Neurotransmitter Systems in Alcohol Dependence

A. Heinz; A. Beck; J. Wrase; J. Mohr; K. Obermayer; J. Gallinat; I. Puls

doi:10.1055/s-0029-1214395

Pharmacopsychiatry, Table of Contents

Pharmacopsychiatry 2009; 42: S95-S101
DOI: 10.1055/s-0029-1214395

Original Paper

Neurotransmitter Systems in Alcohol Dependence

A. Heinz¹ , A. Beck¹ , J. Wrase¹ , J. Mohr¹ ^, ² , K. Obermayer¹ ^, ² , J. Gallinat¹ , I. Puls¹

¹Department of Psychiatry and Psychotherapy, CCM, Charité University Medicine, Berlin, Germany
²Bernstein Center for Computational Neuroscience, Berlin, Germany

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.

Full Text

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