Page 389 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 21 Introduction to the Pharmacology of CNS Drugs 375

CENTRAL NEUROTRANSMITTERS present on inhibitory interneurons, lack the GluA2 subunit and
2+
are also permeable to Ca .
Because drug selectivity is based on the fact that different path- Kainate receptors are not as uniformly distributed as AMPA
ways use different transmitters, a primary goal of neuroscience receptors, being expressed at high levels in the hippocampus,
has been to identify the neurotransmitters in CNS pathways. cerebellum, and spinal cord. They are formed from a number of
Establishing that a chemical substance is a transmitter has been subunit combinations (GluK1–GluK5). Although GluK4 and
far more difficult for central synapses than for peripheral syn- GluK5 are unable to form channels on their own, their presence
apses. The following criteria were established for transmitter in the receptor changes the receptor’s affinity and kinetics. Similar
+
identification. to AMPA receptors, kainate receptors are permeable to Na and
+
K and in some subunit combinations can also be permeable to
1. Localization: A suspected transmitter must reside in the presyn- Ca . Domoic acid, a toxin produced by algae and concentrated
2+
aptic terminal of the pathway of interest. in shellfish, is a potent agonist at kainate and AMPA receptors.
2. Release: A suspected transmitter must be released from a neu- Consumption of contaminated shellfish has been implicated in
ron in response to neuronal activity and in a calcium-depen- illness in animals and humans.
dent manner. NMDA receptors are as ubiquitous as AMPA receptors, being
3. Synaptic Mimicry: Application of the candidate substance present on essentially all neurons in the CNS. All NMDA recep-
should produce a response that mimics the action of the trans- tors require the presence of the subunit GluN1. The channel also
mitter released by nerve stimulation, and application of a selec- contains one or two GluN2 subunits (GluN2A–GluN2D). Unlike
tive antagonist should block the response. AMPA and kainate receptors, all NMDA receptors are highly
+
2+
+
Using the criteria above, a vast number of small molecules have permeable to Ca as well as to Na and K . NMDA receptor func-
been isolated from the brain, and studies using a variety of approaches tion is controlled in a number of intriguing ways. In addition to
suggest that the agents listed in Table 21–2 are neurotransmitters. A glutamate binding, the channel also requires the binding of glycine
brief summary of some of these compounds follows. to a separate site in order for the channel to open. However, the
regulation and physiologic role of glycine binding remain unclear.
Amino Acid Neurotransmitters Another important feature is that while AMPA and kainate recep-
tor activation results in channel opening at resting membrane
The amino acids of primary interest to the pharmacologist fall potential, NMDA receptor activation does not. This is because, at
into two categories: the acidic amino acid glutamate and the neu- resting membrane potential, the NMDA receptor pore is blocked
tral amino acids glycine and GABA. These compounds are pres- by extracellular Mg . Only when the neuron is strongly depolar-
2+
ent in high concentrations in the CNS and are extremely potent ized, as occurs with intense activation of the synapse or by activa-
modifiers of neuronal excitability. tion of neighboring synapses, is the Mg expelled, allowing the
2+
channel to open. Thus, there are three requirements for NMDA
A. Glutamate receptor channel opening: Glutamate and glycine must bind the
Excitatory synaptic transmission is mediated by glutamate, which receptor, and the membrane must be depolarized. The rise in intra-
2+
is present in very high concentrations in excitatory synaptic cellular Ca that accompanies NMDA receptor channel opening
vesicles (~100 mM). Glutamate is released into the synaptic results in a long-lasting enhancement in synaptic strength that is
2+
cleft by Ca -dependent exocytosis. The released glutamate acts referred to as long-term potentiation (LTP). This enhancement
on postsynaptic glutamate receptors and is cleared by glutamate of synaptic strength, which is one major type of synaptic plasticity,
transporters present on surrounding glia (Figure 21–7). In glia, can last for many hours or even days and is generally accepted as an
glutamate is converted to glutamine by glutamine synthetase, important cellular mechanism underlying learning and memory.
released from the glia, taken up by the nerve terminal, and con- The metabotropic glutamate receptors are G protein-coupled
verted back to glutamate by the enzyme glutaminase. The high receptors that act indirectly on ion channels via G proteins.
concentration of glutamate in synaptic vesicles is achieved by the Metabotropic receptors (mGluR1–mGluR8) have been divided
vesicular glutamate transporter (VGLUT). into three groups (I, II, and III). A variety of agonists and
Almost all neurons that have been tested are strongly excited antagonists have been developed that interact selectively with the
by glutamate. This excitation is caused by the activation of both different groups. Group I receptors are typically located postsyn-
ionotropic and metabotropic receptors, which have been exten- aptically and activate phospholipase C, leading to inositol tri-
2+
sively characterized by molecular cloning. The ionotropic recep- sphosphate-mediated intracellular Ca release. In contrast, group
tors are divided into three subtypes based on the action of selective II and group III receptors are typically located on presynaptic
agonists: α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid nerve terminals and act as inhibitory autoreceptors. Activation of
2+
(AMPA), kainic acid (KA), and N-methyl-d-aspartate (NMDA). these receptors causes the inhibition of Ca channels, resulting in
All the ionotropic receptors are composed of four subunits. AMPA inhibition of transmitter release. These receptors are activated only
receptors, which are present on all neurons, are heterotetramers when the concentration of glutamate rises to high levels during
assembled from four subunits (GluA1–GluA4). The majority of repetitive stimulation of the synapse. Activation of these receptors
AMPA receptors contain the GluA2 subunit and are permeable also causes the inhibition of adenylyl cyclase and decreases cAMP
+
2+
+
to Na and K , but not to Ca . Some AMPA receptors, typically generation.