Abstract
An interplay of different neurotransmitter systems has been implicated in the development and maintenance of alcohol dependence. Here we focus on neuroadaptations in reward-related neurotransmitter systems and their impact on central processing of alcohol-associated and reward-indicating stimuli. We discuss genotype effects on cue-induced neuronal activation and present new computational methods based on machine learning to deal with complex genotype-phenotype interactions, e.g. between brain atrophy and genes associated with glutamatergic and dopaminergic neurotransmission.
References
-
1
Agartz I, Momenan R, Rawlings RR. et al .
Hippocampal volume in patients with alcohol dependence.
Arch Gen Psychiatry.
1999;
56
((4))
356-363
-
2
Afifi A, Clark V, May S.
Computer-aided multivariate analysis. Texts in Statistical Science Series (4th ed). Chapman & Hall/CRC, Boca Raton, London, New York, Washington, DC, 2004.
.
;
-
3
Altinbilek B, Manahan-Vaughan D.
Antagonism of group III metabotropic glutamate receptors results in impairment of LTD but not LTP in the hippocampal CA1 region, and prevents long-term spatial memory.
Eur J Neurosci.
2007;
26
((5))
1166-1172
-
4
Barr CS, Newman TK, Becker ML. et al .
Serotonin transporter gene variation is associated with alcohol sensitivity in rhesus macaques exposed to early-life stress.
Alcohol Clin Exp Res.
2003;
27
((5))
812-817
-
5
Bender W, Albus M, Möller HJ. et al .
Towards systemic theories in biological psychiatry.
Pharmacopsychiatry.
2006;
39
((Suppl 1))
S4-S9
-
6
Beresford TP, Arciniegas DB, Alfers J. et al .
Hippocampus volume loss due to chronic heavy drinking.
Alcohol Clin Exp Res.
2006;
30
((11))
1866-1870
-
7
Bermpohl F, Pascual-Leone A, Amedi A. et al .
Novelty seeking modulates medial prefrontal activity during the anticipation of emotional stimuli.
Psychiatry Res.
2008;
164
((1))
81-85
-
8
Berridge KC, Robinson TE.
What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?.
Brain Res Brain Res Rev.
1998;
28
309-369
-
9
Bertolino A, Rubino V, Sambataro F. et al .
Prefrontal-hippocampal coupling during memory processing is modulated by COMT val158met genotype.
Biol Psychiatry.
2006;
60
((11))
1250-1258
-
10
Bortolotto ZA, Fitzjohn SM, Collingridge GL.
Roles of metabotropic glutamate receptors in LTP and LTD in the hippocampus.
Curr Opin Neurobiol.
1999;
9
((3))
299-304
-
11
Bruno V, Battaglia G, Casabona G. et al .
Neuroprotection by glial metabotropic glutamate receptors is mediated by transforming growth factor-beta.
J Neurosci..
1998;
18
((23))
9594-9600
-
12
Cai X, Gu Z, Zhong P. et al .
Serotonin 5-HT1A receptors regulate AMPA receptor channels through inhibiting Ca2+/calmodulin-dependent kinase II in prefrontal cortical pyramidal neurons.
J Biol Chem.
2002a;
277
((39))
36553-36562
-
13
Cai X, Flores-Hernandez J, Feng J. et al .
Activity-dependent bidirectional regulation of GABA(A) receptor channels by the 5-HT(4) receptor-mediated signalling in rat prefrontal cortical pyramidal neurons.
J Physiol.
2002b;
540
((Pt 3))
743-759
-
14
Campusano JM, Abarca J, Forray MI. et al .
Modulation of dendritic release of dopamine by metabotropic glutamate receptors in rat substantia nigra.
Biochem Pharmacol.
2002;
63
((7))
1343-1352
-
15
Cardenas VA, Studholme C, Gazdzinski S. et al .
Deformation-based morphometry of brain changes in alcohol dependence and abstinence.
Neuroimage.
2007;
34
((3))
879-887
-
16
Cavus I, Pan JW, Hetherington HP. et al .
Decreased hippocampal volume on MRI is associated with increased extracellular glutamate in epilepsy patients.
Epilepsia.
2008;
49
((8))
1358-1366
-
17
Chapman J, Clayton D.
Detecting association using epistatic information.
Genet Epidemiol.
2007;
31
((8))
894-909
-
18
Corti C, Battaglia G, Molinaro G. et al .
The use of knock-out mice unravels distinct roles for mGlu2 and mGlu3 metabotropic glutamate receptors in mechanisms of neurodegeneration/neuroprotection.
J Neurosci.
2007;
27
((31))
8297-8308
-
19
Cowen MS, Lawrence AJ.
The role of opioid-dopamine interactions in the induction and maintenance of ethanol consumption.
Prog Neuropsychopharmacol Biol Psychiatry.
1999;
23
1171-1212
-
20
De Bellis MD, Clark DB, Beers SR. et al .
Hippocampal volume in adolescent-onset alcohol use disorders.
Am J Psychiatry.
2000;
157
((5))
737-744
-
21
de Waele JP, Kiianmaa K, Gianoulakis C.
Spontaneous and ethanol-stimulated in vitro release of β-endorphin by the hypothalamus of AA and ANA rats.
Alcohol Clin Exp Res.
1994;
18
1468-1473
-
22
Di Chiara G.
Nucleus accumbens shell and core dopamine: differential role in behavior and addiction.
Behav Brain Res.
2002;
137
((1–2))
75-114
-
23
Di Chiara G, Bassareo V.
Reward system and addiction: what dopamine does and doesn't do.
Curr Opin Pharmacol.
2007;
7
((1))
69-76
-
24
Doudet D, Hommer D, Higley JD. et al .
Cerebral glucose metabolism, CSF 5-HIAA levels, and aggressive behavior in rhesus monkeys.
Am J Psychiatry.
1995;
152
((12))
1782-1787
-
25
Everitt BJ, Belin D, Economidou D. et al .
Review. Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction.
Philos Trans R Soc Lond B Biol Sci.
2008;
363
((1507))
3125-3135
-
26
Feng J, Cai X, Zhao J. et al .
Serotonin receptors modulate GABA(A) receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons.
J Neurosci.
2001;
21
((17))
6502-6511
-
27
Filippini N, Scassellati C, Boccardi M. et al .
Influence of serotonin receptor 2A His452Tyr polymorphism on brain temporal structures: a volumetric MR study.
Eur J Hum Genet.
2006;
14
((4))
443-449
-
28
Frank MJ, Seeberger LC, O’reilly RC.
By carrot or by stick: cognitive reinforcement learning in parkinsonism.
Science.
2004;
306
((5703))
1940-1943
-
29
Frodl T, Koutsouleris N, Bottlender R. et al .
Reduced gray matter brain volumes are associated with variants of the serotonin transporter gene in major depression.
Mol Psychiatry.
2008;
13
((12))
1093-1101
-
30
Goto Y, Grace AA.
Dopamine-dependent interactions between limbic and prefrontal cortical plasticity in the nucleus accumbens: disruption by cocaine sensitization.
Neuron.
2005;
47
((2))
255-266
-
31
Hartka E, Johnstone B, Leino EV. et al .
A meta-analysis of depressive symptomatology and alcohol consumption over time.
Br J Addict.
1991;
86
((10))
1283-1298
-
32
Heinz A, Dufeu P, Kuhn S. et al .
Psychopathological and behavioral correlates of dopaminergic sensitivity in alcohol dependent patients.
Arch Gen Psychiatry.
1996;
53
1123-1128
-
33
Heinz A, Knable MB, Coppola R. et al .
Psychomotor slowing, negative symptoms and dopamine receptor availability-an IBZM SPECT study in neuroleptic-treated and drug-free schizophrenic patients.
Schizophr Res.
1998a;
31
((1))
19-26
-
34
Heinz A, Ragan P, Jones DW. et al .
Reduced central serotonin transporters in alcoholism.
Am J Psychiatry.
1998b;
155
((11))
1544-1549
-
35
Heinz A, Jones DW, Mazzanti C. et al .
A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity.
Biol Psychiatry.
2000;
47
((7))
643-649
-
36
Heinz A, Löber S, Georgi A. et al .
Reward craving and withdrawal relief craving: assessment of different motivational pathways to alcohol intake.
Alcohol Alcohol.
2003;
38
((1))
35-39
-
37
Heinz A, Siessmeier T, Wrase J. et al .
Correlation between dopamine D-2 receptors in the ventral striatum and central processing of alcohol cues and craving.
Am J Psychiatry.
2004a;
161
1783-1789
-
38
Heinz A, Goldman D, Gallinat J. et al .
Pharmacogenetic insights to monoaminergic dysfunction in alcohol dependence.
Psychopharmacology (Berl).
2004b;
174
((4))
561-570
-
39
Heinz A, Reimold M, Wrase J. et al .
Correlation of stable elevations in striatal mu-opioid receptor availability in detoxified alcoholic patients with alcohol craving – A positron emission tomography study using carbon 11-labeled carfentanil.
Arch Gen Psychiatry.
2005a;
62
57-64
-
40
Heinz A, Siessmeier T, Wrase J. et al .
Correlation of alcohol craving with striatal dopamine synthesis capacity and D-2/3 receptor availability: a combined [18F]DOPA and [18F]DMFP PET Study in detoxified alcoholic patients.
Am J Psychiatry.
2005b;
162
1515-1520
-
41
Heinz A, Grace AA, Beck A.
The intricacies of dopamine neuron modulation.
Biol Psychiatry.
2008;
, [In press]
-
42
Hersi AI, Rowe W, Gaudreau P. et al .
Dopamine D1 receptor ligands modulate cognitive performance and hippocampal acetylcholine release in memory-impaired aged rats.
Neuroscience.
1995;
69
((4))
1067-1074
-
43
Hinckers AS, Laucht M, Schmidt MH. et al .
Low level of response to alcohol as associated with serotonin transporter genotype and high alcohol intake in adolescents.
Biol Psychiatry.
2006;
60
((3))
282-287
-
44
Ito R, Dalley JW, Robbins TW. et al .
Dopamine release in the dorsal striatum during cocaine-seeking behavior under the control of a drug-associated cue.
J Neurosci.
2002;
22
((14))
6247-6253
-
45
Jay TM.
Dopamine: a potential substrate for synaptic plasticity and memory mechanisms.
Prog Neurobiol.
2003;
69
((6))
375-390
-
46
Ji Y, Pang PT, Feng L. et al .
Cyclic AMP controls BDNF-induced TrkB phosphorylation and dendritic spine formation in mature hippocampal neurons.
Nat Neurosci.
2005;
8
((2))
164-172
-
47
Kelley AE.
Memory and addiction: shared neural circuitry and molecular mechanisms.
Neuron.
2004;
44
((1))
161-179
-
48
Knecht S, Breitenstein C, Bushuven S. et al .
Levodopa: faster and better word learning in normal humans.
Ann Neurol.
2004;
56
((1))
20-26
-
49
Knutson B, Adams CM, Fong GW. et al .
Anticipation of increasing monetary reward selectively recruits nucleus accumbens.
J Neurosi.
2001;
21
((16))
RC159
-
50
Krebs RM, Schott BH, Düzel E.
Personality traits differentially modulate reward and novelty processing in the human substantia nigra/ventral tegmental area.
Biol Psychiatry.
2008;
, [Epub ahead of print]
-
51
Krystal JH, Staley J, Mason G. et al .
Gamma-aminobutyric acid type A receptors and alcoholism: intoxication, dependence, vulnerability, and treatment.
Arch Gen Psychiatry.
2006;
63
((9))
957-968
-
52
Legault M, Wise RA.
Novelty-evoked elevations of nucleus accumbens dopamine: dependence on impulse flow from the ventral subiculum and glutamatergic neurotransmission in the ventral tegmental area.
Eur J Neurosci.
2001;
13
((4))
819-828
-
53
Lesch KP, Bengel D, Heils A. et al .
Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.
Science.
1996;
274
((5292))
1527-1531
-
54
Lisman JE, Grace AA.
The hippocampal-VTA loop: controlling the entry of information into long-term memory.
Neuron.
2005;
46
703-713
-
55
Marchini J, Donnelly P, Cardon LR.
Genome-wide strategies for detecting multiple loci that influence complex diseases.
Nat Genet.
2005;
37
((4))
413-417
-
56
Marinelli PW, Kiianmaa K, Gianoulakis C.
Opioid propeptide mRNA content and receptor density in the brains of AA and ANA rats.
Life Sci.
2000;
66
1915-1927
-
57
Martinez D, Gil R, Slifstein M. et al .
Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum.
Biol Psychiatry.
2005;
58
779-786
-
58
McFarland K, Davidge SB, Lapish CC. et al .
Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior.
J Neurosci.
2004;
24
((7))
1551-1560
-
59
Mechtcheriakov S, Brenneis C, Egger K. et al .
A widespread distinct pattern of cerebral atrophy in patients with alcohol addiction revealed by voxel-based morphometry.
J Neurol Neurosurg Psychiatry.
2007;
78
((6))
610-614
-
60
Medina KL, Schweinsburg AD, Cohen-Zion M. et al .
Effects of alcohol and combined marijuana and alcohol use during adolescence on hippocampal volume and asymmetry.
Neurotoxicol Teratol.
2007;
29
((1))
141-152
-
61
Meltzer LT, Serpa KA, Christoffersen CL.
Metabotropic glutamate receptor-mediated inhibition and excitation of substantia nigra dopamine neurons.
Synapse.
1997;
26
((2))
184-193
-
62
Nagel BJ, Schweinsburg AD, Phan V. et al .
Reduced hippocampal volume among adolescents with alcohol use disorders without psychiatric comorbidity.
Psychiatry Res.
2005;
139
((3))
181-190
-
63
O’Hara R, Schröder CM, Mahadevan R. et al .
Serotonin transporter polymorphism, memory and hippocampal volume in the elderly: association and interaction with cortisol.
Mol Psychiatry.
2007;
12
((6))
544-555
-
64
Park WK, Bari AA, Jey AR. et al .
Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by increasing AMPA receptor-mediated glutamate transmission in the nucleus accumbens.
J Neurosci.
2002;
22
((7))
2916-2925
-
65
Pfefferbaum A, Sullivan EV, Rosenbloom MJ. et al .
A controlled study of cortical gray matter and ventricular changes in alcoholic men over a 5-year interval.
Arch Gen Psychiatry.
1998;
55
((10))
905-912
-
66
Pizzi M, Consolandi O, Memo M. et al .
Activation of multiple metabotropic glutamate receptor subtypes prevents NMDA-induced excitotoxicity in rat hippocampal slices.
Eur J Neurosci.
1996;
8
((7))
1516-1521
-
67
Puls I, Mohr J, Wrase J. et al .
Synergistic effects of the dopaminergic and glutamatergic system on hippocampal volume in alcohol-dependent patients.
Biol Psychol.
2008;
79
((1))
126-136
-
68
Reimold M, Smolka MN, Schumann G. et al .
Midbrain serotonin transporter binding potential measured with [11C]DASB is affected by serotonin transporter genotype.
J Neural Transm.
2007;
114
((5))
635-639
-
69
Reimold M, Batra A, Knobel A. et al .
Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: a [11C]DASB PET study.
Mol Psychiatry.
2008;
13
((6))
606-613
-
70
Robinson TE, Berridge KC.
The neural basis of drug craving–an incentive-sensitization theory of addiction.
Brain Res Brain Res Rev.
1993;
18
247-291
-
71
Schmidt K, Nolte-Zenker B, Patzer J. et al .
Psychopathological correlates of reduced dopamine receptor sensitivity in depression, schizophrenia, and opiate and alcohol dependence.
Pharmacopsychiatry.
2001;
34
((2))
66-72
-
72
Schuckit MA, Smith TL.
An 8-year follow-up of 450 sons of alcoholic and control subjects.
Arch Gen Psychiatry.
1996;
53
((3))
202-210
-
73
Schuckit MA, Mazzanti C, Smith TL. et al .
Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABA alpha 6 receptors and the serotonin transporter in the level of response to alcohol: a pilot study.
Biol Psychiatry.
1999;
45
((5))
647-651
-
74
Schultz W, Dayan P, Montague PR.
A neural substrate of prediction and reward.
Science.
1997;
275
1593-1599
-
75
Schumann G, Johann M, Frank J. et al .
Systematic analysis of glutamatergic neurotransmission genes in alcohol dependence and adolescent risky drinking behavior.
Arch Gen Psychiatry.
2008;
65
((7))
826-838
-
76
Shalev U, Grimm JW, Shaham Y.
Neurobiology of relapse to heroin and cocaine seeking: a review.
Pharmacol Rev.
2002;
54
((1))
1-42
-
77
Spanagel R, Herz A, Shippenberg TS.
Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway.
Proc Natl Acad Sci USA.
1992;
89
((6))
2046-2050
-
78
Spanagel R, Zieglgänsberger W.
Anti-craving compounds for ethanol: new pharmacological tools to study addictive processes.
Trends Pharmacol Sci.
1997;
18
((2))
54-59
-
79
Spanagel R, Pendyala G, Abarca C. et al .
The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption.
Nat Med.
2005;
11
((1))
35-42
-
80
Sullivan EV, Marsh L, Mathalon DH. et al .
Anterior hippocampal volume deficits in nonamnesic, aging chronic alcoholics.
Alcohol Clin Exp Res.
1995;
19
((1))
110-122
-
81
Tecott LH, Julius D.
A new wave of serotonin receptors.
Curr Opin Neurobiol.
1993;
3
((3))
310-315
-
82
Tretter F, Scherer J.
Schizophrenia, neurobiology and the methodology of systemic modeling.
Pharmacopsychiatry.
2006;
39
((Suppl 1))
S26-S35
-
83
Tsai G, Gastfriend DR, Coyle JT.
The glutamatergic basis of human alcoholism.
Am J Psychiatry.
1995;
152
((3))
332-340
-
84
Volkow ND, Fowler JS, Wang GJ. et al .
Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers.
Synapse.
1993;
14
((2))
169-177
-
85
Volkow ND, Wang GJ, Fowler JS. et al .
Decreases in dopamine receptors but not in dopamine transporters in alcoholics.
Alcohol Clin Exp Res.
1996;
20
1594-1598
-
86
Volkow ND, Chang L, Wang GJ. et al .
Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex.
Am J Psychiatry.
2001;
158
((12))
2015-2021
-
87
Volkow ND, Wang GJ, Telang F. et al .
Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement.
J Neurosci.
2007;
27
((46))
12700-12706
-
88
Volpicelli JR, Watson NT, King AC. et al .
Effect of naltrexone on alcohol “high” in alcoholics.
Am J Psychiatry.
1995;
152
((4))
613-615
-
89
Weiss F, Maldonado-Vlaar CS, Parsons LH. et al .
Control of cocaine-seeking behavior by drug-associated stimuli in rats: effects on recovery of extinguished operant-responding and extracellular dopamine levels in amygdala and nucleus accumbens.
Proc Natl Acad Sci USA.
2000;
97
((8))
4321-4326
-
90
Wise RA.
Neuroleptics and operant behaviour: the anhedonia hypothesis.
Behav Brain Sci.
1982;
5
39-87
-
91
Wittmann BC, Schott BH, Guderian S. et al .
Reward-related FMRI activation of dopaminergic midbrain is associated with enhanced hippocampus-dependent long-term memory formation.
Neuron.
2005;
45
((3))
459-467
-
92
Wrase J, Schlagenhauf F, Kienast T. et al .
Dysfunction of reward processing correlates with alcohol craving in detoxified alcoholics.
Neuroimage.
2007;
35
((2))
787-794
-
93
Yao HH, Ding JH, Zhou F. et al .
Enhancement of glutamate uptake mediates the neuroprotection exerted by activating group II or III metabotropic glutamate receptors on astrocytes.
J Neurochem.
2005;
92
((4))
948-961
-
94
Zhang Y, Liu JS.
Bayesian inference of epistatic interactions in case-control studies.
Nat Genet.
2007;
39
((9))
1167-1173
Correspondence
A. HeinzMD
Department of Psychiatry and Psychotherapy
Charité Campus Mitte
Charité University Medicine Berlin
Charitéplatz 1
10117 Berlin
Germany
Phone: +49/30/450 5170 02
Fax: +49/30 450 5179 21
Email: andreas.heinz@charite.de
