NEUROTRANSMITTERS IN ALCOHOLISM : A GENETIC PERSPECTIVE By Niladri Banerjee M.Tech (Biotechnology) Section-A Amity Institute of

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1 NEUROTRANSMITTERS IN ALCOHOLISM : A GENETIC PERSPECTIVE By Niladri Banerjee M.Tech (Biotechnology) Section-A Amity Institute of Biotechnology

2 Why the topic A novel topic, not usually covered Huge role of neurotransmitters in our daily lives Evidences have emerged as to their roles in sleep disorder, depression, anxiety disorders and addiction behaviours Recently some genes have begun to be implicated in the aforementioned conditions

3 Contents Neuronal Cell Structure What are neurotransmitters? Basic neurobiology of alcohol addiction Genes implicated in alcohol addiction Future scope & Challenges

4 Neuronal Cell Structure

5 Neurotransmitters: Definition & Mechanism in brief Basically amino acids and their modified forms Synthesized in cell body of presynaptic neurons, transported to terminal regions of axons, encapsulated into vesicles there Influx of Ca 2+ ions induces vesicles to fuse with presynaptic membrane, causing the contents to be poured into the synaptic cleft Release of the neurotransmitters into the synaptic cleft causes a change in the post-synaptic membrane potential.

6 Neurotransmitters: Definition & Mechanism in brief (contd) Depending upon change in membrane potential, neurotransmitters are classified as excitatory or inhibitory Excitatory neurotransmitters = Depolarization of postsynaptic membrane Inhibitory neurotransmitters = Hyperpolarization of postsynaptic membrane Neurotransmitters once released act on their respective receptors present on the postsynaptic membrane If they act on receptors present at other synapses, known as neuromodulators Synaptic signal persists as long as neurotransmitter is present, cessation of signal requires recycling of neurotransmitter or its degradation in the synaptic cleft

7 Neurobiology of Alcohol Addiction: The Basics Alcoholism is a medically diagnosed condition and simply consuming alcohol does not make you an alcoholic Alcohol addiction is determined via a questionnaire based screening method, called DSM-IV DSM-IV is acronym for Diagnostics & Statistics Manual of Mental Disorders- IV Alcohol addiction produces distinct changes in brain physiology, as depicted in the diagram in the subsequent page

8 Neurobiology of Alcohol Addiction: The Basics (contd)

9 Neurobiology of Alcohol Addiction: The Basics (contd) Alcohol addiction occurs through 2 means : Positive Reinforcement Negative Reinforcement Positive reinforcement = alcohol induced euphoria, increases probability that an individual seeks out more alcohol [Gilpin NW et al, 2008] Negative reinforcement = particular behaviour, such as seeking alcohol, helps an individual circumvent or alleviate an aversive stimulus, [Gilpin NW et al, 2008]

10 Neurobiology of Alcohol Addiction: The Basics (contd) Early stages of non-dependent alcohol use governed by positive reinforcement, while drinking behaviour in dependent stage is governed by both positive & negative reinforcement The mechanisms of causing positive & negative reinforcements are the various excitatory & inhibitory neurotransmitters Alcohol interacts with several neurotransmitters, which after chronic exposure, result in neuronal changes Categorized by neurotransmitters, the dopaminergic, serotoninergic, GABAergic & glutamatergic systems are briefly discussed

11 Neurobiology of Alcohol Addiction: The Basics (contd) Dopaminergic System Dopamine is the neurotransmitter Controls incentive motivation Has a role in incentive motivation in acute alcohol intoxication Alcohol ingestion + anticipation of alcohol, increases extracellular dopamine levels [Weiss et al, 1993] Injecting dopamine antagonists into nucleus accumbens, blocks alcohol consumption[rassnick et al. 1992,Hodge et al. 1997] Alcohol withdrawal results in decreases in dopamine levels produced in dependent individuals, which may contribute to withdrawal symptoms & relapse [Melis et al. 2005; Volkow et al. 2007]

12 Neurobiology of Alcohol Addiction: The Basics (contd) Serotoninergic system Serotonin is the neurotransmitter Well established link between serotonin depletion, impulsivity and alcohol consumption [Myers and Veale 1968; Virkkunen and Linnoila 1990] Inhibition of serotonin uptake, which thereby prolongs the action of serotonin can suppress alcohol consumption [Johnson, 2008]

13 Neurobiology of Alcohol Addiction: The Basics (contd)

14 Neurobiology of Alcohol Addiction: The Basics (contd) GABAergic system Neurotransmitter is GABA (γ-aminobutyric acid ) Major inhibitory neurotransmitter Alcohol increases GABA activity in the brain via 2 mechanisms: Stimulating presynaptic neuron, increasing GABA release Inhibiting GABA receptors, prolonging effect of GABA Acute and chronic alcohol exposure produce increases in GABA transmission[roberto et al. 2003, 2004]

15 Neurobiology of Alcohol Addiction: The Basics (contd) Glutamatergic system Glutamate is the neurotransmitter Major excitatory neurotransmitter Exerts its effect through receptors i.e receptor binding is essential for excitatory signals to be passed Effects of alcohol can be mimicked by blocking glutamate receptors [Colombo and Grant 1992] Both acute and chronic alcohol consumption suppress glutamate release Acute alcohol exposure reduces extracellular glutamate levels [Carboni et al, 1993] Glutamate mediated signal transmission is reduced following acute alcohol exposure; chronic exposure further reduces it[roberto et al, 2004 ] Acamprosate, a drug, is being used to treat alcoholism as it blocks glutamate receptors, reduces hyper-excitability and therefore reduces alcohol consumption[littleton et al, 2007]

16 Genes implicated in Alcohol Addiction Alcohol addiction of late has been shown to be under the influence of genes Such genes do not confirm if a person will turn alcoholic, but there is high correlation between carriers of such genes and alcohol addiction Candidate genes involved in alcohol addiction code for the receptors of neurotransmitters (eg. Dopamine, GABA, Glutamate) and transporters( serotonin)

17 Genes implicated in Alcohol Addiction (contd) DRD2 gene Codes for D2 subtype of Dopamine receptor Present on chromosome 11 q kinds of polymorphism : Taq1A Taq1B -141c Ins/Del All of these are SNPs All have been implicated via correlational studies

18 Genes implicated in Alcohol Addiction (contd) DRD2:Taq1 A Polymorphism T/C SNP altering a Taq1 restriction site located bp downstream of the termination codon of DRD2 gene Taq1 restriction site: 5 TCGA 3 Alcoholics have this restriction site Connor et al,2002: Presence of this allele results in greater severity of alcoholism across a range of problem drinking indices Esposito-Smythers et al, 2009: Presence of this allele correlates high with alcohol/drug abuse amongst adolescents Berggren et al,2010: Presence of this allele results in increased mortality over a 10 year period amongst alcohol dependent individuals Pinto et al, 2009: This allele is significantly associated with paternal history of alcoholism

19 Genes implicated in Alcohol Addiction (contd) DRD2:Taq1 A Polymorphism(contd) Not all studies have produced positive results Shaikh et al,2001: No correlation between Taq1 A polymorphism and alcohol dependence in South Indian population Konishi et al, 2004: No correlation of this allele and alcohol dependence amongst Mexican-Americans Samochowiec et al, 2006 : No association between Taq 1A allele and alcohol dependence in Polish populatoin

20 Genes implicated in Alcohol Addiction (contd) DRD2:Taq1 B Polymorphism A A/G SNP in intron 1 that alters a Taq1 site located 882 bp upstream of exon 2 Taq1 restriction site: 5 TCGA 3 Konishi et al, 2004: 2 studies, amongst Mexican-Americans produced contradictory results. First study showed no correlation between Taq1 B allele & alcohol dependence. Subsequent study found correlation between this allele and age of onset for alcohol drinking Vaswani et al, 2010: No correlation between Taq 1B allele & alcohol dependence amongst north Indians.

21 Genes implicated in Alcohol Addiction (contd) DRD2:-141c Ins/Del Polymorphism A single nucleotide insertion/deletion polymorphism at -141 bp, i.e. upstream, of the start of transcription.the "insertion" allele corresponds to a BstN1 restriction site; the "deletion" allele does not have that site BstN1 restriction site : 5 CCAGG 3 Ishiguro et al, 1998: Ins allele significantly increased in Japanese alcoholics Konishi et al, 2004: Significant correlation between Ins allele & alcohol dependence amongst Mexican-Americans. Vaswani et al, 2010: Significant association of Ins allele with alcohol dependence amongst north Indians Not all have reported positive correlations; Wiesback et al 2004; Florez et al, 2008 found no correlation between Ins allele and alcohol dependence amongst Caucasians

22 Genes implicated in Alcohol Addiction (contd) SERT gene: HTTLPR Codes for serotonin transporter, which is involved in reuptake of serotonin into presynaptic membrane from synaptic cleft SERotonin Transporter gene: Hydroxy-Tryptamine-Transporter-Linked- Polymorphic-Region Gene is located at chromosome 17q11-12 HTTLPR comprises of a 44bp insertion/deletion of 6-8 repeat elements, 1kb upstream of transcription initiation site of SERT Insertion variant called Long allele(l), deletion variant called Short allele(s)

23 Genes implicated in Alcohol Addiction (contd) SERT gene: HTTLPR(contd) Herman AL et al,2003 : A positive correlation exists between carriers of the short(s) allele with binge-drinking behaviour, drinking more alcohol per occasion, as well as drinking to get drunk more often. Enoch MA et al,2010 :A low 5 -HTTLPR activity due to the presence of the short allele, was more common in men with alcohol+drug dependence compared with controls. Wang XJ et al,2011 : In the Yunan Han population, the genotype L/L or L/S may be a genetic factor that is responsible for decreasing susceptibility of alcohol dependence in Yunnan Han population. Merenäkk L et al, 2011: A positive correlation exists between susbtance abuse amongst adolescents and carriers of the S allele of HTTLPR 583 children studied under Estonian Children Personality Behaviour & Health Study Substance use did not differ by genotype at 9 years of age, at 15 carriers of S allele had higher tobacco use, at 18 carriers of S allele were more active alcohol, tobacco & drug users

24 Genes implicated in Alcohol Addiction (contd) SERT gene: STin2 Another polymorphism of SERT SeroTonin intron 2 VNTR in intron 2 3 distinct alleles : 9 bp repeats 10bp repeats 12bp repeats Limited work has been done so far Florez G et al,2008 : Positive correlation between carriers of 10/10 allele and treatment outcome over 6-month period; carriers of 12/12 allele showed poor treatment outcome Saiz PA et al, 2009: No correlation between any of the 3 alleles and alcohol dependence amongst Spanish Caucasians.

25 Genes implicated in Alcohol Addiction (contd) GABRA1 & GABRA6 Codes for GABA A receptor, alpha 1; GABA A receptor, alpha 6 respectively Located at chromosome 5q34-35; 5q34 respectively A>G mutation in GABRA1; C>T mutation in GABRA6 implicated in alcohol addiction Chang YT et al,2002 : GABRA6 and GABRA1 genes account for alcohol susceptibility in Taiwanese Han Dick et al,2006: Positive correlation between GABRA1 and history of blackouts, age at first drunkenness as well as the level of response to alcohol. Park CS et al, 2006: Positive correlation of GABRA1 & GABRA6 with alcoholism. But not all studies have found positive correlation Song J et al,2003 ; Dick DM et al,2005 : No correlation was observed between GABRA1 & GABRA6 with alcohol dependence

26 Genes implicated in Alcohol Addiction (contd) GRIN2A Glutamate Receptor Ionotropic NMDA 2A Codes for a receptor subunit of NMDA( N-Methyl D-Aspartate) receptors, which is a type of receptor for Glutamate Located at chromosome 16 p13 Domart MC et al,2011 : A variable (GT) n repeat in 5 regulatory region of GRIN2A is associated with alcohol dependence Long alleles significantly more frequent amongst alcohol dependent subjects Schumann G et al, 2008: Positive correlation with family history of alcoholism, early onset of alcoholism, maximum number of drinks in adults & risky drinking patterns in adolescents

27 Future Scope & Challenges Wide variation between different populations (caucasians vs mexicanamericans) and population sub groups( south vs north indians) Difficult to pinpoint if genes are the causative agent or simply increase likelihood( association does not equal causation) or does consumption of alcohol in itself induce the mutations in the genes Genes implicated in wide variety of alcoholism related traits such as addiction, treatment outcomes, age of onset alcohol drinking, mortality etc Few to none follow up studies undertaken Brain scans are not taken for all alcoholics, the DSM-IV and other questionnaire based screening methods are performed, thus liable to discrepancies as they are self-reported Trans-national studies need to be undertaken so as to obtain more robust statistics More longitudinal studies required Combined effect of the candidate genes of all these neurotransmitters needs to be studied

28 Thank You