Page 392 - Basic _ Clinical Pharmacology ( PDFDrive )

378 SECTION V Drugs That Act in the Central Nervous System

B. GABA and Glycine acetylcholine causes slow inhibition of the neuron by activating
Both GABA and glycine are inhibitory neurotransmitters, which are the M 2 subtype of receptor, which opens potassium channels.
typically released from local interneurons. Interneurons that release A far more widespread muscarinic action in response to acetyl-
glycine are restricted to the spinal cord and brain stem, whereas choline is a slow excitation that in some cases is mediated by M
1
interneurons releasing GABA are present throughout the CNS, receptors. These muscarinic effects are much slower than either
including the spinal cord. It is interesting that some interneurons in nicotinic effects on Renshaw cells or the effect of amino acids.
the spinal cord can release both GABA and glycine. Glycine recep- Furthermore, this M muscarinic excitation is unusual in that
1
–
tors are pentameric structures that are selectively permeable to Cl . acetylcholine produces it by decreasing the membrane permeability
Strychnine, which is a potent spinal cord convulsant and has been to potassium, ie, the opposite of conventional transmitter action.
used in some rat poisons, selectively blocks glycine receptors. Eight major CNS nuclei of acetylcholine neurons have been
and characterized with diffuse projections. These include neurons
GABA receptors are divided into two main types: GABA A
GABA . Inhibitory postsynaptic potentials in many areas of the in the neostriatum, the medial septal nucleus, and the reticular
B
brain have a fast and slow component. The fast component is formation that appear to play an important role in cognitive func-
receptors and the slow component by GABA tions, especially memory. Presenile dementia of the Alzheimer
mediated by GABA A B
receptors. The difference in kinetics stems from the differences in type is reportedly associated with a profound loss of cholinergic
coupling of the receptors to ion channels. GABA receptors are neurons. However, the specificity of this loss has been questioned
A
ionotropic receptors and, like glycine receptors, are pentameric because the levels of other putative transmitters, eg, somatostatin,
–
structures that are selectively permeable to Cl . These receptors are are also decreased.
selectively inhibited by picrotoxin and bicuculline, both of which
Monoamine Neurotransmitters
cause generalized convulsions. A great many subunits for GABA A
receptors have been cloned; this accounts for the large diversity in Monoamines include the catecholamines (dopamine and norepi-
the pharmacology of GABA receptors, making them key targets nephrine) and 5-hydroxytryptamine. The diamine neurotrans-
A
receptors are
for clinically useful agents (see Chapter 22). GABA B mitter, histamine, has several similarities to these monoamines.
metabotropic receptors that are selectively activated by the anti- Although these compounds are present in very small amounts in
spastic drug baclofen. These receptors are coupled to G proteins the CNS, they can be localized using extremely sensitive histo-
2+
that, depending on their cellular location, either inhibit Ca chemical methods. These pathways are the site of action of many
+
channels or activate K channels. The GABA component of the drugs; for example, the CNS stimulants cocaine and amphetamine
B
+
inhibitory postsynaptic potential is due to a selective increase in K appear to act primarily at catecholamine synapses. Cocaine blocks
conductance. This inhibitory postsynaptic potential is long-lasting the reuptake of dopamine and norepinephrine, whereas amphet-
+
and slow because the coupling of receptor activation to K channel amines cause presynaptic terminals to release these transmitters.
opening is indirect and delayed. GABA receptors are localized to
B
the perisynaptic region and thus require the spillover of GABA A. Dopamine
receptors are also present on the
from the synaptic cleft. GABA B The major pathways containing dopamine are the projection
axon terminals of many excitatory and inhibitory synapses. In linking the substantia nigra to the neostriatum and the projec-
recep-
this case, GABA spills over onto these presynaptic GABA B tion linking the ventral tegmental region to limbic structures,
2+
tors, inhibiting transmitter release by inhibiting Ca channels. In particularly the limbic cortex. The therapeutic action of the anti-
addition to their coupling to ion channels, GABA receptors also parkinsonism drug levodopa is associated with the former area (see
B
inhibit adenylyl cyclase and decrease cAMP generation.
Chapter 28), whereas the therapeutic action of the antipsychotic
drugs is thought to be associated with the latter (see Chapter 29).
Acetylcholine In addition, dopamine-containing neurons in the ventral hypo-
Acetylcholine was the first compound to be identified pharma- thalamus play an important role in regulating pituitary function.
cologically as a transmitter in the CNS. Eccles showed in the Five dopamine receptors have been identified, and they fall into
early 1950s that excitation of spinal cord Renshaw cells by recur- two categories: D 1 -like (D and D ) and D -like (D , D , D ).
2
5
1
2
4
3
rent axon collaterals from spinal motor neurons was blocked by All dopamine receptors are metabotropic. Dopamine generally
nicotinic antagonists. Furthermore, Renshaw cells were extremely exerts a slow inhibitory action on CNS neurons. This action has
sensitive to nicotinic agonists. This early success at identifying a been best characterized on dopamine-containing substantia nigra
transmitter for a central synapse was followed by disappointment neurons, where D -receptor activation opens potassium channels
2
because it remained the sole central synapse for which the trans- via the G coupling protein.
i
mitter was known until the late 1960s, when comparable data
became available for GABA and glycine. Second, the motor axon B. Norepinephrine
collateral synapse remains one of the best-documented examples Most noradrenergic neurons are located in the locus coeruleus
of a cholinergic nicotinic synapse in the mammalian CNS, despite or the lateral tegmental area of the reticular formation. Although
the rather widespread distribution of nicotinic receptors as defined the density of fibers innervating various sites differs considerably,
by in situ hybridization studies. most regions of the CNS receive diffuse noradrenergic input. All
Most CNS responses to acetylcholine are mediated by a large noradrenergic receptor subtypes are metabotropic. When applied
family of G protein-coupled muscarinic receptors. At a few sites, to neurons, norepinephrine can hyperpolarize them by increasing