This suggests a negative-feedback loop between microRNAs and Dicer to control their own availability (Lewohl et al., 2011). The mechanism contributing to the development of molecular tolerance to alcohol specifically involving the BK channel (discussed above) was found to be controlled by a microRNA (Pietrzykowski et al., 2008). In rodent neurons alcohol upregulates a particular micro-RNA 9 (miR9) which subsequently affects the expression of specific splice variants of the BK channel, some of which are less or more sensitive to alcohol. This mechanism suggests that alcohol-sensitive microRNAs are regulatory master-switches for the development of tolerance, a crucial component of alcohol addiction. Both why is alcohol addicting the sequence and structure of DNA molecules control all downstream processes such as RNA transcription and protein translation, and both can contribute to the development, progression, and persistence of alcoholism. A great deal of work has been done in the field of genes and molecular pathways involved in fetal alcohol syndrome and alcohol-related developmental disorders (Goodlett et al., 2005; Sulik, 2005) and will be covered in other chapters of this book.
Maintenance of alcohol consumption
The degree of acute behavioral tolerance to alcohol exhibited by a naïve subject can predict the likelihood of alcoholism (Treistman and Martin, 2009). The BK channel is a key target in the development of tolerance in invertebrates and mammals (Davies et al., 2003; Martin et al., 2008). There are several variables that influence the response of the BK channel to alcohol, including subunit composition, splice variant, and post-translational mechanisms (see section on microRNA, below). BK channels from neurons of wild-type mice (in which the β4 subunit is well represented) exhibit little tolerance.
Alcohol Addiction and Genetics
However, alcohol reinforcement processes are modulated by this system, and it is suggested that alcohol reward is dependent on CB1 receptor activity. Thus, CB1 receptors in alcohol-avoiding DBA/2 mice exhibit a lower efficacy than CB1 receptors in alcohol-preferring C57BL/6 mice (Hungund and Basavarajappa, 2000). More importantly, CB1 receptor knockout mice display reduced alcohol-induced conditioned place preference and self-administration (Wang et al., 2003; Thanos et al., 2005a).
Lack of Control Over Drinking
The use of AMPA receptor subunit GluRC knockout mice revealed an exceptional role of this subunit in cue-induced alcohol-seeking behaviour (Sanchis-Segura et al., 2006). Not only ionotropic AMPA receptors but also mGluRs might be involved in alcohol-seeking behaviour. In particular, mGluR5 receptor antagonists are effective in the reinstatement model (Bäckström et al., 2004). Activation of group II mGluRs attenuates both stress- and cue-induced reinstatement behaviour (Zhao et al., 2006). However, another study using agonists acting at mGluR2/3 and mGluR8 receptors showed that significant effects of treatment on cue-induced reinstatement occurred only at doses that also decreased spontaneous locomotor activity (Bäckström and Hyytiä, 2005). In addition, there are a number of mechanisms that determine the pharmacokinetics of alcohol.
Experiments with knockout mice also do not suggest the involvement of these receptors in the maintenance of alcohol drinking, as both GluR1 and GluR3 deletions did not have any effect on either home cage alcohol drinking or operant self-administration (Cowen et al., 2003; Sanchis-Segura et al., 2006). Researchers are examining whether the drugs can also help people who are addicted to gambling, sex and shopping, among other things. “These molecules demonstrate exciting early promise in stemming the rising tide of addictive disorders,” Lembke said. Early studies suggest that GLP-1s may be effective in treating opioid, alcohol and nicotine addiction.
- Repeating the same action until it becomes an automatic response forms habitual behaviors.
- Furthermore, the human CB1 receptor, which is encoded by the CNR1 gene, may play a role in the development of alcoholism as it has recently been reported by Zuo et al. (2007) in a large case–control sample.
- They may wish to reduce their alcohol consumption to more moderate levels, rather stopping altogether.
In fact, relapses to alcohol use are known to occur in the majority of clinical cases if no appropriate treatment is provided, indicating that they are a fundamental part of this disease and should be considered as one of the central features of an addicted behaviour. Thus, alcohol inhibits dihydropyridine-sensitive L-type Ca2+ channels, and single-channel recordings suggest that alcohol’s effects on gating are consistent with the interaction of a single drug molecule with a single target site, possibly the L-channel itself (Wang et al., 1994). In addition, alcohol opens G-protein-activated inwardly rectifying K+ channels (GIRKs) (Kobayashi et al., 1999; Lewohl et al., 1999). GLP-1s don’t just make people feel full by delaying the movement of food through the stomach. Specifically, they influence the release of dopamine in the part of the brain linked to motivation, pleasure and reward.
- The dopamine receptor antagonist fluphenazine will block alcohol self-administration when injected into the nucleus accumbens (Rassnick et al., 1992).
- In addition, considerable progress has been made in defining binding cavities for alcohol in several proteins, including ion channels (Harris et al., 2008; Howard et al., 2011, Sauguet et al., 2013).
- Site-directed mutation in the sequence where CREB binds abolished the stimulatory effect by alcohol, suggesting that CREB is involved in mediating alcohol-induced upregulation of the NR2B gene (Rani et al., 2005).
- Once a person becomes an alcoholic, drinking becomes increasingly compulsive and seems to escapes voluntary control.
- Electrophysiologic data support alcohol’s actions on GABA(A) receptors, showing potentiation of GABA-mediated chloride influx following alcohol administration in a variety of preparations.
Administration of haloperidol, a DA antagonist with selectivity for D2-like receptors, led to a suppression of an ADE in mice (Salimov et al., 2000). In addition, a highly selective D3 receptor antagonist caused a dose-dependent reduction of relapse-like drinking in the Sober living house ADE model in Wistar rats (Vengeliene et al., 2006). The major concern in the clinical work with alcohol-dependent patients is the prevention of relapse during periods of abstinence.
- However, stress-induced reinstatement is not affected by this treatment (Lê et al., 1999).
- This cooperation between the microRNAs allows regulation of gene expression with a reduced number of active microRNAs.
- It is important to note that these long-lasting drug-responsive alterations are unlikely to be encoded in RNAs or proteins due to the fast turnover rate of those molecules.
- The Andrew Johnson alcoholism debate is the dispute, originally conducted among the general public, and now typically a question for historians, about whether or not Andrew Johnson, the 17th president of the United States (1865–1869), drank to excess.
- Cue- and stress-induced reinstatement has been found to be blocked by CRF1 receptor antagonists (Lê et al., 2000; Gehlert et al., 2007; Marinelli et al., 2007).
In conclusion, the acute psychotropic effects of alcohol are mediated by the complex interaction with these neurotransmitter/ion channel systems. Following this first hit of alcohol, a second wave of indirect effects on a variety of neurotransmitter/neuropeptide systems is initiated, leading finally to the typical behavioural effects of alcohol ranging from disinhibition to sedation and even hypnosis. A single microRNA has the potential to target many genes, and multiple microRNAs can cooperate to target the same genes (Grimson et al., 2007; Lewohl et al., 2011). MicroRNA-7 (miR-7) and microRNA-153 (miR-153) were found to be differentially expressed between human alcoholic brain tissue and control group brain tissue. Interestingly, miR-7 and miR-153 were found to both regulate the expression of α-synuclein (Doxakis, 2010). Α-synuclein is a protein that plays a major role in neurotransmitter release in presynaptic terminals (Liu et al., 2004; Greten-Harrison et al., 2010) and is involved in dopaminergic neurotransmission and neuro-degenerative disorders (Doxakis, 2010).