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

knockout mice display marked reductions in locomotor activity, initiation
of movement, and rearing behaviors. This reduction in motor
activity is also present in mice that are specifically lacking only the
D 2L
receptor, indicating that the D 2S
isoform plays a lesser role in
regulation of movement and is not able to compensate for the lack
of D 2L
receptor. The D 3
and D 4
receptor knockout animals display
unique locomotor alterations in response to novel environments.
However, these changes may be related to novelty-seeking behavior
rather than actual motor impairments.
Reward: Implications in Addiction. In general, drugs of abuse
cause increased DA levels in the nucleus accumbens, an area critical
for rewarded behaviors. This role for mesolimbic DA in addiction
has led to numerous studies on abused drugs in DA receptor knockout
mice. Studies of D 1
receptor knockout mice show a reduction in
the rewarding properties of ethanol, suggesting that the rewarding
and reinforcing properties of ethanol are dependent, at least in part,
on the D 1
receptor. D 2
receptor knockout mice also display reduced
preference for ethanol consumption. Morphine also lacks rewarding
properties in D 2
knockout mice when measured by conditioned
place-preference or self-administration paradigms. However, mice
lacking the D 2
receptor exhibit enhanced self-administration of high
doses of cocaine. These data implicate a complex and drug-specific
role for the D 2
receptor in rewarding and reinforcing behaviors. The
D 3
receptor, highly expressed in the limbic system, has also been
implicated in the rewarding properties of several drugs of abuse.
However, D 3
knockout mice display drug-associated place preference
similar to wild-type mice following amphetamine or morphine
administration. Recently developed D 3
-selective ligands implicate a
role for the D 3
receptor in motivation for drug-seeking and in drug
relapse, rather than in the direct reinforcing effects of the drugs
(Heidbreder, 2008).
Cognition, Learning and Memory. Mice lacking the D 1
receptor
display deficits in multiple forms of memory. D 1
knockout mice have
impaired spatial memory using the Morris water maze as a read-out.
Deficits in prefrontal cortex-dependent working memory occur in
D 1
knockout mice, in agreement with pharmacological evidence that
cortical working memory can be modulated with D 1
agonists and
antagonists (Williams and Castner, 2006). Amphetamine administration
disrupts prepulse inhibition in wildtype animals but not in D 2
knockout animals. Prepulse inhibition is unaltered in mice lacking
only the D 2L
isoform of the receptor, indicating that the long and
short isoforms of the receptor may serve different purposes in sensorimotor
gating and higher order processing. These findings imply
an important role for the D 2
receptor in disorders with defects in sensorimotor
gating, most notably schizophrenia. Indeed, many of the
antipsychotic drugs used in the treatment of schizophrenia are high
affinity antagonists for the D 2
receptor.
DA Receptor Agonists and Antagonists
DA Receptor Agonists. DA receptor agonists are currently
used in the treatment of PD, restless leg syndrome,
and hyperprolactinemia. One of the primary
limitations to the therapeutic use of dopaminergic agonists
is the lack of receptor subtype selectivity, that is,
stimulation of DA receptor subtypes not involved with
Table 13–7
Experimental Tools at DA Receptors
AGONIST
ANTAGONIST
D1-like Dihydrexidine SCH23390
SKF38393 SKF83566
D2-like 7-OH-DPAT Sulpiride
D 3
7-OH-PIPAT U99194
BP-897
D 4
PD168077 L-745,870
D 5
ADTN —
the disease causes an array of unpleasant side effects.
However, recent advances in receptor-ligand structurefunction
relationships have enabled the development of
subtype-specific drugs, many of which have already
proven to be useful experimental tools (Table 13–7).
Some ligands can preferentially activate one downstream
signaling cascade over another, a property
known as functional selectivity (Urban et al., 2007).
Furthermore, DA receptor activity can be modulated by
drugs that bind to allosteric sites on the receptor,
thereby enhancing or decreasing endogenous DA signaling
in a receptor-specific manner (Schetz, 2005).
All of these interactions between ligands and DA
receptors can be exploited in future drug development
endeavors to evoke a more specific receptor-mediated
response.
DA Receptor Agonists and Parkinson Disease. Parkinson disease
(PD), a neurodegenerative disorder of unknown etiology, is characterized
by extensive degeneration of dopaminergic neurons within
the substantia nigra, resulting in tremor, rigidity, and bradykinesia.
While the principal pharmacotherapy for PD is L-DOPA, limitations
to its therapeutic effects (Chapter 22) have generated intense interest
in developing alternative therapies for PD, with the intent of
either delaying the usage of L-DOPA or alleviating L-DOPA side
effects and restoring its efficacy. One treatment strategy is the use of
DA receptor agonists, which act directly on the depleted nigrostriatal
dopaminergic system and have fewer undesirable side effects. DA
agonists can be used in conjunction with lower doses of L-DOPA in
a combined therapy approach. Two general classes of dopaminergic
agonists are used in the treatment of PD: ergots and non-ergots. The
pharmacological properties of these drugs are described below; their
use in the management of PD is described in Chapter 22.
D1/D2 Receptor Agonists: Ergot Allkaloids. Ergot derivatives are
nonselective compounds that act on several different neurotransmitter
systems, including DA, 5-HT, and adrenergic receptors. In the
U.S., bromocriptine (PARLODEL) and pergolide (PERMAX) are
approved for the treatment of PD (see Table 13–6 for structures);
however, their use has fallen out of favor because of the associated
risk for serious cardiac complications. Bromocriptine is a potent D 2
357
CHAPTER 13
5-HYDROXYTRYPTAMINE (SEROTONIN) AND DOPAMINE