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

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SECTION II
NEUROPHARMACOLOGY
Mesocortical Mesolimbic Nigrostriatal
Tuberoinfundibular
Figure 13–9. Major DA pathways in brain.
detrimental movement side effects associated with dopaminergic
therapy, including tardive dyskinesia. DA released in the tuberoinfundibular
pathway is carried by the hypophyseal blood supply to the
pituitary, where it regulates prolactin secretion.
Electrophysiology. DA receptors regulate multiple distinct voltagegated
ion channels that impact firing of action potentials and neural
transmission. D1-like receptor activation modulates Na + , as well as
N-, P- and L-type Ca 2+ currents, via a PKA-dependent pathway. D2
receptors regulate K + currents. DA also modulates the activity of ligand-gated
ion channels, including NMDA and AMPA receptors. As
such, DA is not a classical excitatory or inhibitory neurotransmitter,
but rather acts as a modulator of neurotransmission. A lack of subtypespecific
ligands, and overlapping expression patterns, makes investigation
of individual DA receptors difficult. As a consequence, most
studies have investigated D1 and D2 families of receptors (with family-specific
ligands) in discrete brain regions, especially the striatum
and prefrontal cortex.
Dopaminergic neurons are strongly influenced by excitatory
glutamate and inhibitory GABA input. In general, glutamate inputs
enable burst-like firing of dopaminergic neurons, resulting in high
concentrations of synaptic DA. GABA inhibition of DA neurons
causes a tonic, basal level of DA release into the synapse (Goto et al.,
2007). Interestingly, DA release also modulates GABA and glutamate
neurons, thus providing an additional level of interaction and
complexity between DA and other neurotransmitters. Strong phasic
or slow tonic release of DA, and the subsequent activation of DA
receptors, has differential effects on the induction of long-term
potentiation (LTP) and long-term depression (LTD). In the striatum,
phasic activation of DA neurons and stimulation of D1 receptors
favors LTP induction, while tonic DA release with concomitant
activation of both D1- and D2-like receptors favors LTD (Gerdeman
et al., 2003).
Roles of DA in Behavior: Lesioning and
Knockout Studies
For several decades, pharmacological agents have been
used to specifically ablate dopaminergic neurons. This
technique allowed functional characterization of discrete
dopaminergic brain regions in animal models.
More recently, the generation of knockout mice lacking
specific DA receptor subtypes has furthered understanding
of the dopaminergic system, from brain
regions to the functional impact of individual receptors
(Holmes et al., 2004; Sibley,1999). These tools, along
with dopaminergic ligands, have enabled exploration
of the broad-reaching effects of DA on physiological
processes and behaviors.
Locomotion: Models of Parkinson Disease (PD). In the early
1980s, several young people in California developed rapid-onset
parkinsonism. All of the affected individuals had injected a synthetic
analog of meperidine that was contaminated with 1-methyl-4-
phenyl-1,2,3, 6-tetrahydropyridine (MPTP). MPTP is metabolized
by MAO-B to the neurotoxic MPP + , which is selectively taken into
dopaminergic neurons by the DA transporter. Once inside the cell,
MPP + causes intra- and extracellular DA release, which is oxidized
to form quinones and reactive oxygen species that cause in neuronal
death. Because of the high specificity of MPP + for the DA transporter,
neuronal death is largely restricted to the substantia nigra and
ventral tegmental area, resulting in a phenotype remarkably similar
to Parkinson’s disease. 6-Hydroxydopamine (6-OHDA) is similar to
MPTP in both mechanism of action and utility as an animal model.
In contrast to MPTP, however, 6-OHDA does not cross the bloodbrain
barrier and it is not specific to dopaminergic neurons (it is also
a substrate for NET, the neuronal NE transporter). Thus, in animal
models of Parkinson disease, 6-OHDA must be injected intracranially
and co-administered with a blocker of NET. Lesioning animals
with MPTP or 6-OHDA results in tremor, grossly diminished
locomotor activity, and rigidity. As with Parkinson disease, these
motor deficits are alleviated with L-DOPA therapy or dopaminergic
agonists. These neurotoxins are valuable tools for studying potential
neuroprotective agents and novel treatment strategies, such as
neural grafting and stem cell transplantation; their effects underscore
the singular importance of the dopaminergic system in locomotor
activity and Parkinson disease.
Other pharmacological agents are also known to alter locomotor
activity via dopaminergic actions, including cocaine and amphetamine.
These drugs of abuse bind to DAT and inhibit reuptake of
synaptic DA. Amphetamine is a substrate for the transporter, blocks it
competitively, and enters the neuron, where it displaces (releases) DA
from vesicular stores, causing an efflux of DA from the neuronal
cytosol into the synapse, possibly by reversal of the DA transporter.
The accumulation of synaptic DA increases stimulation of DA receptors
and results in heightened locomotor activity. Mice lacking DAT
are hyperactive, and do not display increased locomotion in response
to cocaine or amphetamine treatment.
Targeted disruption of the DA receptor genes has revealed
specific information about the receptor subtypes that mediate locomotor
activity. Mice lacking the D 1
receptor show generalized alterations
in locomotor activity, although there is not good agreement
about the specific motor phenotype. Studies with D 1
receptor knockout
mice indicate that the D 1
receptor, but not the D 5
receptor, is
primarily responsible for the increase in locomotor activity that
occurs following administration of D1-family agonists. D 2
receptor