Page 394 - Basic _ Clinical Pharmacology ( PDFDrive )

380 SECTION V Drugs That Act in the Central Nervous System

B. Nitric Oxide
Presynaptic
neuron 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. Although a physiologic role
for nitric oxide has been clearly established for vascular smooth
muscle, its role in synaptic transmission and synaptic plasticity
CB 1 remains controversial. Nitric oxide diffuses freely across mem-
branes and thus has been hypothesized to be a retrograde messen-
ger, 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
2-AG in the cerebellum.

Exogenous C. Purines
cannabinoids
α 2-AG (e.g. THC) Receptors for purines, particularly adenosine, ATP, UTP, and
β γ DAG
PLC DAG UDP, are found throughout the body, including the CNS.
lipase High concentrations of ATP are found in and released from
mGluR1/5
catecholaminergic synaptic vesicles, and ATP may get converted
to adenosine extracellularly by nucleotidases. Adenosine in the
CNS acts on metabotropic A receptors. Presynaptic A recep-
1
1
tors inhibit calcium channels and inhibit release of both amino
acid and monoamine transmitters. ATP co-released with other
neurotransmitters can bind to two classes of receptors. The P2X
Postsynaptic
neuron family of ATP receptors includes nonselective ligand-gated cation
channels, whereas the P2Y family is metabotropic. The physi-
FIGURE 21–8 Endogenous cannabinoid system. Activation of ological roles for ATP co-release remain elusive, but pharmaco-
postsynaptic group I metabotropic glutamate receptors (mGluR1/5) logical studies suggest these receptors are involved in memory,
leads to the G protein-mediated membrane-delimited activation of wakefulness, and appetite and may play roles in multiple neuro-
phospholipase C (PLC) that produces the second messengers inositol psychiatric disorders.
trisphosphate (IP 3 , not shown) and diacylglycerol (DAG). DAG can
then be converted to the endogenous cannabinoid 2-arachidon- REFERENCES
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