Acting through a receptor subtype called GABAA, GABA leads to a state of sedation and decreased anxiety. Sedative medications such as the benzodiazepines (e.g., Valium®) also act at the GABAA receptor. Some reports suggest that short-term alcohol exposure increases the inhibitory effect of GABAA receptors (Mihic and Harris 1995). Other research, however, shows that alcohol does not increase GABAA receptor function in some brain regions and under certain experimental conditions. Many factors probably determine whether GABAA receptors respond to short-term alcohol exposure (Mihic and Harris 1995).
Investigating Alcohol’s Effects on Memory
These atypical antipsychotics have a significantly improved side effect profile compared to the traditional first generation of dopamine D2 antagonists. Thus, there has been a renewed interest in evaluating these medications as potential treatment for alcohol dependence with the assumption that the atypical antipsychotics might reduce craving and consumption of alcohol without the substantial adverse effect profile [152]. Furthermore, they are clinically used for alcohol‐dependent patients during the acute detoxification phase to prevent agitation, hallucinations and delirium tremens [153]. The alcohol dopamine mesocorticolimbic dopamine system (or the so‐called brain reward system, Figure 1) is one of the established neurobiological systems involved during the development and maintenance of alcohol dependence and thus one potential treatment target. Here, we aim to review the animal and human data describing the role of dopamine and the mesolimbic dopamine system during acute and chronic alcohol exposure. Finally, preclinical and clinical studies evaluating the potential of available dopaminergic agents as well as indirect dopamine modulators as novel medications for alcohol dependence are discussed.
Dopamine release was altered in a sex-dependent manner in chronic alcohol self-administering macaques
- Indeed, a recent study examining optogenetically evoked dopamine release in mice found no change in dopamine release in the NAc core and medial shell following chronic alcohol treatment, suggesting that the chronic alcohol effect may be due to mechanisms upstream of the dopamine terminal [58].
- Alcohol use is typically initiated during adolescence, and studies have found that alcohol can impact neurodevelopmental trajectories during this period.
- The preclinical and clinical evidence of the underlying interaction between alcohol and the dopamine D2 receptors within the mesocorticolimbic dopamine system during the acute as well as during chronic intake is reviewed below.
- Repeated alcohol exposure in mice activates another PTK, Src, which in turn stimulates Nf-κB/Tnfα signaling in microglia, resulting in microglia engulfment of mPFC synapses, as well as synaptic pruning and increased anxiety-like behaviors [57].
Recently, a genome-wide transcriptional assessment of human striatum found that G protein coupled receptors, the primary targets of many neurotransmitters and neuromodulators, were the top canonical pathway affected in striatum of AUD patients [70]. Reverse translation of these findings into a rodent model demonstrated putative therapeutic potential for a positive allosteric modulator of the muscarinic M4 receptor which, when delivered systemically in rats, reduced a wide range of alcohol self-administration behaviors [70]. Alcohol-induced epigenetic alterations are often mediated by altered expression or activity of epigenetic enzymes, which thus represent a promising new avenue for targeted therapeutic interventions. For example, increased enrichment of DNA methylation in the mPFC was linked to enhanced DNA methyltransferase (Dnmt) activity [23]. Inhibition of Dnmt rescued the methylation and transcriptional changes and prevented the escalation of alcohol intake [23]. Decreased binding of Cbp and lysine demethylase Kdm6b was also shown at specific target genes upon adolescent intermittent alcohol exposure, resulting in anxiety-like behaviors in adult rats [22].
Your Brain on Alcohol
Alcohol is metabolized to acetaldehyde, via the action of alcohol dehydrogenase (ADH), CYP2E1 and catalase. Acetaldehyde is known to be toxic active metabolite, it is implicated in; the induction of alcoholic cardiomyopathy [75], the development of cancers [76] and to have some neurobehavioral effects [77]. During intoxication the production of acetaldehyde can cause flushing, increased heart rate, dry mouth, nausea and headache [78].
The Neuroscience of Emotions: Clinical Relevance for Understanding Depression, Anxiety, and Addiction
Together with OSU6162’s favourable side effect profile [198, 197, 199], these results render support for a larger placebo‐controlled efficacy trial in alcohol‐dependent patients to evaluate OSU6162’s effect on drinking outcomes. As a further development of the partial agonist concept, Nobel Laureate Arvid Carlsson and co‐workers, developed a novel family of compounds based on their ability to stabilize, that is to stimulate, suppress or show no effect on the dopamine activity depending on the prevailing dopaminergic tone [189]. The mechanism of action is, however, not completely understood, and although in vitro studies indicate that OSU6162, like aripiprazole, acts as a partial agonist at D2 receptors [191, 192], behavioural studies have failed to demonstrate any intrinsic activity of the compound ([195]). Instead it has been suggested that OSU6162 produces functionally opposite effects by acting as an antagonist at both presynaptic autoreceptors and postsynaptic D2 receptors [189, 193–195].
Given the limitations of current non-invasive human neuroimaging methods, rodent studies have been instrumental in probing the neural circuits of behavior. While AB is difficult to model in rodents, much is known about Pavlovian conditioned responses to reward-predictive cues. For example, mesolimbic dopamine projections from the ventral tegmental area (VTA) to the NAc play a critical role in both Pavlovian conditioning and the expression of conditioned responses [16, 17]. In addition, fast dopamine release events (dopamine transients) commence at the onset of a conditioned cue [18, 19]. Pavlovian conditioned responses to alcohol cues in rodents provide a model of alcohol AB that allows direct measurements and mechanistic manipulations of the neural circuitry underlying AB [20,21,22]. Taken together, preclinical evidence indicates a key role for dopaminergic pathways in mediating responses to alcohol-related cues [23,24,25].
Supplementary Data 1
(It is important to note that high-DA reward responding was specific to the discriminative learning phase and DA activity decreased post-learning40). That NAc DA activity at sucrose reinforcement increased positively with reward anticipation suggests that whilst reward prediction error (RPE) is likely to be relevant to discriminative reward learning, three tests of 25 trials were insufficient for RPE to be established. In a mouse study in which a large number of tone-sucrose discriminative learning sessions were applied, it was indeed the case that the major NAc core DA activity shifted forward from sucrose retrieval to discriminative tone onset, in accordance with the RPE model41. Furthermore, in the present study, that CON mouse NAc DA activity at sucrose reinforcement increased as the interval between DS onset and reward reinforcement decreased, is also to some extent consistent with the RPE model42,43. Neuroimaging studies have also dramatically advanced our understanding of the brain’s response to alcohol and the neurochemical basis of alcohol dependence. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) use radiotracers that bind specifically to key receptors of interest, to quantify receptor location and availability.
- Although alcohol’s direct interaction with this cholinergic‐dopaminergic reward link remains to be fully elucidated, a study show that voluntary alcohol intake in high‐alcohol‐consuming rats causes a concomitant release of ventral tegmental acetylcholine and accumbal dopamine [39].
- Slowly over a period of time, the person craves more of the drug, to achieve the same kind of high as earlier.
- Our findings support prior work indicating the importance of dopaminergic signaling in salience network FC [101, 115], and supporting a potentially key role for this functional network in AB [116].
- Serotonin plays a role in many brain processes, including regulation of body temperature, sleep, mood, appetite and pain.
- Furthermore, FSCV allows for the study of dopamine uptake using Michaelis–Menten based kinetic modeling of uptake parameters, allowing researchers to assess dopamine transporter function.
- The primary neurotransmitter regulating the rewarding sensation was determined to be dopamine [11].
What effects does alcohol have on mental health?
Both acute and chronic alcohol exposure produce molecular and cellular neuroadaptations influencing the activity of discrete brain regions and cell types [3–5]. Reinforcement is a key phenomenon in the development of addiction to alcohol and other drugs. Positive reinforcement is the process by which an action that results in pleasure, or reward, becomes repetitive. Many people find the mental effects of alcohol consumption (e.g., euphoria) rewarding; this effect may lead to positive reinforcement and persistent alcohol-seeking behavior. The brain’s adaptive changes to the continued presence of alcohol result in feelings of discomfort and craving when alcohol consumption is abruptly reduced or discontinued.
- The dopamine stabilizer OSU6162 was recently evaluated in a placebo‐controlled human laboratory alcohol craving study in 56 alcohol dependent individuals [197].
- It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression.
- As these cells degrade, motor function is compromised, which includes tremors, rigidity, bradykinesia or slowed movement, as well as changes in speech and gait.
- Apart from the dopamine pathways, the addiction to alcohol has also been suggested through the serotonin pathways.
- It must be acknowledged that PET/SPECT is somewhat limited as a technique because of its radioactivity meaning that young people and repeat scanning cannot be carried out.
Supplementary Data 5
