1A serves autoinhibition via somatodendritic autoreceptors, 5-HT1D serves autoinhibition via presynaptic receptors, 5-HT2A excites target neurons via phosphoinositol stimulation, 5-HT2C stimulates excitatory ionotropic channels in the area postrema (vomiting center).

Histaminergic neurons project from the hypothalamic tuberomammillary nucleus to all parts of the cerebral cortex. They help to maintain the state of arousal.

Neuropeptides include VIP, substance P, enkephalin, and endorphins. In general, they are cotransmitters having a modulatory effect. Their target receptors are all G protein-coupled.

Adenosine is derived from ATP. In the autonomic nervous system, it is an excitatory cotransmitter with ACh. In the CNS, it is inhibitory, and adenosine-containing compounds are sedative.

Nitric oxide is a lipid- and water-soluble gaseous radical synthesized from arginine in response to Ca2+ entry following depolarization. It activates guanylate cyclase and increases cyclic AMP in target neurons, thereby modulating the activity of conventional transmitters. It is a peripheral vasodilator, and in the hippocampus it participates in memory formation by eliciting long-term potentiation.