Alcoholism, also called dependence on alcohol (ethanol), is a chronic relapsing disorder that is progressive and has serious detrimental health outcomes. As one of the primary mediators of the rewarding effects of alcohol, dopaminergic ventral tegmental area (VTA) projections to the nucleus accumbens (NAc) have been identified. Acute exposure to alcohol stimulates dopamine release into the NAc, which activates D1 receptors, stimulating PKA signaling and subsequent CREB-mediated gene expression,  whereas chronic alcohol exposure leads to an adaptive downregulation of this pathway, in particular of CREB function. The decreased CREB function in the NAc may promote the intake of drugs of abuse to achieve an increase in reward and thus may be involved in the regulation of positive affective states of addiction. PKA signaling also affects NMDA receptor activity and may  play an important role in neuroadaptation in response to chronic alcohol exposure.

Human Diseases; Substance dependence

Mus musculus (mouse) [GN:mmu]

PMID:19342616

Spanagel R

Alcoholism: a systems approach from molecular physiology to addictive behavior.

Physiol Rev 89:649-705 (2009)

PMID:16102840

Newton PM, Messing RO

Intracellular signaling pathways that regulate behavioral responses to ethanol.

Pharmacol Ther 109:227-37 (2006)

PMID:14729391

Mailliard WS, Diamond I

Recent advances in the neurobiology of alcoholism: the role of adenosine.

Pharmacol Ther 101:39-46 (2004)

PMID:16278489

Ron D, Jurd R

The "ups and downs" of signaling cascades in addiction.

Sci STKE 2005:re14 (2005)

PMID:12605085

Diana M, Brodie M, Muntoni A, Puddu MC, Pillolla G, Steffensen S, Spiga S, Little HJ

Enduring effects of chronic ethanol in the CNS: basis for alcoholism.

Alcohol Clin Exp Res 27:354-61 (2003)

PMID:19756388

Moonat S, Starkman BG, Sakharkar A, Pandey SC

Neuroscience of alcoholism: molecular and cellular mechanisms.

Cell Mol Life Sci 67:73-88 (2010)

PMID:15500908

Pandey SC

The gene transcription factor cyclic AMP-responsive element binding protein: role in positive and negative affective states of alcohol addiction.

Pharmacol Ther 104:47-58 (2004)

PMID:16764827

Zhang TA, Maldve RE, Morrisett RA

Coincident signaling in mesolimbic structures underlying alcohol reinforcement.

Biochem Pharmacol 72:919-27 (2006)

PMID:12068305

Maldve RE, Zhang TA, Ferrani-Kile K, Schreiber SS, Lippmann MJ, Snyder GL, Fienberg AA, Leslie SW, Gonzales RA, Morrisett RA

DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens.

Nat Neurosci 5:641-8 (2002)

PMID:12085089

Lovinger DM

NMDA receptors lose their inhibitions.

Nat Neurosci 5:614-6 (2002)

PMID:16776597

Hyman SE, Malenka RC, Nestler EJ

Neural mechanisms of addiction: the role of reward-related learning and memory.

Annu Rev Neurosci 29:565-98 (2006)

PMID:10774721

Berke JD, Hyman SE

Addiction, dopamine, and the molecular mechanisms of memory.

Neuron 25:515-32 (2000)

PMID:20729980

Clapp P, Bhave SV, Hoffman PL

How Adaptation of the Brain to Alcohol Leads to Dependence: A Pharmacological Perspective.

Alcohol Res Health 31:310-339 (2008)

PMID:20947635

Jeanes ZM, Buske TR, Morrisett RA

In vivo chronic intermittent ethanol exposure reverses the polarity of synaptic plasticity in the nucleus accumbens shell.

J Pharmacol Exp Ther 336:155-64 (2011)

PMID:18991950

Lee AM, Messing RO

Protein kinases and addiction.

Ann N Y Acad Sci 1141:22-57 (2008)

PMID:17270154

Repunte-Canonigo V, Lutjens R, van der Stap LD, Sanna PP

Increased expression of protein kinase A inhibitor alpha (PKI-alpha) and decreased PKA-regulated genes in chronic intermittent alcohol exposure.

Brain Res 1138:48-56 (2007)

PMID:18310464

Logrip ML, Janak PH, Ron D

Dynorphin is a downstream effector of striatal BDNF regulation of ethanol intake.

FASEB J 22:2393-404 (2008)

PMID:18616668

Shukla SD, Velazquez J, French SW, Lu SC, Ticku MK, Zakhari S

Emerging role of epigenetics in the actions of alcohol.

Alcohol Clin Exp Res 32:1525-34 (2008)

PMID:19077056

Pascual M, Boix J, Felipo V, Guerri C

Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in  the adult rat.

J Neurochem 108:920-31 (2009)

PMID:20626732

Li J, Cheng Y, Bian W, Liu X, Zhang C, Ye JH

Region-specific induction of FosB/DeltaFosB by voluntary alcohol intake: effects  of naltrexone.

Alcohol Clin Exp Res 34:1742-50 (2010)