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Chapter: Basic & Clinical Pharmacology : Introduction to the Pharmacology of Central Nervous System (CNS) Drugs

Central Neurotransmitters

Central Neurotransmitters
A vast number of small molecules have been isolated from the brain, and studies using a variety of approaches suggest that the agents listed in Table 21–2 are neurotransmitters.


A vast number of small molecules have been isolated from the brain, and studies using a variety of approaches suggest that the agents listed in Table 21–2 are neurotransmitters. A brief sum-mary of the evidence for some of these compounds follows.

Amino Acids

The amino acids of primary interest to the pharmacologist fall into two categories: the acidic amino acid glutamate and the neu-tral amino acids glycine and GABA. All these compounds are present in high concentrations in the CNS and are extremely potent modifiers of neuronal excitability.

A. Glutamate

Excitatory synaptic transmission is mediated by glutamate, which is present in very high concentrations in excitatory synaptic vesi-cles (100 mM). Glutamate is released into the synaptic cleft by Ca2+-dependent exocytosis (Figure 21–7). The released glutamate acts on postsynaptic glutamate receptors and is cleared by gluta-mate transporters present on surrounding glia. In glia, glutamate is converted to glutamine by glutamine synthetase, released fromthe glia, taken up by the nerve terminal, and converted back to glutamate by the enzyme glutaminase. The high concentration of glutamate in synaptic vesicles is achieved by the vesicular gluta-mate transporter (VGLUT).

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, which have been exten-sively characterized by molecular cloning. The ionotropic recep-tors can be further divided into three subtypes based on the action of selective agonists: α-amino-3-hydroxy-5-methylisoxazole-4-propionicacid (AMPA), kainicacid(KA), andN-methyl-D-aspartate (NMDA).

All the ionotropic receptors are composed of four sub-units. 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 recep-tors, typically present on inhibitory interneurons, lack the GluA2 subunit and are also permeable to Ca2+.

Kainate receptors are not as uniformly distributed as AMPA receptors, being expressed at high levels in the hippocampus, cere-bellum, and spinal cord. They are formed from a number of sub-unit 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+.

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 NR2 subunits (GluN2A–GluN2D).

Unlike AMPA and kainate receptors, all NMDA receptors are highly permeable to Ca2+ as well as to Na+ and K+. NMDA recep-tor function is controlled in a number of intriguing ways. In addi-tion to glutamate binding, the channel also requires the binding of glycine to a separate site. The physiologic role of glycine bind-ing is unclear because the glycine site appears to be saturated at normal ambient levels of glycine. Another key difference between AMPA and kainate receptors on the one hand, and NMDA recep-tors on the other, is that AMPA and kainate receptor activation results in channel opening at resting membrane potential, whereas NMDA receptor activation does not. This is due to the voltage-dependent block of the NMDA pore by extracellular Mg2+. When the neuron is strongly depolarized, as occurs with intense activa-tion of the synapse or by activation of neighboring synapses, Mg2+ is expelled and the channel opens. Thus, there are two require-ments for NMDA receptor channel opening: Glutamate must bind the receptor and the membrane must be depolarized. The rise in intracellular Ca2+ that accompanies channel opening results in a long-lasting enhancement in synaptic strength that is referred to as long-term potentiation (LTP). The change can last for many hours or even days and is generally accepted as an important cellular mechanism underlying learning and memory.


The metabotropic glutamate receptors are G protein-coupled receptors that act indirectly on ion channels via G proteins. Metabotropic receptors (mGluR1–mGluR8) have been divided into three groups (I, II, and III). A variety of agonists and antago-nists have been developed that interact selectively with the differ-ent groups. Group I receptors are typically located postsynaptically and are thought to cause neuronal excitation by activating a non-selective cation channel. These receptors also activate phospholi-pase 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 inhib-itory autoreceptors. Activation of these receptors causes the inhi-bition 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 causes the inhibition of adenylyl cyclase and decreases cAMP generation.

The postsynaptic membrane at excitatory synapses is thickened and referred to as the postsynaptic density (PSD; Figure 21–7). This is a highly complex structure containing glutamate receptors, signaling proteins, scaffolding proteins, and cytoskeletal proteins. A typical excitatory synapse contains AMPA receptors, which tend to be located toward the periphery, and NMDA receptors, which are concentrated in the center. Kainate receptors are present at a subset of excitatory synapses, but their exact location is unknown. Metabotropic glutamate receptors (group I), which are localized just outside the postsynaptic density, are also present at some excitatory synapses.

B. GABA and Glycine

Both GABA and glycine are inhibitory neurotransmitters, which are typically released from local interneurons. Interneurons that release glycine are restricted to the spinal cord and brainstem, whereas interneurons releasing GABA are present throughout the CNS, including the spinal cord. It is interesting that some interneurons in the spinal cord can release both GABA and gly-cine. Glycine receptors are pentameric structures that are selec-tively permeable to Cl. Strychnine, which is a potent spinal cord convulsant and has been used in some rat poisons, selectively blocks glycine receptors.

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. The difference in kinetics stems from the dif-ferences in coupling of the receptors to ion channels. 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 bicu-culline, both of which cause generalized convulsions. A great many subunits for GABAA receptors have been cloned; this accounts for the large diversity in the pharmacology of GABAAreceptors, making them key targets for clinically useful agents . 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 postsyn-aptic 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 open-ing is indirect and delayed. 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 was the first compound to be identified pharma-cologically as a transmitter in the CNS. Eccles showed in the early 1950s that excitation of Renshaw cells by motor axon collaterals in the spinal cord was blocked by nicotinic antago-nists. Furthermore, Renshaw cells were extremely sensitive to nicotinic agonists. These experiments were remarkable for two reasons. First, this early success at identifying a transmitter for a central synapse was followed by disappointment because it remained the sole central synapse for which the transmitter was known until the late 1960s, when comparable data became available for GABA and glycine. Second, the motor axon col-lateral synapse remains one of the best-documented examples of a cholinergic nicotinic synapse in the mammalian CNS, despite the rather widespread distribution of nicotinic recep-tors as defined by in situ hybridization studies. Most CNS responses to acetylcholine are mediated by a large family of G protein-coupled muscarinic receptors. At a few sites, acetylcho-line 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 acetylcho-line 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 permea-bility to potassium, ie, the opposite of conventional transmitter action.

A number of pathways contain acetylcholine, including neu-rons in the neostriatum, the medial septal nucleus, and the reticu-lar formation. Cholinergic pathways 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. However, the specificity of this loss has been questioned because the levels of other putative transmitters, eg, somatostatin, are also decreased.


Monoamines include the catecholamines (dopamine and norepi-nephrine) and 5-hydroxytryptamine. Although these compounds are present in very small amounts in the CNS, they can be local-ized using extremely sensitive histochemical methods. These path-ways are the site of action of many drugs; for example, the CNS stimulants cocaine and amphetamine appear to act primarily at catecholamine synapses. Cocaine blocks the reuptake of dopamine and norepinephrine, whereas amphetamines cause presynaptic terminals to release these transmitters.

A. Dopamine

The major pathways containing dopamine are the projection linking the substantia nigra to the neostriatum and the projec-tion linking the ventral tegmental region to limbic structures, particularly the limbic cortex. The therapeutic action of the antiparkinsonism drug levodopa is associated with the former area , whereas the therapeutic action of the antipsychotic drugs is thought to be associated with the latter . Dopamine-containing neurons in the tubero-basal ventral hypothalamus play an important role in regulating hypothalamohypophysial function. 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 D2-receptor activation opens potassium channels via the Gi coupling protein.

B. Norepinephrine

Most noradrenergic neurons are located in the locus caeruleus 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 nor-adrenergic 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 caeruleus neurons. 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 cir-cuit neurons are inhibited. The direct mechanism involves blockade of potassium conductances that slow neuronal dis-charge. Depending on the type of neuron, this effect is medi-ated by either α1 or β receptors. Facilitation of excitatory synaptic transmission is in accordance with many of the behav-ioral processes thought to involve noradrenergic pathways, eg, attention and arousal.

C. 5-Hydroxytryptamine

Most 5-hydroxytryptamine (5-HT, serotonin) pathways originate from neurons in the raphe or midline regions of the pons and upper brainstem. 5-HT is contained in unmyelinated fibers thatdiffusely 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-HT 3 receptor, all of these receptors are metabotropic. 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 5-HT1A receptors and GABAB receptors activate the same population of potassium channels. Some cell types are slowly excited by 5-HT owing to its blockade of potassium channels via 5-HT 2 or 5-HT4 receptors. Both excitatory and inhibitory actions can occur on the same neuron. It has often been speculated that 5-HT pathways may be involved in the hallucinations induced by LSD (lysergic acid), since this compound can antagonize the peripheral actions of 5-HT. However, LSD does not appear to be a 5-HT antagonist in the CNS, and typical LSD-induced behavior is still seen in animals after raphe nuclei are destroyed. Other proposed regula-tory functions of 5-HT-containing neurons include sleep, tem-perature, appetite, and neuroendocrine control.


A great many CNS peptides have been discovered that produce dramatic effects both on animal behavior and on the activity of individual neurons. Many of the peptides have been mapped with immunohistochemical techniques and include opioid peptides (eg, enkephalins, endorphins), neurotensin, substance P, soma-tostatin, cholecystokinin, vasoactive intestinal polypeptide, neu-ropeptide Y, and thyrotropin-releasing hormone. As in the peripheral autonomic nervous system, peptides often coexist with a conventional nonpeptide transmitter in the same neuron. A good example of the approaches used to define the role of these peptides in the CNS comes from studies on substance P and its association with sensory fibers. Substance P is contained in and released from small unmyelinated primary sensory neurons in the spinal cord and brainstem and causes a slow excitatory postsyn-aptic 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 syn-apses, 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.

Many of these peptides are also found in peripheral structures, including peripheral synapses.

Nitric Oxide

The CNS contains a substantial amount of nitric oxide syn-thase (NOS) within certain classes of neurons. This neuronal NOS is an enzyme activated by calcium-calmodulin, and acti-vation of NMDA receptors, which increases intracellular cal-cium, results in the generation of nitric oxide. Although a physiologic role for nitric oxide has been clearly established for vascular smooth muscle, its role in synaptic transmission and synaptic plasticity remains controversial. 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.


The primary psychoactive ingredient in cannabis, 9-tetrahydrocannabinol ( 9-THC), 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. These ligands are not stored, as are classic neurotransmitters, but instead are rapidly synthesized by neurons in response to depolarization and consequent calcium influx. Activation of metabotropic receptors (eg, by acetylcholine and glutamate) can also activate the formation of 2-AG. In further contradistinction to classic neurotransmitters, endogenous cannabinoids can function as retrograde synaptic messengers: They are released from post-synaptic neurons and travel backward across synapses, activat-ing CB1 receptors on presynaptic neurons and suppressing transmitter release. This suppression can be transient or long lasting, depending on the pattern of activity. Cannabinoids may affect memory, cognition, and pain perception by this mechanism.

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