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A
review
on
alcohol
:
from
the
central
action
mechanism
to
chemical
dependency
R
ev
A
ssoc
M
ed
B
ras
2015; 61(4):381-387
383
Effects of alcohol on opioid and dopaminergic transmission
Alcohol also exerts effects on the reward system through
the opioid and dopaminergic systems.
26
This effect is me-
diated by the release of dopamine in the ventral tegmen-
tal area and in the nucleus accumbens of the limbic sys-
tem.
19,27-29
A large number of natural opioid receptors are
found around these areas. There are three classes of opi-
oid receptors involved in opioid dependence: mu, delta
and kappa.
26,29
Opioids activate the reward system in an
indirect manner through two actions. The first consists
of the binding of opioids to opioid receptors within the
reward system.
27,29
This binding triggers a signal to re-
lease the neurotransmitter dopamine into the synaptic
cleft where it binds to D-1 and D-2 receptors of the nerve
cell, activating the reward system in the CNS.
19,29,30
The
second action would be through the GABA system, which
inhibits the release of dopamine. However, opioids block
the action of this system. As a consequence, the effects of
dopamine become more potent and long lasting.
31
With-
in this context, alcohol acts directly on these opioid re-
ceptors, with the description of a positive effect on mu
opioid receptors, which is related to the feeling of plea-
sure and stimulation of dopamine release, and a negative
effect on delta receptors, increasing alcohol addiction.
Studies also report that alcohol can increase the number
of beta opioid receptors, which stimulate the release of
dopamine. Therefore, the opioid system acts directly on
the reward system and is associated with the development
of addiction.
29
Effects of alcohol on serotoninergic transmission
Serotonin (5-HT) and endorphins seem to contribute to
the symptoms of well-being and mood elevation observed
in alcohol intoxication.
25,32-34
Many studies have analyzed
the effects of alcohol on serotonin neurotransmission in
the brain. These studies showed that serotonin transmis-
sion is increased after the acute administration of alcohol
and reduced during alcohol withdrawal.
33,35
Reduced neu-
rotransmission of serotonin in dependent animals might
be associated with relapse. For example, when serotonin
neurotransmission was inhibited by the injection of a GA-
BA
A
receptor agonist into the brainstem (which reduces
serotonin activity), the consumption of alcohol by the an-
imals was lower.
36
There are several serotonin receptor sub-
types
37
and serotonin may affect alcohol consumption by
the activation of specific receptors.
32,33
In this respect, ac-
tivation of 5-HT2C or 5-HT1A receptors has been shown
to reduce alcohol consumption.
32,33,38,39
However, contro-
versy exists in the literature, showing that both an increase
and a decrease in 5-HT1B receptor production can in-
such as influx through ionotropic receptor channels, in-
flux through voltage-sensitive calcium channels which
are activated by membrane depolarization, and the release
of Ca
2
from endoplasmic reticulum stores. The last mech-
anism is controlled by the ryanodine receptor, which is
activated by intracellular Ca
2
concentrations.
18
This in-
crease in intracellular Ca
2
can lead to attention deficits
and impaired sleep-wake regulation in the
locus coeruleus
and even to the blackout phenomenon in the hippocam-
pus.
19
Recent studies have shown that Ca
2
increases, me-
diated by the activation of AMPA/kainate receptors,
metabotropic receptors and K depolarization, are altered
by the acute administration of ethanol to cultured cere-
bellar Purkinje neurons, which are known to possess abun-
dant Ca
2
channels.
3
In this respect, it was demonstrated
that the administration of an AMPA receptor agonist in-
creases Ca
2
concentrations in the somatic and dendritic
regions of Purkinje neurons; however, ethanol altered this
response in a dose-dependent manner. No effect was ob-
served at a dose of 10 mM, whereas doses of 33 and 66
mM caused a significant reduction. Similarly, metabo-
tropic receptor agonists also increased Ca
2
-concentrations
in the two regions of Purkinje neurons. However, these
signals were enhanced by the administration of 10 mM
ethanol, but not of 33 or 66 mM. The results of that study
suggest that the components of the Ca
2
-signaling path-
way that are sensitive to ethanol are located in Purkinje
neurons. Ethanol exerts a maximum effect on AMPA re-
ceptors at a dose of 33 mM and the activation of metabo-
tropic receptors is highly sensitive to the acute effect of
ethanol. However, ethanol sensitivity related to glutama-
tergic transmission probably depends on the glutamate
receptor subtype, since the Ca
2
signals related to the ac-
tivation of ionotropic and metabotropic receptors vary
in sensitivity and in the response to ethanol.
18
On the oth-
er hand, the NMDA receptor is the main receptor involved
in neuronal death due to increased permeability of the
Ca
2
channel associated with this receptor.
20-22
This recep-
tor has been suggested to play an important role in the
neurotoxicity observed in alcohol abuse and in alcohol
withdrawal syndrome. This neurotoxicity is related to a
decrease in mitochondrial membrane potential and in Na
/K ATPase and Mg2 -ATPase activity.
12,23,24
In contrast, the long-term use of alcohol leads to an
increase in glutamatergic receptors in the hippocampus,
an area that is important for memory and that is involved
in seizures.
5
As a consequence, during alcohol withdraw-
al the glutamate receptors that were accustomed to the
continuous presence of alcohol become hyperactive and
can trigger seizures or even strokes.
25