A review on alcohol: from the central action mechanism to chemical dependency

alcohol is a psychotropic depressant of the central nervous system (CNS) that promotes simultaneous changes in several neuronal pathways, exerting a profound neurological impact that leads to various behavioral and biological alterations.

Objectives:

to describe the effects of alcohol on the CNS, identifying the signaling pathways that are modified and the biological effects resulting from its consumption.

Methods:

a literature review was conducted and articles published in different languages over the last 15 years were retrieved.

Results:

the studies reviewed describe the direct effect of alcohol on several neurotransmitter receptors (gamma-aminobutyric acid [GABA], glutamate, endocannabinoids AEA and 2-AG, among others), the indirect effect of alcohol on the limbic and opioid systems, and the effect on calcium and potassium channels and on proteins regulated by GABA in the hippocampus.

Discussion and conclusion:

the multiple actions of alcohol on the CNS result in a general effect of psychomotor depression, difficulties in information storage and logical reasoning and motor incoordination, in addition to stimulating the reward system, a fact that may explain the development of addiction. Knowledge on the neuronal signaling pathways that are altered by alcohol allows the identification of effectors which could reduce its central action, thus, offering new therapeutic perspectives for the rehabilitation of alcohol addicts.

Keywords:
alcohol-induced disorders; nervous system; neurotransmitter receptors

Neurotransmission pathway (neurotransmitter)	Receptor	Biological effect
Gabaminergic (GABA)	Ionotropic: GABAa and GABAc ⁴4 Álcool. In: Diehl A, Cordeiro DC, Laranjeira R (eds.). Dependência química: prevenção tratamento e políticas públicas. 1.ed. Porto Alegre: Artmed, 2011. p.129-44.^,³⁵35 Laranjeira R, Nicastri S, Jerônimo C, Marques AC. Consenso sobre a síndrome de abstinência do álcool (SAA) e o seu tratamento. Rev Bras Psiquiatr. 2000; 22(2):62-71.^,³⁷37 Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav. 2002; 71(4):533-54. 38 Sartania N, Strange PG. Role of conserved serine residues in the interaction of agonists with D3 dopamine receptors. J Neurochem. 2002; 72(6):2621-4.^-³⁹39 Tomkins DM, Joharchi N, Tampakeras M, Martin JR, Wichmann J, Higgins GA. An investigation of the role of 5-HT2C receptors in modifying ethanol self-administration behaviour. Pharmacol Biochem Behav. 2002; 71(4):735-44.Metabotropic: GABAc	Inhibition of CNS, manifesting as sedation, loss of inhibitions, and relaxation⁴4 Álcool. In: Diehl A, Cordeiro DC, Laranjeira R (eds.). Dependência química: prevenção tratamento e políticas públicas. 1.ed. Porto Alegre: Artmed, 2011. p.129-44.^,³⁴34 Boullosa O, Lopez-Mato AM. Recent advances in the serotonin neurotransmitters configuration. Psiquiatr Biol. 1995; 3(3):37-51.^,³⁶36 Lee R, Petty, F, Coccaro, EF. Cerebrospinal fluid GABA concentration: Relationship with impulsivity and history of suicidal behavior, but not aggression, in human subjects. J. Psychiatry Res. 2008; 43(4):353-9.
Opioid (dopamine)	Mu¹⁶16 Young C, Straiko MM, Johnson SA, Creeley C, Olney JW. Ethanol causes and lithium prevents neuroapoptosis and suppression of perk in the infant mouse brain. Neurobiol Dis. 2008; 31(3):355-60.^,¹⁸18 Gruol DL, Parsons KL, DiJulio N. Acute ethanol alters calcium signals elicited by glutamate receptor agonists and K depolarization in cultured cerebellar Purkinje neurons. Brain Res. 1997; 773(1):82-9. 19 Castro LA, Baltieri DA. Tratamento farmacológico da dependência do álcool. Rev Bras Psiq. 2004; 26(supl.):43-6. 20 Mayer M, Westbrook G. Permeation and block of NMDA receptor channels by divalent cations in mouse cultured central neurons. J Physiol. 1987; 394(1):501-27. 21 Hartley DM, Kurth MC, Bjerkness L, Weiss JH, Choi DW. Glutamate receptor-induced 45Ca2+ accumulation in cortical cell culture correlates with subsequent neuronal degeneration. J Neurosci. 1993; 13(5):1993-2000.^-²²22 Tymian M, Charlton MP, Carlen PL, Tator, CH. Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci. 1993; 13(5):2085-104.	Pleasure, satisfaction, increased search for alcohol¹⁹19 Castro LA, Baltieri DA. Tratamento farmacológico da dependência do álcool. Rev Bras Psiq. 2004; 26(supl.):43-6.^,²²22 Tymian M, Charlton MP, Carlen PL, Tator, CH. Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci. 1993; 13(5):2085-104.
Serotoninergic	5-HT3⁴⁸48 Kranzler HR, Pierucci-Lagha A, Feinn R, Hernandez-Avila C . Effects of ondansetron in early-versus late-onset alcoholics: a prospective, open-label study. Alcohol Clin Exp Res. 2003; 27(7):1150-5.^,⁴⁹49 Kranzler HR, Burleson JA, Del Boca FK, Babor TF, Korner P, Brown J, Bohn MJ. Buspirone treatment of anxious alcoholics. Arch Gen Psychiatry. 1994; 51(9):720-31.^,⁵⁶56 Basavarajappa BS, Saito M, Cooper TB, Hungund BL. Chronic ethanol inhibits the anandamide transport and increases extracellular anandamide levels in cerebellar granule neurons. Eur J Pharmacol. 2003; 466(1-2):73-83.	Feeling of well-being and mood elevation¹²12 Lovinger DM. Excitotoxicity and alcohol-related brain damage. Alcohol Clin Exp Res. 1993; 17(1):19-27.^,²³23 Clapp P, Bhave SJ, Hoffman PL. How adaptation of the brain to alcohol leads to dependence: a pharmacological perspective. Alcohol Res Health. 2008; 31(4):310-39.^,²⁴24 Chang-Mu C, Jen-Kun L, Shing-Hwa L, Shoei-Yn LS. Characterization of neurotoxic effects of NMDA and the novel neuroprotection by phytopolyphenols in mice. Behav Neurosci. 2010; 124(4):541-53.^,⁴⁸48 Kranzler HR, Pierucci-Lagha A, Feinn R, Hernandez-Avila C . Effects of ondansetron in early-versus late-onset alcoholics: a prospective, open-label study. Alcohol Clin Exp Res. 2003; 27(7):1150-5.^,⁵⁰50 Cocaína e crack. In: Diehl A, Cordeiro DC, Laranjeira R, Lacerda ALT, Junior AR, Bonadio AN, et al. (eds.). Dependência química. 1.ed. Porto Alegre: Artmed, 2011. p.170-9.

Neurotransmission pathway (neurotransmitter)	Receptor	Biological effect
Glutamatergic (glutamate)	Ionotropic: AMPA, kainate or NMDA²⁹29 Zaleski M, Morato GS, Silva VA, Lemos T. Aspectos neurofarmacológicos do uso crônico e da síndrome de abstinência do álcool. Rev Bras Psiquiatr. 2004; 26(1):40-2. Metabotropic: rM1, rM8²⁹29 Zaleski M, Morato GS, Silva VA, Lemos T. Aspectos neurofarmacológicos do uso crônico e da síndrome de abstinência do álcool. Rev Bras Psiquiatr. 2004; 26(1):40-2.	Reduced cognitive functions, attention deficit, and impaired sleep-wake regulation; blackout phenomenon²¹21 Hartley DM, Kurth MC, Bjerkness L, Weiss JH, Choi DW. Glutamate receptor-induced 45Ca2+ accumulation in cortical cell culture correlates with subsequent neuronal degeneration. J Neurosci. 1993; 13(5):1993-2000.^,²⁹29 Zaleski M, Morato GS, Silva VA, Lemos T. Aspectos neurofarmacológicos do uso crônico e da síndrome de abstinência do álcool. Rev Bras Psiquiatr. 2004; 26(1):40-2.^,⁴⁰40 Blednov IA, Cravatt BF, Boehm SL, Walker D, Harris RA. Role of endocannabinoids in alcohol consumption and intoxication: studies of mice lacking fatty acid amide hydrolase. Neuropsychopharmacol. 2007; 32(7):1570-82.^,⁴¹41 Hoplight BJ, Sandygren NA, Neumaier JF. Increased expression of 5-HT1B receptors in rat nucleus accumbens via virally mediated gene transfer increases voluntary alcohol consumption. Alcohol. 2006; 38(2):73-9.
Opioid (dopamine)	Delta¹⁶16 Young C, Straiko MM, Johnson SA, Creeley C, Olney JW. Ethanol causes and lithium prevents neuroapoptosis and suppression of perk in the infant mouse brain. Neurobiol Dis. 2008; 31(3):355-60.^,²²22 Tymian M, Charlton MP, Carlen PL, Tator, CH. Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci. 1993; 13(5):2085-104.	Reduced search for alcohol¹⁹19 Castro LA, Baltieri DA. Tratamento farmacológico da dependência do álcool. Rev Bras Psiq. 2004; 26(supl.):43-6.^,²²22 Tymian M, Charlton MP, Carlen PL, Tator, CH. Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci. 1993; 13(5):2085-104.
Endocannabinoid (AEA, 2-AG)	CB1, CB2²⁶26 Aminoff MJ. Neurology and General Medicine. 4.ed. Churchill Living, 2007.^,²⁷27 Gilpin NW, Koob GF. Neurobiology of alcohol dependence: focus on motivational mechanisms. Alcohol Res. Health. 2008; 31(3):185-95.	Motor incoordination, difficulty in logical reasoning²⁵25 Bittencourt AL. Mecanismo de ação do etanol: envolvimento de etanol, gaba e dopamina. Rev Psiq Clin. 2000; 27(1):26-31.
MAPK	ERKs¹³13 Beresford TP, Arciniegas DB, Alfers J, Clapp L, Martin B, Liu YDD, et al. Hippocampus volume loss due to chronic heavy drinking. Alcohol Clin Exp Res. 2006; 30(11):1866-70.	Loss of explicit memory⁸8 Gruol DL, Netzeband JG, Parsons KL. Calcium signals pathways linked to glutamate recptor activation in the somatic and dendritic regions of cultured cerebellar purkinje neurons. J. Neuropysiol. 1996; 76(5):3325-40.^,¹³13 Beresford TP, Arciniegas DB, Alfers J, Clapp L, Martin B, Liu YDD, et al. Hippocampus volume loss due to chronic heavy drinking. Alcohol Clin Exp Res. 2006; 30(11):1866-70.
Calcium channels	L-type in the cerebellum²²22 Tymian M, Charlton MP, Carlen PL, Tator, CH. Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci. 1993; 13(5):2085-104.	Unsteady gait and loss of spatial notion²²22 Tymian M, Charlton MP, Carlen PL, Tator, CH. Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci. 1993; 13(5):2085-104.
GIRK channels	Potassium channels²2 Heckmann W, Silveira CM. Dependência do álcool: aspectos clínicos e diagnósticos. In: Andrade AG, Anthony JC (eds.). O álcool e suas consequências, uma abordagem multiconcenitual. Barueri: Minha Editora, 2009. p.67-87.^,³3 Haes TM. Álcool e sistema nervoso central. Rev Fac Med Rib Preto. 2010; 43(2):153-63.	Altered neurotransmission²2 Heckmann W, Silveira CM. Dependência do álcool: aspectos clínicos e diagnósticos. In: Andrade AG, Anthony JC (eds.). O álcool e suas consequências, uma abordagem multiconcenitual. Barueri: Minha Editora, 2009. p.67-87.^,³3 Haes TM. Álcool e sistema nervoso central. Rev Fac Med Rib Preto. 2010; 43(2):153-63.

Neurosteroid	Action	Biological effect
Allopregnanolone	Positive allosteric modulator of GABA_A⁶²62 Barbosa ADE, Morato GS. Influência da epipregnanolona sobre a modulação da tolerância rápida ao etanol pelos neuroesteróides. Rev Bras Psiquiatr. 2007; 29(4):337-45.	Reduction in sleep latency and in sleeping time⁶²62 Barbosa ADE, Morato GS. Influência da epipregnanolona sobre a modulação da tolerância rápida ao etanol pelos neuroesteróides. Rev Bras Psiquiatr. 2007; 29(4):337-45.
Pregnenolone sulfate	Negative allosteric modulator of GABA_A⁶²62 Barbosa ADE, Morato GS. Influência da epipregnanolona sobre a modulação da tolerância rápida ao etanol pelos neuroesteróides. Rev Bras Psiquiatr. 2007; 29(4):337-45.	Reduction in sleep duration⁶²62 Barbosa ADE, Morato GS. Influência da epipregnanolona sobre a modulação da tolerância rápida ao etanol pelos neuroesteróides. Rev Bras Psiquiatr. 2007; 29(4):337-45.
Dehydroepiandrosterone sulfate	Negative allosteric modulator of GABA_A⁶²62 Barbosa ADE, Morato GS. Influência da epipregnanolona sobre a modulação da tolerância rápida ao etanol pelos neuroesteróides. Rev Bras Psiquiatr. 2007; 29(4):337-45.	Reduction in sleep duration and motor stimulus⁶²62 Barbosa ADE, Morato GS. Influência da epipregnanolona sobre a modulação da tolerância rápida ao etanol pelos neuroesteróides. Rev Bras Psiquiatr. 2007; 29(4):337-45.
Allotetrahydrodeoxycorticosterone	Positive allosteric modulator GABA_A⁶²62 Barbosa ADE, Morato GS. Influência da epipregnanolona sobre a modulação da tolerância rápida ao etanol pelos neuroesteróides. Rev Bras Psiquiatr. 2007; 29(4):337-45.	Motor inhibition⁶²62 Barbosa ADE, Morato GS. Influência da epipregnanolona sobre a modulação da tolerância rápida ao etanol pelos neuroesteróides. Rev Bras Psiquiatr. 2007; 29(4):337-45.

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