DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

366 from the bloodstream into the brain, selective barriers to permeation (or biochemical), cellular, multicellular (or systems),
into and out of the brain also exist for small, charged molecules such and behavioral. Intensively exploited molecular and
as neurotransmitters, their precursors and metabolites, and some
biochemical approaches have been the traditional focus
drugs. These diffusional barriers are viewed as a combination of the
for characterizing drugs that alter behavior. Molecular
partition of solute across the vasculature (which governs passage by
definable properties such as molecular weight, charge, and discoveries provide biochemical probes for identifying
lipophilicity) and the presence or absence of energy- dependent transport
the appropriate neuronal sites and the mechanisms
systems (Chapter 5). Important exceptions are the specific
uptake transporters for amino acids. This accounts for the therapeutic
utility of L- dopa (levodopa) used for treatment of Parkinson disease.
through which neuronal processes are modified.
Identified targets for centrally acting drugs include ion
channels that mediate change in excitability induced by
The brain clears metabolites of transmitters into the neurotransmitters, neurotransmitter receptors to which
fluid- containing lateral ventricles by excretion via the acid transport
drugs bind to elicit biological responses, and transport
system of the choroid plexus. Substances that rarely gain access to
the brain from the bloodstream often can reach the brain when proteins that reaccumulate released transmitter. The
injected directly into the cerebrospinal fluid. Under certain conditions,
it may be possible to open the BBB, at least transiently, to per-
norepinephrine, dopamine, or serotonin (NET, DAT,
membrane transporters, including those selective for
mit the entry of chemotherapeutic agents. Cerebral ischemia and
inflammation also modify the BBB, increasing access to substances
that ordinarily would not affect the brain.
and SERT), accumulate released transmitter and package
it for reuse. Inhibition of reuptake increases the
concentration and dwell time of transmitter in the
synaptic space; serotonin selective reuptake inhibitors
Response to Damage: Repair and
Plasticity in the CNS
used for the treatment of depression and cocaine, which
inhibits the reuptake of DA, have dramatic effects.
Inhibition of vesicular storage (e.g., inhibition of
VMAT2 and storage of norepinephrine by reserpine)
leads to depletion of releasable neurotransmitter.
SECTION II
NEUROPHARMACOLOGY
Because the neurons of the CNS are terminally differentiated cells,
they do not undergo proliferative responses to damage, although
recent evidence suggests the possibility of neural stem cell proliferation
as a natural means for replacement of neurons in selected
areas of the CNS and as a means of therapeutic repair (Aimone et al.,
2010; Marchetto et al., 2010). In the CNS, unlike in the peripheral
nervous system, glia- associated proteins are not uniformly upregulated
following an injury. (Madinier A, et al., 2009). There are, in
addition, proteins in myelin like Nogo- A that are potent inhibitors
of axonal regeneration in the CNS (Giger et al., 2008).
INTEGRATIVE CHEMICAL
COMMUNICATION IN THE CNS
The principal role of the CNS is to integrate information
from a variety of external and internal sources, and
to coordinate the needs of the organism with the
demands of the environment. These integrative functions
transcend individual transmitter systems and
emphasize the means by which neuronal activity is normally
coordinated. Only through a detailed understanding
of these integrative functions, and their failure in
certain pathophysiological conditions, can effective and
specific therapeutic approaches be developed for neurological
and psychiatric disorders. A central concept of
neuropsychopharmacology is that drugs that influence
behavior and improve the functional status of patients
with neurological or psychiatric diseases act by
enhancing or blunting the effectiveness of one or a combination
of specific transmitters and channels.
Four research strategies provide the scientific substrates
of neuropsychological phenomena: molecular
Research at the cellular level identifies specific neurons and
their most proximate synaptic connections that may mediate a behavior
or the behavioral effects of a given drug. For example, research
into the basis of emotion exploits both molecular and behavioral
leads to identify the most likely brain sites at which behavioral
changes pertinent to emotion can be analyzed. Such research provides
clues as to the nature of the interactions in terms of interneuronal
communication (i.e., excitation, inhibition, or more complex
forms of synaptic interaction).
An understanding at the systems level is required to assemble
the structural and functional properties of specific central transmitter
systems, linking the neurons that make and release a given
neurotransmitter to its behavioral effects. While many such
transmitter- to- behavior linkages have been postulated, it has proven
difficult to validate the essential involvement of specific transmitterdefined
neurons in mediating specific mammalian behaviors.
Research at the behavioral level may illuminate the integrative phenomena
that link populations of neurons (often in an operationally
or empirically defined manner) into extended specialized circuits or
“systems” that integrate the physiological expression of a learned,
reflexive, or spontaneously generated behavioral response. The
entire concept of animal models of human psychiatric diseases rests
on the assumption that scientists can appropriately infer from observations
of behavior and physiology (heart rate, respiration, locomotion,
etc.) that the states experienced by animals are equivalent to
the emotional states experienced by human beings expressing similar
physiological changes (Cowan et al., 2000, 2002).
CNS Transmitter Discovery Strategies. The earliest transmitters
considered for central roles were acetylcholine (ACh) and norepinephrine
(NE), largely because of their established roles in the