RAMB Julho/Agosto 2015

ostardi

JVV

384

ssoc

ras

2015; 61(4):381-387

crease ethanol consumption.

32,33,40-42

The overproduction

of the 5-HT1B receptor is supposed to produce more sig-

nificant changes. On the other hand, inhibition of the

5-HT3 receptor has been shown to substantially reduce

alcohol consumption.

The effects of ethanol on the dopaminergic system in-

directly activate serotoninergic pathways as demonstrat-

ed by the observation that these effects can be attenuated

by 5-HT3 receptor antagonists.

The relationship between

ethanol and 5-HT3 receptors has also been demonstrated

in studies focusing on the theory that low 5-HT levels in

the brain are a risk factor for alcoholism.

Some active in-

gredients of drugs, such as ondansetron, a 5-HT3 antago-

nist, are successful in reducing alcohol consumption.

46-48

Buspirone, a partial 5-HT1A receptor agonist, also exerts

a reducing effect on alcohol consumption.

Taken togeth-

er, these studies show that the function and localization

of different types of serotonin receptors determine their

role in the modulation of alcohol consumption.

Effects of alcohol on the endocannabinoid system

Alcohol tolerance and addiction are associated with the

endocannabinoid system. This system consists of canna-

binoid receptors coupled to G proteins and endogenous

cannabinoids (arachidonyl ethanolamine and 2-arachid-

onyl glycerol).

40,50-52

The best known receptors are CB1

and CB2. The CB1 receptor is widely distributed in the

brain and is located in the presynaptic terminal. This re-

ceptor is responsible for the main psychoactive effects of

cannabinoids. The CB2 receptor mainly mediates periph-

eral effects and its expression plays an important role in

the immune system.

New therapeutic agonists of this

receptor have shown a great potential in the treatment of

alcoholic liver diseases.

The higher density of CB1 receptors in certain brain

regions may explain the involvement of this neurotrans-

mission system in the main effects of ethanol. The high

concentration of this receptor in basal ganglia and in the

cerebellummay be responsible for alcohol-induced motor

incoordination. The presence of the CB1 receptor in the

hippocampus and in different regions of the cerebral cor-

tex may explain cognitive deficits and recent amnesia.

This relationship occurs by the understanding of the

relationship between endocannabinoids and ethanol,

based on the observation of independent studies that the

chronic administration of ethanol increased the concen-

trations of fatty acid esters in the brain.

54,55

The latter are

used for the production of arachidonyl ethanolamine,

whose degradation was inhibited by ethanol through

blockade of the microsomal transporter.

Other studies

demonstrated increased levels of the endocannabinoid

2-arachidonyl glycerol after chronic exposure to ethanol.

With respect to the effects of alcohol on CB1 receptors, it

is known that chronic ethanol consumption or adminis-

tration reduces the expression of these receptors in dif-

ferent brain regions,

58,59

in addition to compromising sig-

nal transduction by decreasing the affinity of this receptor

for its G protein.

Effects of alcohol on voltage-dependent Ca

channels

Another central action of alcohol related to motor coor-

dination is its effect on voltage-dependent Ca

channels.

These channels play an important role in cell depolariza-

tion and repolarization. In addition, they regulate a series

of cellular activities, including the release of neurotrans-

mitters. Alcohol mainly acts on L-type calcium channels,

inhibiting the opening of these channels. The lower in-

flux of positively charged ions into the cell renders it less

excitable, in addition to inhibiting the release of neu-

rotransmitters. A larger number of these channels are

found in cerebellum. Therefore, the action of alcohol in

this region may explain the motor incoordination such

as unsteady gait, attention deficits, and impaired sleep-

wake regulation.

Effects of alcohol on GIRK channels

Another important effect of alcohol on the nervous sys-

tem involves the activation of a specific type of potassium

(K) channel, called G protein-coupled inwardly-rectifying

K (GIRK) channels. However, the molecular mechanism

underlying this activation is not fully understood. GIRK

channels possess specific structures that permit binding

to the alcohol molecule. These structures mediate the al-

cohol-induced activation of GIRK channels, but do not

influence the inhibition of these channels.

Since they are

proteins present on the plasma membrane of nerve cells

that form K-selective pores, a neuron frequently express-

es multiple types of K channels, which exert different

functions in cell signaling. Many ion channels, such as

those mediated by neurotransmitters (e.g., serotonin), are

sensitive to ethanol and other alcohols. It can, therefore,

be speculated that the excitation of these channels is as-

sociated with increased alcohol consumption.

Effects of alcohol on neurosteroids

Several neuroactive steroids exhibit rapid non-genomic

activity in the CNS. These rapid mechanisms of action

include the modulation of NMDA and GABA

receptor

activity. Studies have shown that positive or negative al-

losteric modulators of the NMDA receptor complex bind