become more sophisticated. At this point it is well to consider that the classical
definitions and concepts in this field have been undergoing considerable change, and
that the distinctions between neurotransmitters, cotransmitters, neuromodulators, and
neurohormonesoften become blurred. Many peptide hormones of the hypothalamus
and hypophysis, for instance, have been recognized as having neurotransmitter activity
at other sites, and neurohormones and the discipline of neuroendocrinology have
become increasingly important in the biosciences.
In recent decades, an explosive development in the discovery of cotransmitters has
greatly expanded our understanding of neurotransmission, and of the homeostatic equi-
librium that is regulated by aminergic and peptidergic cotransmitters even in systems as
simple as that of Hydra. Postsynaptically, cotransmitters can influence the same recep-
tor on the target, bind to two different receptors on the same target, or bind to two dif-
ferent receptors on two different targets. This multipotential reactivity may explain the
fact that some drugs and endogenous substances are partial agonists only: they may
miss the help of a cotransmitter that the full agonist receives. Cross-reactivity of
cotransmitter combinations may also explain the many side effects and shortcomings of
neuroactive drugs that have been designed without the benefit of knowing the complete
story ofin vivo processes at the target.
It should be kept in mind that a single synapse may operate with as many as four
transmitters simultaneously, in any combination of amine and peptide, or even peptide
and peptide, within the groupings shown. The peptide neurotransmitters are stored
separately, always in large synaptic vesicles; are synthesized in the cell body of the
neuron; and are transported to the synapse after post-translational processing by fast
(ATP-driven) transport systems. Amine neurotransmitters are synthesized in the synapse
and are stored in small or large vesicles. Different populations of the same type of
neurons may differ in their content of cotransmitters.
4.1.5 Neuronal Systems: Brain Structures Relevant to Drug DesignThe neuronal systems of vertebrates are divided into the central nervous system (CNS),
comprising the brain and the spinal cord, and the peripheral nervous system (PNS),
comprising the autonomic nervous system and sensorimotor nervous system that serve
the rest of the body.
Thebrain is really a collection of highly specialized components of enormous
anatomical complexity. The brains of different mammals are very different, and the evo-
lutionary changes in the brain are seen primarily as an increase in relative size and in
the complexity of cortical folding, thus increasing the area devoted to association(i.e.,
learning and decision making). A basic schematic illustration of the human brain is
shown in figure 4.4.
The central nervous system consists of the brain and spinal cord. The average adult
brain weighs 1250–1380 grams. The brain is divided into three gross parts: the brain-
stem, the cerebrum, and the cerebellum. Structurally, the brain may be likened to a bou-
quet of flowers with the cerebrum (as two cerebral hemispheres) “blossoming”
outwards above the brainstem; the cerebellum is attached at the back of the brainstem.
The brainstem consists of the following structures:medulla oblongata(at the lower
end where the brainstem meets the spinal cord),pons,mesencephalon(midbrain), and
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