Page 393 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 21 Introduction to the Pharmacology of CNS Drugs 379

potassium conductance. This effect is mediated by α receptors their CNS function. The pathways for many of the peptides have
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and has been characterized most thoroughly on locus coeruleus been mapped with immunohistochemical techniques and include
neurons. In many regions of the CNS, norepinephrine actually opioid peptides (eg, enkephalins, endorphins), neurotensin,
enhances excitatory inputs by both indirect and direct mecha- substance P, somatostatin, cholecystokinin, vasoactive intestinal
nisms. The indirect mechanism involves disinhibition; that is, polypeptide, neuropeptide Y, and thyrotropin-releasing hormone.
inhibitory local circuit neurons are inhibited. The direct mecha- Unlike the classical neurotransmitters above, which are pack-
nism involves blockade of potassium conductances that slow aged in small synaptic vesicles, neuropeptides are generally pack-
neuronal discharge. Depending on the type of neuron, this effect aged in large, dense core vesicles. As in the peripheral autonomic
is mediated by either α or β receptors. Facilitation of excitatory nervous system, peptides often coexist with a conventional non-
1
synaptic transmission is in accordance with many of the behav- peptide transmitter in the same neuron, but the release of the
ioral processes thought to involve noradrenergic pathways, eg, neuropeptides and the small-molecule neurotransmitters can be
attention and arousal. independently regulated. Released neuropeptides may act locally
or may diffuse long distances and bind to distant receptors. Most
C. 5-Hydroxytryptamine neuropeptide receptors are metabotropic and, like monoamines,
Most 5-hydroxytryptamine (5-HT, serotonin) pathways originate primarily serve modulatory roles in the nervous system. Neuro-
from neurons in the midline raphe nuclei of the pons and upper peptides have been implicated in a wide range of CNS functions
brain stem. 5-HT is contained in unmyelinated fibers that dif- including reproduction, social behaviors, appetite, arousal, pain,
fusely innervate most regions of the CNS, but the density of the reward, and learning and memory. Thus, neuropeptides and their
innervation varies. 5-HT acts on more than a dozen receptor receptors are active targets of drug discovery efforts.
subtypes. Except for the 5-HT receptor, all of these receptors A good example of the approaches used to define the role of
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are metabotropic. The ionotropic 5-HT receptor exerts a rapid these peptides in the CNS comes from studies on substance P and
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excitatory action at a very limited number of sites in the CNS. its association with sensory fibers. Substance P is contained in and
In most areas of the CNS, 5-HT has a strong inhibitory action. released from small unmyelinated primary sensory neurons in the
This action is mediated by 5-HT receptors and is associated spinal cord and brain stem and causes a slow excitatory postsyn-
1A
with membrane hyperpolarization caused by an increase in potas- aptic potential in target neurons. These sensory fibers are known
sium conductance. It has been found that 5-HT receptors and to transmit noxious stimuli, and it is therefore surprising that—
1A
GABA receptors activate the same population of potassium although substance P receptor antagonists can modify responses to
B
channels. Some cell types are slowly excited by 5-HT owing to its certain types of pain—they do not block the response. Glutamate,
blockade of potassium channels via 5-HT or 5-HT receptors. which is released with substance P from these synapses, presumably
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Both excitatory and inhibitory actions can occur on the same plays an important role in transmitting pain stimuli. Substance P
neuron. 5-HT has been implicated in the regulation of virtually is certainly involved in many other functions because it is found in
all brain functions, including perception, mood, anxiety, pain, many areas of the CNS that are unrelated to pain pathways.
sleep, appetite, temperature, neuroendocrine control, and aggres-
sion. Given the broad roles of 5-HT in CNS function and the Orexin
rich molecular diversity of 5-HT receptors, it is not surprising that
many therapeutic agents target the 5-HT system (see Chapters 16, Orexins are peptide neurotransmitters produced in neurons in
29, 30, and 32). the lateral and posterior hypothalamus that, like the monoamine
systems, project widely throughout the CNS. Orexins are also
D. Histamine called hypocretins due to the near simultaneous discovery by
In the CNS, histamine is exclusively made by neurons in the two independent laboratories. Like most neuropeptides, orexin is
tuberomammillary nucleus (TMN) in the posterior hypothala- released from large, dense core vesicles and bind to two G protein-
mus. These neurons project widely throughout the brain and coupled receptors. Orexin neurons also release glutamate and are
spinal cord where they modulate arousal, attention, feeding thus excitatory. The orexin system, like the monoamine systems,
behavior, and memory (see Chapter 16). There are four histamine projects widely throughout the CNS to influence physiology and
to H ), all of which are metabotropic. Centrally act- behavior. In particular, orexin neurons exhibit firing patterns asso-
receptors (H 1 4
ing antihistamines are generally used for their sedative properties, ciated with wakefulness and project to and activate monoamine
and antagonism of H receptors is a common side effect of many and acetylcholine neurons involved in sleep-wake cycles (see also
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drugs including some tricyclic antidepressants and antipsychotics. Chapter 22). Animals lacking orexin or its receptors have narco-
lepsy and disrupted sleep-wake patterns. In addition to promoting
Neuropeptides wakefulness, the orexin system is involved in energy homeostasis,
feeding behaviors, autonomic function, and reward.
A great many CNS peptides have been discovered that produce
dramatic effects both on animal behavior and on the activity of Other Signaling Substances
individual neurons. In many cases, peptide hormones discovered
in the periphery (see Chapter 17) also act as neurotransmitters in A. Endocannabinoids
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the CNS. As most of these peptides were initially named based The primary psychoactive ingredient in cannabis, Δ -
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on their peripheral functions, the names are often unrelated to tetrahydrocannabinol (Δ -THC), affects the brain mainly by