Currently, due to the knowledge of the addictive potential of dopamine agonists, combined with the lack of consistent findings from clinical studies, it is suggested that dopamine receptor agonists do not hold promise as a treatment for alcohol dependence. A partial agonist, such as aripiprazole, has a lower intrinsic activity at the receptor than a full agonist e.
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In the presence of high levels of the full agonist, a partial agonist will have functional antagonistic activity by binding to the receptor and preventing the response from the full agonist. Partial dopamine D2 agonists, therefore, offer the opportunity to treat the dysregulated dopamine activity during acute alcohol consumption as well as alcohol dependence.
In line with the hypothesis that a partial dopamine D2 agonist would block the reinforcing effects of alcohol, aripiprazole attenuates alcohol's ability to increase the locomotor activity in mice [ , ] an indirect measure of activation of the mesolimbic dopamine system. A pilot study showed that aripiprazole reduces the rate of relapse and craving in patients with alcohol dependence [ ]. This study showed that aripiprazole decreased heavy drinking days compared to placebo during week four and eight; however, the effect was lost by the maximum dose at week twelve [ ].
The mechanism of action is, however, not completely understood, and although in vitro studies indicate that OSU, like aripiprazole, acts as a partial agonist at D2 receptors [ , ], behavioural studies have failed to demonstrate any intrinsic activity of the compound [ ]. Instead it has been suggested that OSU produces functionally opposite effects by acting as an antagonist at both presynaptic autoreceptors and postsynaptic D2 receptors [ , — ]. Collectively, together with the finding that OSU did not induce conditioned place preference [ 29 ] an indication that the compound has no rewarding properties of its own , these results indicate that OSU has many of the favourable characteristics of a potential medication for alcohol dependence.
Interestingly, the treatment effects of OSU were driven by those individuals with high level of baseline impulsivity, corroborating previous results with the partial dopamine D2 agonist aripiprazole [ ]. These results suggest that pharmacological stabilization of the dopamine system might prove as an effective target for alleviating some of the reward driven behaviours during alcohol dependence. As mentioned previously, in addition the affecting the dopamine system directly, alcohol interacts with the mesolimbic dopamine system indirectly via several other neurotransmitters.
There is a wide range of such compounds, and here, we will only mention a few, specifically targeting glycine receptors and nAChRs, with a clear interaction with dopamine transmission in the mesolimbic dopamine system [ 64 ].
Emerging data suggests that the activity of dopamine neurons in the VTA projecting to the NAc is regulated by several afferents, such as, for example the cholinergic neurons projecting from the laterodorsal tegmental nucleus LDTg for review see [ ]. These nAChR antagonists are limited in a clinical setting due to low blood—brain barrier permeability and an unfavourable side effect profile. 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.
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. Extensive preclinical and clinical research support the hypothesis that alcohol's acute reinforcing effects are mediated through a dopamine surge in the mesocorticolimbic dopamine system and that the chronic and excessive alcohol consumption, in contrast, induces a dopamine deficient state driving the processes of craving and relapse.
These complex relationships need to be investigated further.
Given dopamine's pivotal role in the development and maintenance of alcohol dependence, medications targeting dopamine does constitute an important area of research. The side effects profile of many of the evaluated compounds, including typical antipsychotic drugs, render them clinically unfavourable. Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Help us write another book on this subject and reach those readers. Login to your personal dashboard for more detailed statistics on your publications.
Edited by William Meil. Edited by Roy Priti. We are IntechOpen, the world's leading publisher of Open Access books. Built by scientists, for scientists. Our readership spans scientists, professors, researchers, librarians, and students, as well as business professionals. Downloaded: Abstract Alcohol dependence, a chronic relapsing psychiatric disorder, is a major cause of mortality and morbidity.
Jerlhag pharm. Introduction Alcohol dependence is a chronic relapsing psychiatric disorder significantly contributing to the global burden of disease [ 1 ] and affects about four percent of the world's population over the age of 15 WHO. The brain reward system: the mesocorticolimbic dopamine system The mesocorticolimbic dopamine system has an established role in driving the rewarding sensations from natural rewards such as food, sex and exercise, which are important behaviours to ensure our survival [ 6 , 7 ] as well as among drugs of abuse, including alcohol for review see [ 8 ].
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Interaction between alcohol and the mesocorticolimbic dopamine system 1. Preclinical evidence: chronic alcohol exposure and dopamine As mentioned above, it has been hypothesized that the chronic intake of alcohol induces a dopamine deficit state in the brain reward system and that this dysfunction may drive craving and relapse to drinking [ , 18 , 19 ]. The dopamine system: a potential treatment target for alcohol dependence 2. Clinical evidence for the use of dopamine D2 antagonists for the treatment of alcohol dependence Based on the preclinical evidence of a reduction in alcohol consumption via blockade of dopamine D2 receptors, the potential of dopamine D2 antagonists as a pharmacotherapy for alcohol dependence has been investigated in clinical populations.
Preclinical evidence for the use of atypical dopamine D2 receptor antagonists i. Dopamine D2 agonists As described previously, in vivo microdialysis studies rodent and imaging studies in individuals with alcohol dependence have demonstrated that chronic exposure to alcohol induce a dopamine deficit state. Clinical evidence for the use of dopamine agonists for the treatment of alcohol dependence Bromocriptine, a dopamine agonist has been used clinically for Parkinson's disease.
Pharmacological agents inducing indirect modulation of dopamine As mentioned previously, in addition the affecting the dopamine system directly, alcohol interacts with the mesolimbic dopamine system indirectly via several other neurotransmitters. Conclusion Extensive preclinical and clinical research support the hypothesis that alcohol's acute reinforcing effects are mediated through a dopamine surge in the mesocorticolimbic dopamine system and that the chronic and excessive alcohol consumption, in contrast, induces a dopamine deficient state driving the processes of craving and relapse.
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