Introduction To CNS Pharmacology PDF

INTRODUCTION TO CNS PHARMACOLOGY AND BASIC PRINCIPLES OF ACTION OF DRUGS AFFECTING NEUROTRANSMISSION Asst. Prof.Yekta ÇULPAN Department of Medical Pharmacology Marmara University School of Medicine  INTRODUCTION Near...

INTRODUCTION TO CNS PHARMACOLOGY AND BASIC PRINCIPLES OF ACTION OF DRUGS AFFECTING NEUROTRANSMISSION Asst. Prof.Yekta ÇULPAN Department of Medical Pharmacology Marmara University School of Medicine  INTRODUCTION Nearly all drugs with CNS effects act on specific receptors that modulate synaptic transmission. While a few agents such as general anesthetics and alcohol may have nonspecific actions on membranes (although these exceptions are not fully accepted), even these non-receptor-mediated actions result in demonstrable alterations in synaptic transmission. A full appreciation of the effects of a drug on the CNS requires an understanding of the multiple levels of brain organization, from genes to circuits to behavior.  ORGANIZATION OF THE CNS The CNS is composed of the brain and spinal cord. It is responsible for integrating sensory information and generating motor output and other behaviors needed to successfully interact with the environment and enhance species survival. The human brain contains about 100 billion interconnected neurons surrounded by various supporting glial cells. Throughout the CNS, neurons are either clustered into groups called nuclei or are present in layered structures such as the cerebellum or hippocampus. Connections among neurons both within and among these clusters form the circuitry that regulates information flow through the CNS.  NEURONS Neurons are electrically excitable cells that process and transmit information via an electrochemical process. There are many types of neurons in the CNS, a typical neuron possesses a cell body (or soma) and specialized processes called dendrites and axons.  NEURONS Dendrites, which form highly branched complex dendritic “trees,” receive and integrate the input from other neurons and conduct this information to the cell body. The axon carries the output signal of a neuron from receive and integrate the input from other neurons and conduct this information to the cell body. The axon carries the output signal of a neuron from the cell body, sometimes over long distances. Neurons may have hundreds of dendrites but generally have only one axon, although axons may branch distally to contact multiple targets. The axon terminal contacts other neurons at specialized junctions called synapses where neurotransmitter chemicals are released and interact with receptors on other neurons.  NEUROGLIA In addition to neurons, there are many non-neuronal support cells, called glia, that perform a variety of essential functions in the CNS. Astrocytes are the most abundant cell in the brain and play homeostatic support roles, including providing metabolic nutrients to neurons and maintaining extracellular ion concentrations. Astrocyte processes are closely associated with neuronal synapses, where they are involved in the removal and recycling of neurotransmitters after release. In addition, astrocytes play increasingly recognized active roles in regulating synapse formation and function. For example, astrocytes express neurotransmitter receptors and can release neuromodulators that can alter neuronal activity.  NEUROGLIA Oligodendrocytes are cells that wrap around the axons of projection neurons in the CNS forming the myelin sheath. Similar to the Schwann cells in peripheral neurons, the myelin sheath created by the oligodendrocytes insulates the axons and increases the speed of signal propagation. Damage to oligodendrocytes occurs in multiple sclerosis, and thus they are a target of drug discovery efforts.  NEUROGLIA Microglia are specialized macrophages derived from the bone marrow that settle in the CNS and are the major immune defense system in the brain. These cells are actively involved in neuroinflammatory processes in many pathologic states including neurodegenerative diseases. In addition, roles for microglia in normal brain function are increasingly appreciated. For example, microglia engulf and eliminate synapses, a process called synaptic pruning, which is crucial for normal circuit development. Excessive microglia-mediated synapse elimination has been linked to schizophrenia and Alzheimer disease.  BLOOD-BRAIN B ARRIER The blood-brain barrier (BBB) is a protective functional separation of the circulating blood from the extracellular fluid of the CNS that limits the penetration of substances, including drugs. This separation is accomplished by the presence of tight junctions between the capillary endothelial cells as well as a surrounding layer of astrocyte end-feet. As such, to enter the CNS, drugs must either be highly hydrophobic or engage specific transport mechanisms. For example, the second-generation antihistamines cause less drowsiness because they were developed to be significantly more polar than older antihistamines, limiting their crossing of the BBB.  BLOOD-BRAIN B ARRIER Many nutrients, such as glucose and the essential amino acids, have specific transporters that allow them to cross the BBB. L-DOPA, a precursor of the neurotransmitter dopamine, can enter the brain using an amino acid transporter, whereas dopamine cannot cross the BBB. Thus, the orally administered drug L-DOPA, but not dopamine, can be used to boost CNS dopamine levels in the treatment of Parkinson disease. Some parts of the brain, the so-called circumventricular organs, lack a normal BBB.  CIRC UMVENTRICU LAR ORGANS Median Eminence Neurohypophysis (Posterior Pituitary) Pineal Gland Subcommissural Organ (SCO) Area Postrema Subfornical Organ (SFO) Organum Vasculosum of the Lamina Terminalis (OVLT)  ION CHANNELS & NEUROTRANSMITTER RECEPTORS The membranes of neurons contain two types of channels defined by the mechanisms controlling their gating (opening and closing): voltage-gated and ligand-gated channels. Voltage-gated channels respond to changes in the membrane potential of the cell. In nerve cells, these channels are highly concentrated on the initial segment of the axon, which initiates the all-or-nothing fast action potential, and along the length of the axon where they propagate the action potential to the nerve terminal.  ION CHANNELS & NEUROTRANSMITTER RECEPTORS There are also many types of voltage-gated sodium, calcium and potassium channels on the cell body, dendrites, and initial segment, which act on a slower time scale and modulate the rate at which the neuron discharges. For example, some types of potassium channels opened by depolarization of the cell result in slowing of further depolarization and act as a brake to limit action potentials. SO M E TOXIN S US ED TO C HARAC TER IZE IO N C HANN ELS  ION CHANNELS & NEUROTRANSMITTER RECEPTORS Neurotransmitters exert their effects on neurons by binding to two distinct classes of receptor. The first class is referred to as ligand-gated channels, or ionotropic receptors. These receptors consist of multiple subunits, and binding of the neurotransmitter ligand directly opens the channel, which is an integral part of the receptor complex. These channels are insensitive or only weakly sensitive to membrane potential. Activation of these channels typically results in a brief opening of the channel. Ligand-gated channels are responsible for fast synaptic transmission typical of hierarchical projection pathways in the CNS.  ION CHANNELS & NEUROTRANSMITTER RECEPTORS The second class of neurotransmitter receptors are referred to as metabotropic receptors. These are seven-transmembrane G protein–coupled receptors (GPCRs). The binding of neurotransmitter to this type of receptor does not result in the direct gating of a channel. Rather, binding to the receptor engages a G protein, which results in the production of second messengers that mediate intracellular signaling cascades.  ION CHANNELS & NEUROTRANSMITTER RECEPTORS In neurons, activation of metabotropic neurotransmitter receptors often leads to the modulation of voltage-gated channels. These interactions can occur entirely within the plane of the membrane and are referred to as membrane-delimited pathways. In this case, the G protein (often the βγ subunits) interacts directly with a voltage-gated ion channel. In general, two types of voltage-gated ion channels are the targets of this type of signaling: calcium channels and potassium channels.  ION CHANNELS & NEUROTRANSMITTER RECEPTORS When G proteins interact with calcium channels, they inhibit channel function. This mechanism accounts for the inhibition of neurotransmitter release that occurs when presynaptic metabotropic receptors are activated. In contrast, when these receptors are postsynaptic, they activate (cause the opening of) potassium channels, resulting in a slow postsynaptic inhibition. Metabotropic receptors can also modulate voltage-gated channels less directly by the generation of diffusible second messengers (e.g., β-adrenergic receptors).  ION CHANNELS & NEUROTRANSMITTER RECEPTORS Finally, an important consequence of the involvement of G proteins in receptor signaling is that, in contrast to the brief effect of ionotropic receptors, the effects of metabotropic receptor activation can last tens of seconds to minutes. Metabotropic receptors predominate in the diffuse modulatory neuronal systems in the CNS.  THE SYNAPSE & SYNAPTIC POTENTIALS Nerve Synapse Animation The calcium channels responsible for the release of neurotransmitter are generally resistant to the calcium channel-blocking agents but are sensitive to blockade by certain marine toxins and metal ions. The time delay from the arrival of the presynaptic action potential to the onset of the postsynaptic response is approximately 0.5 ms. Most of this delay is consumed by the release process, particularly the time required for calcium channels to open.  POSTSYNAPTIC POTENTIALS AND ACTION POTENTIAL GE NE RATION  THE SYNAPSE & SYNAPTIC POTENTIALS When an excitatory pathway is stimulated, a small depolarization or excitatory postsynaptic potential (EPSP) is recorded. This potential is due to the excitatory transmitter acting on an ionotropic receptor, causing an increase in cation permeability. When an inhibitory pathway is stimulated, the postsynaptic membrane is hyperpolarized owing to the selective opening of chloride channels, producing an inhibitory postsynaptic potential (IPSP). A second type of inhibition is presynaptic inhibition whereby neurotransmitter release directly inhibits additional release at the same synapse (autoreceptors), or by spilling over to neighboring synapses. SITES OF DRU G ACTION 1. Action potential in presynaptic fiber 2. Synthesis of transmitter 3. Storage 4. Metabolism 5. Release 6. Reuptake into the nerve ending or uptake into a glial cell 7. Degradation 8. Receptor for the transmitter 9. Receptor-induced increase or decrease in ionic conductance 10. Retrograde signaling  EX AMPLES FOR DRUG ACTION SITES Reserpine depletes monoamine synapses of transmitters by interfering with intracellular storage. Amphetamine induces the release of catecholamines from adrenergic synapses. Capsaicin causes the release of the peptide substance P from sensory neurons. Tetanus toxin blocks the release of transmitters. Cocaine blocks the uptake of catecholamines at adrenergic synapses. Anticholinesterases block the degradation of acetylcholine.  EX AMPLES FOR DRUG ACTION SITES Opioids mimic the action of enkephalin. Strychnine blocks the receptor for the inhibitory transmitter glycine. Ketamine blocks the NMDA subtype of glutamate ionotropic receptors by binding in the ion channel pore. Methylxanthines modify neurotransmitter responses mediated through the second messenger cAMP.  RETROGRAD SIGNALING The traditional view of the synapse is that it functions like a valve, transmitting information in one direction. However, it is now clear that the synapse can generate signals that feed back onto the presynaptic terminal to modify transmitter release. Endocannabinoids are the best documented example of such retrograde signaling. Postsynaptic activity leads to the synthesis and release of endocannabinoids, which then bind to receptors on the presynaptic terminal. Although the gas nitric oxide (NO) has long been proposed as a retrograde messenger, its physiologic role in the CNS is still not well understood.  CELLULAR ORGANIZATION OF THE BRAIN Most of the neuronal systems in the CNS can be divided into two broad categories: Hierarchical systems Nonspecific or diffuse neuronal systems.  HIERARCHIC AL SYSTEMS Hierarchical systems include all the pathways directly involved in sensory perception and motor control. Within each nucleus and in the cortex, there are two types of cells: relay or projection neurons and local circuit neurons.  PROJECTION NEURONS The projection neurons form the interconnecting pathways that transmit signals over long distances. Their cell bodies are relatively large, and their axons can project long distances but also emit small collaterals that synapse onto local interneurons. These neurons are excitatory, and their synaptic influences, which involve ionotropic receptors, are very short-lived. The excitatory transmitter released from these cells is, in most instances, glutamate.  LOC AL CIRCU IT NEURONS Local circuit neurons are typically smaller than projection neurons, and their axons arborize in the immediate vicinity of the cell body. Most of these neurons are inhibitory, and they release either GABA or glycine. They synapse primarily on the cell body of the projection neurons but can also synapse on the dendrites of projection neurons as well as with each other. Two common types of pathways for these neurons (see Figure A) include recurrent feedback pathways and feedforward pathways. A special class of local circuit neurons in the spinal cord forms axoaxonic synapses on the terminals of sensory axons (see Figure B). HIERARCHIC AL PATHWAYS IN THE CNS  DIFFUSE NEURONAL SYSTEMS Neuronal systems containing many of the other neurotransmitters, including the monoamines and acetylcholine, differ in fundamental ways from the hierarchical systems. These neurotransmitters are produced by only a limited number of neurons whose cell bodies are located in small discrete nuclei, often in the brain stem.  DIFFUSE NEURONAL SYSTEMS For example, noradrenergic cell bodies are found primarily in a compact cell group called the locus coeruleus located in the caudal pontine central gray matter and number only approximately 12,000 neurons on each side of the human brain. However, the neurons from these limited nuclei project widely and diffusely throughout the brain and spinal cord. Because the axons from these diffusely projecting neurons are fine and unmyelinated, they conduct very slowly, at about 0.5 m/s (in hierarchical systems neurons are myelinated and at a rate of 50 m/s). The axons branch repeatedly and are extraordinarily divergent.  DIFFUSE NEURONAL SYSTEMS Most neurotransmitters utilized by diffuse neuronal systems, including norepinephrine, act predominantly on metabotropic receptors and therefore initiate long-lasting synaptic effects. These systems have been implicated in such global functions as sleeping and waking, attention, appetite, and emotional states.  DIFFUSE NEU ROTRANS MITTER PATHWAYS IN THE CNS CENTRAL NEUROTRANSMITTERS  NEUROTRANSMITTER The following criteria were established for transmitter identification; 1. Localization: A suspected transmitter must reside in the presynaptic terminal of the pathway of interest. 2. Release: A suspected transmitter must be released from a neuron in response to neuronal activity and in a calcium-dependent manner. 3. Synaptic Mimicry: Application of the candidate substance should produce a response that mimics the action of the transmitter released by nerve stimulation, and application of a selective antagonist should block the response.  NEUROTRANSMITTERS Amino Acid Neurotransmitters (Glutamate, GABA, Orexin and Glycine) Endocannabinoids Acetylcholine Nitric Oxide Monoamines (Dopamine, Norepinephrine, 5- Hydroxytryptamine, and Histamine (diamine)) Purines (Adenosine, ATP, UDP, UDT) Neuropeptides – (Opioid peptides (eg, enkephalins, endorphins), Neurotensin, Substance P, Somatostatin, Cholecystokinin,Vasoactive İntestinal Polypeptide, Neuropeptide Y, and Thyrotropin- Releasing Hormone)  GLU TAMATE Excitatory synaptic transmission is mediated by glutamate, which is present in very high concentrations in excitatory synaptic vesicles (~100 mM). Almost all neurons that have been tested are strongly excited by glutamate. This excitation is caused by the activation of both ionotropic and metabotropic receptors.  GLU TAMATE The ionotropic receptors are divided into three subtypes based on the action of selective agonists: α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainic acid (KA), and N methyl-D-aspartate (NMDA). All the ionotropic receptors are composed of four subunits.  GLU TAMATE-AMPA AMPA receptors, which are present on all neurons, are heterotetramers assembled from four subunits (GluA1–GluA4). The majority of AMPA receptors contain the GluA2 subunit and are permeable to Na+ and K+, but not to Ca2+. Some AMPA receptors, typically present on inhibitory interneurons, lack the GluA2 subunit and are also permeable to Ca2+.  GLU TAMATE-KA Kainate receptors are not as uniformly distributed as AMPA receptors, being expressed at high levels in the hippocampus, cerebellum, and spinal cord. They are formed from a number of subunit combinations (GluK1–GluK5). Although GluK4 and GluK5 are unable to form channels on their own, their presence in the receptor changes the receptor’s affinity and kinetics. Similar to AMPA receptors, kainate receptors are permeable to Na+ and K+ and in some subunit combinations can also be permeable to Ca2+. Domoic acid, a toxin produced by algae and concentrated in shellfish, is a potent agonist at kainate and AMPA receptors. Consumption of contaminated shellfish has been implicated in illness in animals and humans.  GLU TAMATE-NMDA NMDA receptors are as ubiquitous as AMPA receptors, being present on essentially all neurons in the CNS. All NMDA receptors require the presence of the subunit GluN1. The channel also contains one or two GluN2 subunits (GluN2A–GluN2D). Unlike AMPA and kainate receptors, all NMDA receptors are highly permeable to Ca2+ as well as to Na+ and K+. NMDA receptor function is controlled in a number of intriguing ways. In addition to glutamate binding, the channel also requires the binding of glycine to a separate site in order for the channel to open.  GLU TAMATE-NMDA Another important feature is that while AMPA and kainate receptor activation results in channel opening at resting membrane potential, NMDA receptor activation does not. This is because, at resting membrane potential, the NMDA receptor pore is blocked by extracellular Mg2+. Only when the neuron is strongly depolarized, as occurs with intense activation of the synapse or by activation of neighboring synapses, is the Mg2+ expelled, allowing the channel to open.  GLU TAMATE-NMDA Thus, there are three requirements for NMDA receptor channel opening: Glutamate and glycine must bind the receptor, and the membrane must be depolarized. The rise in intracellular Ca2+ that accompanies NMDA receptor channel opening results in a long-lasting enhancement in synaptic strength that is referred to as long-term potentiation (LTP). This enhancement of synaptic strength, which is one major type of synaptic plasticity, can last for many hours or even days and is generally accepted as an important cellular mechanism underlying learning and memory.  GLU TAMATE-METABOTROPHIC The metabotropic glutamate receptors are G protein–coupled receptors that act indirectly on ion channels via G proteins. The metabotropic glutamate receptors (mGluR1–mGluR8) have been divided into three groups (I, II, and III). Group I receptors are typically located postsynaptically and activate phospholipase C, leading to inositol trisphosphate–mediated intracellular Ca2+ release. In contrast, group II and group III receptors are typically located on presynaptic nerve terminals and act as inhibitory autoreceptors.  GLU TAMATE-METABOTROPHIC Activation of these receptors causes the inhibition of Ca2+ channels, resulting in inhibition of transmitter release. These receptors are activated only when the concentration of glutamate rises to high levels during repetitive stimulation of the synapse. Activation of these receptors also causes the inhibition of adenylyl cyclase and decreases cAMP generation.  GABA AND GLYC INE Both GABA and glycine are inhibitory neurotransmitters, which are typically released from local interneurons. Interneurons that release glycine are largely restricted to the spinal cord and brain stem, whereas interneurons releasing GABA are present throughout the CNS, including the spinal cord. Glycine receptors are pentameric structures that are selectively permeable to Cl–. Strychnine, which is a potent spinal cord convulsant and has been used in some rat poisons, selectively blocks glycine receptors.  GABA GABA receptors are divided into two main types: GABAA and GABAB. Inhibitory postsynaptic potentials in many areas of the brain have a fast and slow component. The fast component is mediated by GABAA receptors and the slow component by GABAB receptors. GABAA receptors are ionotropic receptors and, like glycine receptors, are pentameric structures that are selectively permeable to Cl–. These receptors are selectively inhibited by picrotoxin and bicuculline, both of which cause generalized convulsions.  GABA GABAB receptors are metabotropic receptors that are selectively activated by the antispastic drug baclofen. These receptors are coupled to G proteins that, depending on their cellular location, either inhibit Ca2+ channels or activate K+ channels. The GABAB component of the inhibitory postsynaptic potential is due to a selective increase in K+ conductance. This inhibitory postsynaptic potential is long-lasting and slow because the coupling of receptor activation to K+ channel opening is indirect and delayed.  GABA GABAB receptors are localized to the perisynaptic region and thus require the spillover of GABA from the synaptic cleft. GABAB receptors are also present on the axon terminals of many excitatory and inhibitory synapses. In this case, GABA spills over onto these presynaptic GABAB receptors, inhibiting transmitter release by inhibiting Ca2+ channels. In addition to their coupling to ion channels, GABAB receptors also inhibit adenylyl cyclase and decrease cAMP generation.  ACETYLCHOLINE Acetylcholine was the first compound to be identified pharmacologically as a neurotransmitter in the CNS. The ionotropic nicotinic receptors in the CNS are composed of subunits entirely distinct from the nicotinic channels at the neuromuscular junction and are widely distributed throughout the brain and spinal cord. However, most CNS responses to acetylcholine are mediated by a large family of G protein–coupled muscarinic receptors.  ACETYLCHOLINE At a few sites, acetylcholine causes slow inhibition of the neuron by activating the M2 subtype of receptor, which opens potassium channels. A far more widespread muscarinic action in response to acetylcholine is a slow excitation that in some cases is mediated by M1 receptors. These muscarinic effects are much slower than either nicotinic effects on Renshaw cells or the effect of amino acids. Furthermore, this M1 muscarinic excitation is unusual in that acetylcholine produces it by decreasing the membrane permeability to potassium, ie, the opposite of conventional transmitter action.  ACETYLCHOLINE Eight major CNS nuclei of acetylcholine neurons have been characterized with diffuse projections. These include neurons in the neostriatum, the medial septal nucleus, and the reticular formation that appear to play an important role in cognitive functions, especially memory. Presenile dementia of the Alzheimer type is reportedly associated with a profound loss of cholinergic neurons.  DOPAMINE The major pathways containing dopamine are the projection linking the substantia nigra to the neostriatum and the projection linking the ventral tegmental region to limbic structures, particularly the limbic cortex. The therapeutic action of the antiparkinsonian drug levodopa is associated with the former area, whereas the therapeutic action of the antipsychotic drugs is thought to be associated with the latter. In addition, dopamine-containing neurons in the ventral hypothalamus play an important role in regulating pituitary function.  DOPAMINE Five dopamine receptors have been identified, and they fall into two categories: D1-like (D1 and D5) and D2-like (D2, D3, D4). All dopamine receptors are metabotropic. Dopamine generally exerts a slow inhibitory action on CNS neurons. This action has been best characterized on dopamine- containing substantia nigra neurons, where D 2-receptor activation opens potassium channels via its G protein.  NOREPINEPHRINE Most noradrenergic neurons are located in the locus coeruleus or the lateral tegmental area of the reticular formation. Although the density of fibers innervating various sites differs considerably, most regions of the CNS receive diffuse noradrenergic input. All noradrenergic receptor subtypes are metabotropic. When applied to neurons, norepinephrine can hyperpolarize them by increasing potassium conductance. This effect is mediated by α2 receptors and has been characterized most thoroughly on locus coeruleus neurons.  NOREPINEPHRINE In many regions of the CNS, norepinephrine actually enhances excitatory inputs by both indirect and direct mechanisms. The indirect mechanism involves disinhibition; that is, inhibitory local circuit neurons are inhibited. The direct mechanism involves blockade of potassium conductance that slow neuronal discharge. Depending on the type of neuron, this effect is mediated by either α1 or β receptors. Facilitation of excitatory synaptic transmission is in accordance with many of the behavioral processes thought to involve noradrenergic pathways, eg, attention and arousal.  5-HYDROXYTRYPTAMINE Most 5-hydroxytryptamine (5-HT, serotonin) pathways originate from neurons in the midline raphe nuclei of the pons and upper brain stem. 5-HT is contained in unmyelinated fibers that diffusely innervate most regions of the CNS, but the density of the innervation varies. 5-HT acts on more than a dozen receptor subtypes. Except for the 5-HT3 receptor, all of these receptors are metabotropic.  5-HYDROXYTRYPTAMINE The ionotropic 5-HT3 receptor exerts a rapid excitatory action at a very limited number of sites in the CNS. In most areas of the CNS, 5-HT has a strong inhibitory action. This action is mediated by 5-HT1A receptors and is associated with membrane hyperpolarization caused by an increase in potassium conductance. It has been found that 5HT1A receptors and GABAB receptors activate the same population of potassium channels.  5-HYDROXYTRYPTAMINE Some cell types are slowly excited by 5-HT owing to its blockade of potassium channels via 5-HT2 or 5-HT4 receptors. Both excitatory and inhibitory actions can occur on the same neuron. 5-HT has been implicated in the regulation of virtually all brain functions, including perception, mood, anxiety, pain, sleep, appetite, temperature, neuroendocrine control, and aggression.  HISTAMINE In the CNS, histamine is exclusively made by neurons in the tuberomammillary nucleus (TMN) in the posterior hypothalamus. These neurons project widely throughout the brain and spinal cord where they modulate arousal, attention, feeding behavior, and memory. There are four histamine receptors (H1 to H4), all of which are metabotropic. Centrally acting antihistamines are generally used for their sedative properties, and antagonism of H1 receptors is a common side effect of many drugs including some tricyclic antidepressants and antipsychotics.  NEUROPEPTIDES Neuropeptides include opioid peptides (e.g., enkephalins, endorphins), neurotensin, substance P, somatostatin, cholecystokinin, vasoactive intestinal polypeptide, neuropeptide Y, and thyrotropin-releasing hormone. Unlike the classic neurotransmitters mentioned before, which are packaged in small synaptic vesicles, neuropeptides are generally packaged in large, dense core vesicles. As in the peripheral autonomic nervous system, peptides often coexist with a conventional nonpeptide transmitter in the same neuron, but the release of the neuropeptides and the small-molecule neurotransmitters can be independently regulated. Released neuropeptides may act locally or may diffuse long distances and bind to distant receptors.  NEUROPEPTIDES Most neuropeptide receptors are metabotropic and, like monoamines, primarily serve modulatory roles in the nervous system. Neuropeptides have been implicated in a wide range of CNS functions including reproduction, social behaviors, appetite, arousal, pain, reward, and learning and memory.  NEUROPEPTIDES Substance P is contained in and released from small unmyelinated primary sensory neurons in the spinal cord and brain stem and causes a slow excitatory postsynaptic potential in target neurons. These sensory fibers are known to transmit noxious stimuli, and it is therefore surprising that—although substance P receptor antagonists can modify responses to certain types of pain—they do not block the response. Glutamate, which is released with substance P from these synapses, presumably plays an important role in transmitting pain stimuli. Substance P is certainly involved in many other functions because it is found in many areas of the CNS that are unrelated to pain pathways.  OREXIN Orexins are peptide neurotransmitters produced in neurons in the lateral and posterior hypothalamus that, like the monoamine systems, project widely throughout the CNS. Orexins are also called hypocretins due to the near simultaneous discovery by two independent laboratories. Like most neuropeptides, orexin is released from large, dense core vesicles and bind to two G protein–coupled receptors. Orexin neurons also release glutamate and are thus excitatory.  OREXIN The orexin system, like the monoamine systems, projects widely throughout the CNS to influence physiology and behavior. In particular, orexin neurons exhibit firing patterns associated with wakefulness and project to and activate monoamine and acetylcholine neurons involved in sleep-wake cycles. Animals lacking orexin or its receptors have narcolepsy and disrupted sleep- wake patterns. In addition to promoting wakefulness, the orexin system is involved in energy homeostasis, feeding behaviors, autonomic function, and reward.  ENDOC ANNABINOIDS The primary psychoactive ingredient in cannabis, Δ9tetrahydrocannabinol (Δ9THC), affects the brain mainly by activating a specific cannabinoid receptor, CB1. CB1 receptors are expressed at high levels in many brain regions, and they are primarily located on presynaptic terminals. Several endogenous brain lipids, including anandamide and 2-arachidonylglycerol (2- AG), have been identified as CB1 ligands and are called endocannabinoids. These ligands are not stored, as are classic neurotransmitters, but instead are rapidly synthesized by neurons in response to calcium influx or activation of metabotropic receptors (eg, by acetylcholine and glutamate).  ENDOC ANNABINOIDS In further contrast to classic neurotransmitters, endocannabinoids function as retrograde synaptic messengers: they are released from postsynaptic neurons and travel backward across synapses, activating CB1 receptors on presynaptic neurons and suppressing transmitter release. This suppression can be transient or long lasting, depending on the pattern of activity. Cannabinoids, both endogenous and exogenous, may affect memory, cognition, and pain perception by this mechanism.  ENDOC ANNABINOIDS In further contrast to classic neurotransmitters, endocannabinoids function as retrograde synaptic messengers: they are released from postsynaptic neurons and travel backward across synapses, activating CB1 receptors on presynaptic neurons and suppressing transmitter release. This suppression can be transient or long lasting, depending on the pattern of activity. Cannabinoids, both endogenous and exogenous, may affect memory, cognition, and pain perception by this mechanism.  NITRIC OXIDE The CNS contains a substantial amount of nitric oxide synthase (NOS) within certain classes of neurons. This neuronal NOS is an enzyme activated by calcium-calmodulin, and activation of NMDA receptors, which increases intracellular calcium, results in the generation of nitric oxide. Nitric oxide diffuses freely across membranes and thus has been hypothesized to be a retrograde messenger, although this has not been demonstrated conclusively. Perhaps the strongest case for a role of nitric oxide in neuronal signaling in the CNS is for long-term depression of synaptic transmission in the cerebellum.  PURINES Receptors for purines, particularly adenosine, ATP, UTP, and UDP, are found throughout the body, including the CNS. High concentrations of ATP are found in and released from catecholaminergic synaptic vesicles, and ATP may be released by astrocytes to modulate neuronal function. ATP binds to two classes of receptors. The P2X family of ATP receptors includes nonselective ligand-gated cation channels, whereas the P2Y family is metabotropic. The physiologic roles for ATP release in the CNS are poorly understood, but pharmacologic studies suggest these receptors are involved in memory, wakefulness, and appetite and may play roles in multiple neuropsychiatric disorders.  PURINES Extracellular ATP also gets converted to adenosine by nucleotidases. Adenosine in the CNS acts on metabotropic A1 and A2A adenosine receptors. Presynaptic A1 receptors inhibit calcium channels and inhibit release of both amino acid and monoamine transmitters. Postsynaptic A2A receptors increase cAMP production and have a mildly excitatory effect on neurons. Increasing levels of extracellular adenosine in the CNS promote drowsiness and sleep, largely through A2A receptors. Caffeine, as a nonselective antagonist at adenosine receptors, promotes wakefulness in part through blocking the action of adenosine on A2A receptors.  RESOURCES Katzung's Basic & Clinical Pharmacology 16th Edition Goodman & Gilman’s The Pharmacological Basis of Therapeutics 13th Edition Kayaalp Akılcıl Tedavi Yönünden Tıbbi Farmakoloji 14. Basım Rang and Dale's Pharmacology 9th Edition