RAMB Julho/Agosto 2015

ostardi

JVV

382

ssoc

ras

2015; 61(4):381-387

ethods

For this study, books and articles published in printed

and electronic journals of the PubMed, Medline and Sci-

elo databases were searched, using the following Health

Sciences Descriptors (DeCS) and Medical Subject Head-

ings (MeSH): alcohol, receptor, and central action.

A total of 159 studies on the effect of alcohol on the

CNS were reviewed and 62 were selected, with priority be-

ing given to articles published over the last 15 years. Ar-

ticles investigating the systemic actions of alcohol in the

organism, articles describing only alcohol-induced genet-

ic and structural modifications in receptors, and articles

not reporting interactions with specific receptors or the

biological effects induced by the interaction of alcohol

with the CNS were excluded.

esults

Effects of alcohol on gabaminergic and glutamatergic

transmission

Alcohol is a psychotropic depressant of the CNS.

3,4

This

property is associated with the action of alcohol on dif-

ferent neurotransmitters, including the stimulation of

gamma-aminobutyric acid (GABA), the main inhibitory

neurotransmitter of the CNS, and the inhibition of glu-

tamate, the main central excitatory neurotransmitter. Al-

cohol potentiates the effects of GABA by acting directly

on its receptors, enhancing their inhibitory effects.

These

inhibitory effects include sedation, loss of inhibitions

and relaxation, and might be related to the production

of certain neurosteroids, such as allopregnanolone. The

latter may be a mediator of these effects in the brain, since

neuroactive steroids are positive allosteric modulators of

neurotransmitter receptors, such as GABA

The GABA

receptor-ionophore complex is widely dis-

tributed throughout the CNS and its activation causes

opening of chloride channels, with consequent hyperpo-

larization of the membrane and production of a postsyn-

aptic inhibitory potential.

This receptor consists of var-

ious classes of subunits (a, b, g, d, and r) that confer

different pharmacological properties.

7-9

In studies on eth-

anol-dependent animals, messenger RNA (mRNA) levels

of the a1 and a2 subunits of the GABA

receptor were

found to be significantly reduced, whereas a significant

increase was observed in mRNA levels of the a4, g1 and

g2S subunits.

In contrast, conflicting results have been

reported in other studies also using chemically dependent

animals, i.e., low levels of a4 peptides and no difference

in the levels of subunit g2.

10,11

These results suggest that

changes in the expression of GABA

receptor subunit

genes lead to populations of receptors with properties

that differ from the non-ethanol-dependent state.

this respect, molecular biology studies using Xenopus lae-

vis oocytes indicate that ethanol only potentiates recep-

tors that contain the long variant of the g2 subunit. Since

only the long, but not the short, subunit possesses a phos-

phorylation site, it is possible that the phosphorylation

state is important for the inhibitory effect of ethanol.

In the case of long-term alcohol use, GABA receptor

down-regulation reduces the number of receptors, an event

that would explain the effect of alcohol tolerance, i.e., the

fact that individuals require higher doses of alcohol to

achieve the same symptoms of inhibition as obtained pre-

viously with lower doses.

13,14

The loss of inhibitory effects

and GABA receptor deficiency result in withdrawal symp-

toms.

Studies also indicate that the long-term use of alco-

hol causes detectable memory impairments, mainly by

reducing hippocampal mass mediated by GABA.

The

hippocampus is related to explicit memories, i.e., memo-

ries we can talk about, such as last night’s dinner or the

date of a historical event. Explicit memory involves the

conscious recollection of information. The hippocampus

is known to be necessary for the acquisition of this type

of memory, since damage to this region prevents individ-

uals from establishing new explicit memories.

Howev-

er, it is possible to recover older explicit memories that

were stored before the damage had occurred. A key ele-

ment in these events is a signal transduction pathway me-

diated by Mitogen-Activated Protein Kinases (MAPK).

MAPKs are important, signaling proteins that are acti-

vated by neurotransmitters and different growth factors.

One member of this family is extracellular signal-regu-

lated kinase (ERK). The ERK cascade is used in all brain

regions where synaptic plasticity occurs and its activation

is needed for the formation of new memories. If ERK ac-

tivity is blocked by the injection of an inhibitor into a cer-

tain brain region, such as the amygdala, the formation of

all modes of learning associated with this structure will

be blocked. Similarly, the blockade of ERK activity in the

hippocampus prevents the hippocampal formation of ex-

plicit memories. Excessive alcohol consumption suppress-

es the phosphorylation of these protein kinases (ERK),

which is regulated by GABA.

Thus, ethanol abuse pre-

vents activation of the memory circuit, in this case, the

explicit memory supported by the hippocampus.

In the case of glutamate, the loss of ionotropic (AMPA,

kainate or NMDA) and metabotropic receptors (rM1, rM8)

leads to a reduction in excitatory glutamatergic neuro-

transmission.

The activation of ionotropic receptors in-

creases intracellular calcium (Ca

) through different routes,