High levels of D2 receptor expression may protect against alcoholism and have been shown to reduce drinking in human subjects (Kraschewski et al., 2009; Volkow et al., 2006). To date, most of the studies of chronic ethanol-induced changes in DA receptor function have focused on striatal changes and very few have focused on changes in PFC. However, the more recent appreciation of the important role that cognitive dysfunction plays in addiction has suggested that changes in DA receptors in PFC may accompany these changes that occur in striatum. These observations are in general agreement with recent studies examining prefrontal function in chronic alcohol-exposed mice (Holmes et al., 2012; Kroener et al., 2012).
Understanding Dopamine and Its Role in Addiction
Serotonin (5-hydroxytryptamine, or 5-HT) is involved in emotional regulation and social behavior, and alcohol alters its signaling by interacting with multiple receptor subtypes. The 5-HT3 and 5-HT2A receptors are particularly relevant to alcohol’s does alcohol cause dopamine release rewarding and disinhibitory effects. Chronic alcohol consumption induces compensatory upregulation of NMDA receptors, heightening excitatory signaling and contributing to tolerance.
2.2. Clinical evidence for the use of atypical dopamine D2 antagonists for the treatment of alcohol dependence
The potential of nAChR’s as novel treatment target was revived with the marketing of the partial nAChR agonist varenicline as a smoking cessation agent. It has been shown that varenicline reduce alcohol intake and alcohol‐seeking behaviour in long‐term drinking rats 205 and modulate NAc dopamine after systemic administrations of alcohol alone and in combination with nicotine 206. Based marijuana addiction on this clinical finding and the knowledge that olanzapine also has a high affinity for the D4 receptors, it was hypothesized whether the dopamine receptor D4 gene maybe involved in meditating its clinical effects.
Gene variants related to DA systems and alcohol dependence
- For the McGill study, researchers recruited 26 healthy social drinkers (18 men, 8 women), 18 to 30 years of age.
- Based on this clinical finding and the knowledge that olanzapine also has a high affinity for the D4 receptors, it was hypothesized whether the dopamine receptor D4 gene maybe involved in meditating its clinical effects.
- We offer free aftercare for the men who complete our program and have a strong alumni network that remains active in the community.
- Ongoing research is exploring new treatment approaches for alcohol use disorders that target the dopamine system.
- „With Nalmefene, we seem to be able to ‚block the buzz‘ which makes people continue to drink larger amounts. With such a harm reduction approach, a new chapter in treating alcoholism could be opened,“ said Mann.
Moreover, data from a randomized clinical trial in alcohol‐dependent individuals show that the smoking cessation agent reduced the weekly percent heavy drinking days drinks, decreased the drinks per drinking day as well as prevented alcohol craving 211. It should, however, be noted that recent clinical trials in alcohol‐dependent individuals were unable to find a beneficial effect of varenicline based on self‐reported alcohol consumption 212, 213. Besides glycine receptors and nAChR, there are various signalling systems indirectly targeting the mesolimbic dopamine system with promising preclinical findings on alcohol‐mediated behaviours. Collectively, these data indicate that indirect modulation of dopamine signalling might be a potential target for novel treatment strategies for alcohol dependence and that these targets should be investigated in more detail in human laboratory studies as well as randomized clinical trials. Studies elucidating the underlying mechanism of action of the complex dopamine–alcohol interaction have been conducted. On the other hand, local administration of the dopamine D2 receptor antagonist, sulpiride, into the anterior VTA did not alter alcohol nor sucrose intake in high‐alcohol‐preferring rats 142.
Consequently, an alcohol-induced increase in 5-HT3 receptor activity would enhance dopamine release in these brain regions, thereby contributing to alcohol’s rewarding effects. This hypothesis is supported by the results of studies in animal models (Campbell and McBride 1995; Grant 1995; Wozniak et al. 1990), which also found that 5-HT3 receptor antagonists interfered with the serotonin-induced dopamine release in the brain’s reward systems. These findings may help explain the antagonists’ ability to reduce drinking behavior. With regards to the VTA, both in vitro and in vivo studies show that alcohol increases the firing of dopamine neurons in the VTA projecting to NAc 75–79, 40. Similarly, in a situation of synaptic transmission blockade, alcohol has been found to increase the firing of dissociated VTA dopamine neurons 76, 77 implying that alcohol activates ventral tegmental dopamine neurons independent of afferent signalling. Furthermore, studies with intra‐VTA alcohol infusions highlight that different subregions within the heterogeneous VTA might have different ability to modulate the alcohol‐induced dopamine response.
The 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. Over time, the brain’s reward system becomes overstimulated by alcohol-induced dopamine surges.
1.1. Preclinical evidence for the use of dopamine D2 receptor antagonists to attenuate alcohol‐mediated behaviours
For example, rats receiving a palatable food for the first time exhibited significant dopaminergic signal transmission in the NAc shell. A second feeding session that took place within 1 day of the first feeding session, however, induced no or only weak dopaminergic signal transmission. Only about 5 days after the first feeding session did the animals recover the full dopaminergic response to this stimulus. As discussed later in this article, however, alcohol does not induce a comparable habituation.
MDMA’s Impact on the Brain: Neurotransmitters, Effects, and Potential Risks
Dopamine also activates memory circuits in other parts of the brain that remember this pleasant experience and leave you thirsting for more. But over time, alcohol can cause dopamine levels to plummet, leaving you feeling miserable and desiring more alcohol to feel better. Disulfiram administration helps patients learn non-drinking behaviours and the ability to exercise self-control. Most individuals cease alcohol use after the administration of disulfiram due to the strong expectancy of negative consequences.
Does alcohol damage your brain?
It should also be mentioned that infusion of the dopamine D1‐like agonist SKF into NAc had no effect on alcohol self‐administration in rats 141. Albeit the data are somewhat contradictory, it might be hypothesized that accumbal as well as ventral tegmental dopamine D2 receptors may regulate alcohol reinforcement in rodents. In healthy controls, alcohol consumption stimulates dopamine release mediating its reinforcing effects. Repeated bouts of intoxications will overtime downregulate the dopamine activity in the mesocorticolimbic pathway, leading to an increased risk of developing alcohol dependence and other impulse control disorders. Further, it has been speculated that this dopamine deficiency is responsible for driving craving and compulsive drinking and contributes to relapse even after a period of protracted abstinence 18, 19. 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.