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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
385
to distinct sites on this receptor, which differ from the
binding sites of glycine, dizocilpine (MK-801), Mg2 and
spermine. Furthermore, pregnenolone sulfate and dehy-
droepiandrosterone sulfate, which are negative allosteric
modulators of the GABA
A
receptor, act as non-competi-
tive antagonists to reduce the activity of GABA
A
and gly-
cine receptors, whereas androsterone, progesterone, allo-
tetrahydrodeoxycorticosterone, allopregnanolone,
pregnenolone and epipregnanolone act as positive allo-
steric modulators of this receptor.
62
Recently, interactions of neurosteroids with the ef-
fects of ethanol have been demonstrated. Allopregnano-
lone was shown to decrease sleep latency and to increase
the ethanol-induced sleeping time, whereas pregneno-
lone sulfate and dehydroepiandrosterone sulfate reduced
sleep duration. In addition, an increase in blood allopreg-
nanolone levels induced by ethanol was demonstrated in
rats. With respect to the motor impairment caused by
ethanol, dehydroepiandrosterone sulfate exerts a stimu-
latory effect, whereas an inhibitory effect is observed for
allotetrahydrodeoxycorticosterone.
62
In view of their multiple relationships with alcohol,
these neuroactive steroids are studied for the treatment of
alcoholism and may be useful for the development of drugs
designed to minimize the effects caused by alcohol.
62
Tables 1, 2 and 3 summarize the neuronal pathways
that are stimulated and inhibited by alcohol, their respec-
tive neurotransmitters and/or signaling pathways, recep-
tors, and the effects induced by the presence of alcohol
in the CNS.
D
iscussion
and
conclusion
The results of this review show the multiple actions of al-
cohol on numerous central neurotransmission pathways,
highlighting its role as a potent “dirty drug” and a CNS
disorganizer. The results were organized in Tables 1 and 2,
according to the pathways activated or inhibited by alco-
hol, respectively. This approach permitted to associate
the classical biological actions of ethanol with the mo-
lecular signaling pathways involved. Among the central
actions stimulated by alcohol, its inhibitory gabaminer-
gic effect, in conjunction with the inhibition of certain
excitatory glutamatergic receptors, endocannabinoids,
cerebellar calcium channels and hippocampal proteins
(ERKs) which are essential for memory formation, results
in sedation, loss of inhibitions, relaxation, loss of cogni-
tive functions, attention deficit, impaired sleep-wake reg-
ulation (blackout effect), and the final state of psycho-
motor depression.
On the other hand, the excitatory action of alcohol
on mu receptors of the opioid system and subsequent ac-
tivation of the limbic system by dopamine and of 5-HT1B
receptors by serotonin result in the effect of well-being
and mood elevation. In addition, the down-regulation of
dopamine and GABA receptors explains the increase in
alcohol consumption and subsequent development of
chemical dependency.
Finally, a better understanding of the effect of 5-HT3
antagonists that are able to reduce alcohol consumption,
as well as of neurosteroids modulating gabaminergic re-
ceptors, should lead to the identification of new thera-
peutic perspectives. However, since dealing with the sub-
ject exhaustively was not the objective of this review, and
since many of the studies cited are very recent, it is likely
that interactions of alcohol with other neuronal path-
ways, as well as their interrelations, will be described in
the future.
R
esumo
Uma revisão sobre o álcool: do mecanismo de ação cen-
tral à dependência química
Introdução:
o álcool é uma substância psicotrópica de-
pressora do sistema nervoso central (SNC), que promo-
ve alteração simultânea de inúmeras vias neuronais, ge-
rando profundo impacto neurológico e traduzindo-se em
diversas alterações biológicas e comportamentais.
TABLE 1
Neurotransmission pathways stimulated by alcohol, their respective neurotransmitter and receptor, and biological
response induced in the central nervous system.
Neurotransmission pathway
(neurotransmitter)
Receptor
Biological effect
Gabaminergic (GABA)
Ionotropic: GABA
a
and GABA
c
4,35,37-39
Metabotropic: GABA
c
Inhibition of CNS, manifesting as sedation, loss of
inhibitions, and relaxation
4,34,36
Opioid (dopamine)
Mu
16,18-22
Pleasure, satisfaction, increased search for alcohol
19,22
Serotoninergic
5-HT3
48,49,56
Feeling of well-being and mood elevation
12,23,24,48,50
CNS: central nervous system.