Alcohol is a multiple-action depressor of the Central Nervous System, and the depression caused by it is dose-dependent. Although alcohol is mainly used because of its stimulating action, this action is only apparent and happens only with moderate doses. It results from the depression of inhibitory controlling mechanisms. Under the effect of alcohol the cortex is freed from its integrative role, thus resulting confuse and disorganized thinking, as well as disruption of adequate motor control.
Ethanol diffuses through lipids, modifying proteins fluidity and functions. High concentrations of ethanol can decrease the eletron-transporting functions of the Na+K+/ATPase pump, thus impairing electrical conduction in the nerve cells.
Neuropharmacology of Alcohol
Only recently was it possible
to understand the neurobiological mechanisms responsible for many clinical
manifestations of alcoholism. Ethanol affects different cerebral neurotransmitters.
One of them is the inhibitory neurotransmitter gamma-aminobutyric acid
The interaction between ethanol and the GABA receptor is evident in studies showing decrease in the symptoms of alcoholic-withdrawal syndrome by the use of substances that increase GABA activity, like GABA-reuptake blockers and benzodiazepines, thus demonstrating the possible influence of the GABAergic system on the physiopathology of human alcoholism.
Ethanol potentiates GABA-receptor actions via a mechanism independent of benzodiazepine-receptor.
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GABAergic pathways play an important inhibitory action on the other neuronal pathways. GABA-receptor is associated with the chloride channel and the benzodiazepine receptor, making up a functional complex. When GABA binds to its receptor, it promotes an increase in the opening frequency of chloride channels, thus allowing a greater flow of this ion to the intracellular medium, making it more negative, and thus promoting neuronal hyperpolarization.
Low alcohol concentrations could promote facilitation of GABAergic inhibition on the cerebral cortex and spinal cord.
Some phenomena observed in alcoholism, such as tolerance and dependence, could be explained by the effects consequent to chronic ethanol exposure.
The quick tolerance to the increased chloride influx mediated by GABA begins already in the first hours and becomes established during chronic alcohol use.
Alcohol selectively modifies the cerebral synaptic action of glutamate. The glutamatergic system, whose neurons use glutamate as neurotransmitter, and is one of the main excitatory pathways in the central nervous system, also seems to play a relevant role in the nervous alterations induced by ethanol. Glutamate is the major neuroexcitatory neurotransmitter in the brain, accounting for 40% of all synapses.
Post-synaptic actions of glutamate in the central nervous system are mediated through two types of receptor: One of them is the inotropic receptor, related to ionic channels causing neuronal depolarization. The second type of receptor is the metabotropic (since its answers need cellular signalization metabolic steps); its intracellular actions are mediated by G-protein.
One of the inotropic glutamate receptors has two families diferentially identified by their pharmacological, biophysical, and molecular characteristics. In the first family we find the NMDA (n-metil-D-aspartate receptor), voltage-dependent, that sustains the currents, and is associated with ion channels permeable to calcium, sodium and potassium. In the second family of glutamate receptors we find the AMPA/Ka, whose preferental agonist is a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid.
Glutamate participates in synaptic plasticity and in long term potentiation (LTP), and it seems to play a critical role in memory and cognition.
The prevailing eletrophysiological effect of ethanol is the reduction of excitatory glutamatergic neurotransmission. It has been observed that low concentrations of ethanol can inhibit the stimulating actions mediated by NMDA upon hippocampal cells in culture.
In concentrations associated to "in vivo" intoxication, ethanol inhibits NMDA receptor current.
These findings could also explaim part of the genesis of physical dependence to alcohol, through a process that is the opposite to that of GABA. That means that when ethanol is interrupted, glutamatergic pathways induce overexcitement of the central nervous system, causing convulsions, anxiety, and delirium.
Calcium influx into the cells has an important function in the release of neurotransmitters in the synaptic cleft, as well as in the activity of cellular second messengers. Ethanol, in concentrations of 25mM, seems to inhibit calcium flow through ionic channels, thus decreasing neurotransmitters release. This could also be one of the mechanisms responsible for dependence and tolerance, because when alcohol-intake is stopped these ionic channels would increase calcium influx and, consequently, neurotransmission, giving rise to signs and symptoms of withdrawal syndrome.
See abstracts on alcoholism