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

634 2006). Acutely, ethanol results in GABA release; chronic heavy use
alters the pattern of expression of genes impacting on GABA A
subunits.
Intoxication with ethanol can be viewed as a GABA-rich state,
and withdrawal phenomena are related in part to GABA A
activity
deficiencies. Several GABA A
receptor gene polymorphisms correlate
with a predisposition toward heavy drinking and alcohol use disorders
(Dick et al., 2006a,b).
The nicotinic ACh receptor is also sensitive to
the effects of ethanol. Drinking acutely increases ACh in the ventral
tegmental area, with a subsequent increase in DA in the nucleus
accumbens (Joslyn et al., 2008). Varenicline, a partial agonist at the
4
2
subtype of the nicotininc ACh receptor (Chapter 11), decreases
ethanol-seeking behavior and ethanol consumption in a rodent
model, similar to its actions to effects on nicotine dependence
(Steensland et al., 2007). Effects of ethanol on these receptors may
be particularly important because there is an association between
nicotine exposure (smoking) and alcohol consumption in humans.
Furthermore, several studies indicate that nicotine increases alcohol
consumption in animal models (Smith et al., 1999).
Excitatory ionotropic glutamate receptors are divided into the
N-methyl-D-aspartate (NMDA) and non-NMDA receptor classes, with
the latter consisting of kainate- and AMPA-receptor subtypes (see
Chapter 14). Ethanol inhibits the function of the NMDA- and kainatereceptor
subtypes; AMPA receptors are largely resistant to alcohol
(Carta et al., 2003). As with the GABA A
receptors, phosphorylation of
the glutamate receptor can modulate sensitivity to ethanol.
A number of other types of channels are sensitive to alcohol
at concentrations routinely achieved in vivo. Ethanol enhances the
activity of large conductance, Ca 2+ -activated K + channels in neurohypophyseal
terminals (Dopico et al., 1999), perhaps contributing
to the reduced release of oxytocin and vasopressin after ethanol consumption.
Ethanol inhibits N- and P/Q-type Ca 2+ channels in a manner
that can be antagonized by channel phosphorylation by PKA
(Solem et al., 1997). BK (Maxi-K, slo1) channels also are a target for
alcohol action (Davies et al., 2003). G protein-gated inwardly rectifying
K + channels (GIRK or Kir channels) can be activated by the βγ
subunits of the G i
/G o
family, by PIP 2
, and, via a different mechanism,
by alcohols. Small alcohols bind to a hydrophobic binding
pocket on GIRKs, leading to channel activation via stabilization of
the open conformation (Aryal et al., 2009).
SECTION II
NEUROPHARMACOLOGY
Other Neurotransmitter Systems. Dopamine-related systems have
central importance regarding the feelings of reward and craving associated
with all intoxicating substances (Koob and Kreek, 2007). Of
special importance are alterations in DA activity in the ventral
tegmental and related areas, especially the nucleus accumbens,
which are likely to play a major role in feelings of euphoria and
reward. Acute alcohol results in an increase in synaptic DA; repeated
administration is associated with changes in both D 2
and D 4
receptors
that may be important in the perpetuation of alcohol use as well
as in relapse (Voronin et al., 2008).
The impact of ethanol on dopaminergic pathways is closely
linked to changes in stress-related systems. These changes are
hypothesized to relate to reinforcement from beverage alcohol and
other drugs of abuse, as well as withdrawal symptoms and negative
moods related to problems with regulation of the DA-rich
brain reward systems. Dopaminergic activity in the nucleus
accumbens is affected by multiple types of opioid receptors, and
acute ethanol causes the release of endorphins (Job et al., 2007).
These actions subsequently activate μ opioid receptors in the ventral
tegmentum and nucleus accumbens, with associated release
of DA. Thus, many of the effects of alcohol on reward systems,
and changes in how the CNS reacts to ethanol (including sensitization),
may relate to alterations in opioid systems (Pastor and
Aragon, 2006).
The acute administration of ethanol is associated with a significant
increase in 5-HT in the synaptic space; continued use of
ethanol produces an up-regulation of 5-HT receptors. Lower levels
of 5-HT in the synapse, perhaps related to a more rapid reuptake by
the 5-HT transporter, is associated with higher levels of alcohol
intake and, potentially, lower levels of intensity of reaction to beverage
alcohol (Barr et al., 2005). Changes in DA systems are likely
to relate to alterations in 5-HT as well.
Cannabinoid receptors, especially CB 1
encoded by the gene
CNR1, are also affected by ethanol (Hutchinson et al., 2008; Perra
et al., 2008). CB 1
is a GPCR that is densely represented in the ventral
tegmentum, nucleus accumbens, and prefrontal cortex.
Activation of CB 1
occurs with acute ethanol administration and
affects the release of DA, GABA, and glutamate, and reward circuits
of the brain. Antagonists of CB 1
receptors, such as rimonabant, may
block the effect of ethanol on dopaminergic systems.
Protein Kinases and Signaling Enzymes. Knockout mice lacking
the isoform of PKC display reduced effects of ethanol measured
behaviorally and a loss of enhancement by ethanol of GABA’s
effects measured in vitro (Harris et al., 1995). Intracellular signaltransduction
cascades, such as MAPK, tyrosine kinases, and neurotrophic
factor receptors, also are thought to be affected by ethanol
(Valenzuela and Harris, 1997). Translocation of PKC and PKA
between subcellular compartments also is sensitive to alcohol
(Constantinescu et al., 1999).
Ethanol enhances the activities of several isoforms of adenylyl
cyclase, with AC7 being the most sensitive (Tabakoff and
Hoffman, 1998). This promotes increased production of cyclic AMP
and thus increased activity of PKA. Ethanol’s actions appear to be
mediated by activation of G s
and promotion of the interaction
between G s
and adenylyl cyclase.
Ethanol Consumption and CNS Function. There are a series of relatively
common and temporary effects of ethanol with relatively high
prevalence rates reflecting changes in the GABA system that are
generally caused by CNS depressants. Large doses of ethanol can
interfere with encoding of memories, producing anterograde amnesias,
commonly referred to as alcoholic blackouts; affected individuals
are unable to recall all or part of experiences during the period
of heavy intake. At even 2-3 drinks, ethanol consumption can produce
disturbances in sleep architecture, with frequent awakenings
and restless sleep; high doses are associated with vivid and disturbing
dreams late as a consequence of earlier suppression of night rapid
eye movement dream state at higher blood ethanol levels. Perhaps
reflecting the effect of ethanol on respirations as well as the musclerelaxant
effects of this drug, heavier drinking can be associated with
sleep apnea, especially in older alcohol-dependent subjects (Sakurai
et al., 2007). The transient CNS effects of heavy ethanol consumption
that produce a hangover—the “next morning” syndrome of
headache, thirst, nausea, and cognitive impairment—contribute to
much time lost from work and school, and may reflect mechanisms