International Review Of Neurobiology[JOURNAL]
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200 papers
Cannabidiol and Alzheimer's disease.
Marques BL, Campos AC
Int Rev Neurobiol · 2024 · PMID 39029982 · Publisher ↗
Alzheimer's disease (AD) stands as the most prevalent form of neuropsychiatric disorder among the elderly population, impacting a minimum of 50 million individuals worldwide. Current pharmacological treatments rely on th...
Alzheimer's disease (AD) stands as the most prevalent form of neuropsychiatric disorder among the elderly population, impacting a minimum of 50 million individuals worldwide. Current pharmacological treatments rely on the prescribing cholinesterase inhibitors and memantine. However,recently anecdotal findings based on low-quality real-world data had prompted physicians, patients, and their relatives to consider the use of cannabinoids, especially Cannabidiol (CBD), for alleviating of AD symptoms. CBD the primary non-psychotomimetic compound found in the Cannabis sp. plant, exhibits promising therapeutic potential across various clinical contexts. Pre-clinical and in vitro studies indicate that CBD could mitigate cognitive decline and amyloid-beta-induced neurodegeneration by modulating oxidative stress and neuroinflammation. In addition, CBD demonstrates significant effects in promoting neuroplasticity, particularly in brain regions such as the hippocampus. However, the available clinical evidence presents conflicting results, and no randomized placebo-controlled trials have been published to date. In conclusion, although pre-clinical and in vitro studies offer encouraging insights into the potential benefits of CBD in AD models, new and well-designed clinical trials are imperative to ascertain the clinical relevance of CBD use in the management of AD symptoms, especially in comparison to conventional treatments.
Cannabidiol: Pharmacodynamics and pharmacokinetic in the context of neuropsychiatric disorders.
Lirio PHC, Gaspari PDM, Campos AC
Int Rev Neurobiol · 2024 · PMID 39029981 · Publisher ↗
In this chapter we explored the growing interest in cannabinoids, particularly cannabidiol (CBD), over the last two decades due to their potential therapeutic applications in neurodegenerative and psychiatric disorders....
In this chapter we explored the growing interest in cannabinoids, particularly cannabidiol (CBD), over the last two decades due to their potential therapeutic applications in neurodegenerative and psychiatric disorders. CBD, a major non-psychotomimetic compound derived from Cannabis sativa, is highlighted as a safer alternative to other cannabinoids like Δ9-tetrahydrocannabinol (THC). Clinical trials have been investigating CBD formulations for conditions such as schizophrenia, multiple sclerosis, Alzheimer's, Parkinson's diseases, and stress-related disorders. However, limited access to CBD-approved formulations primarily due to their high-cost and concerns about the quality of market-available products, challenges regulatory agencies globally. The pharmacokinetics of CBD, especially after oral administration, present challenges with erratic absorption and low bioavailability. CBD's "promiscuous" pharmacodynamics involve interactions with various targets beyond the endocannabinoid system, complicating precise dosing in therapeutic interventions. This chapter delves into CBD's dose-response curves, revealing complexities that pose challenges in clinical practice. Nanobiotechnology emerges as a promising solution, with recent developments showing improved bioavailability, stability, and reduced toxicity through nanoencapsulation of CBD. While this phytocannabinoid holds immense promise in neuropsychopharmacology, we provided a comprehensive overview of the current state of CBD research and suggests potential future directions regarding the pharmacology of CBD, harnessing the benefits of this intriguing compound.
Historical perspective on the therapeutic potential of cannabidiol.
Guimarães FS
Int Rev Neurobiol · 2024 · PMID 39029980 · Publisher ↗
Cannabidiol (CBD) is one of over 200 cannabinoids present in the Cannabis plant. Unlike the plant's primary cannabinoid, delta-9-tetrahydrocannabinol (THC), CBD does not produce psychotomimetic effects nor induce depende...
Cannabidiol (CBD) is one of over 200 cannabinoids present in the Cannabis plant. Unlike the plant's primary cannabinoid, delta-9-tetrahydrocannabinol (THC), CBD does not produce psychotomimetic effects nor induce dependence. Initially considered an inactive cannabinoid, interest in its pharmacological properties and therapeutic potential has grown exponentially over the last 20 years. Currently employed as a medication for certain epileptic syndromes, numerous pre-clinical and clinical studies support its potential use in various other disorders. In this chapter, we provide a brief historical overview of how this compound evolved from an "inactive substance" to a multifunctional clinical agent. Additionally, we discuss the current challenges in researching its potential therapeutic effects.
Contribution of neurophysiology to the diagnosis and monitoring of ALS.
Vucic S, de Carvalho M, Bashford J … +1 more , Alix JJP
Int Rev Neurobiol · 2024 · PMID 38802184 · Publisher ↗
This chapter describes the role of neurophysiological techniques in diagnosing and monitoring amyotrophic lateral sclerosis (ALS). Despite many advances, electromyography (EMG) remains a keystone investigation from which...
This chapter describes the role of neurophysiological techniques in diagnosing and monitoring amyotrophic lateral sclerosis (ALS). Despite many advances, electromyography (EMG) remains a keystone investigation from which to build support for a diagnosis of ALS, demonstrating the pathophysiological processes of motor unit hyperexcitability, denervation and reinnervation. We consider development of the different diagnostic criteria and the role of EMG therein. While not formally recognised by established diagnostic criteria, we discuss the pioneering studies that have demonstrated the diagnostic potential of transcranial magnetic stimulation (TMS) of the motor cortex and highlight the growing evidence for TMS in the diagnostic process. Finally, accurately monitoring disease progression is crucial for the successful implementation of clinical trials. Neurophysiological measures of disease state have been incorporated into clinical trials for over 20 years and we review prominent techniques for assessing disease progression.
Non-coding genome contribution to ALS.
Moll T, Harvey C, Alhathli E … +3 more , Gornall S, O'Brien D, Cooper-Knock J
Int Rev Neurobiol · 2024 · PMID 38802183 · Publisher ↗
The majority of amyotrophic lateral sclerosis (ALS) is caused by a complex gene-environment interaction. Despite high estimates of heritability, the genetic basis of disease in the majority of ALS patients are unknown. T...
The majority of amyotrophic lateral sclerosis (ALS) is caused by a complex gene-environment interaction. Despite high estimates of heritability, the genetic basis of disease in the majority of ALS patients are unknown. This limits the development of targeted genetic therapies which require an understanding of patient-specific genetic drivers. There is good evidence that the majority of these missing genetic risk factors are likely to be found within the non-coding genome. However, a major challenge in the discovery of non-coding risk variants is determining which variants are functional in which specific CNS cell type. We summarise current discoveries of ALS-associated genetic drivers within the non-coding genome and we make the case that improved cell-specific annotation of genomic function is required to advance this field, particularly via single-cell epigenetic profiling and spatial transcriptomics. We highlight the example of TBK1 where an apparent paradox exists between pathogenic coding variants which cause loss of protein function, and protective non-coding variants which cause reduced gene expression; the paradox is resolved when it is understood that the non-coding variants are acting primarily via change in gene expression within microglia, and the effect of coding variants is most prominent in neurons. We propose that cell-specific functional annotation of ALS-associated genetic variants will accelerate discovery of the genetic architecture underpinning disease in the vast majority of patients.
Recent advances in the genetics of familial and sporadic ALS.
Al-Chalabi A, Andrews J, Farhan S
Int Rev Neurobiol · 2024 · PMID 38802182 · Publisher ↗
ALS shows complex genetic inheritance patterns. In about 5% to 10% of cases, there is a family history of ALS or a related condition such as frontotemporal dementia in a first or second degree relative, and for about 80%...
ALS shows complex genetic inheritance patterns. In about 5% to 10% of cases, there is a family history of ALS or a related condition such as frontotemporal dementia in a first or second degree relative, and for about 80% of such people a pathogenic gene variant can be identified. Such variants are also seen in people with no family history because of factor influencing the expression of genes, such as age. Genetic susceptibility factors also contribute to risk, and the heritability of ALS is between 40% and 60%. The genetic variants influencing ALS risk include single base changes, repeat expansions, copy number variants, and others. Here we review what is known of the genetic landscape and architecture of ALS.
New developments in pre-clinical models of ALS to guide translation.
De Cock L, Bercier V, Van Den Bosch L
Int Rev Neurobiol · 2024 · PMID 38802181 · Publisher ↗
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder in which selective death of motor neurons leads to muscle weakness and paralysis. Most research has focused on understanding and treating mo...
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder in which selective death of motor neurons leads to muscle weakness and paralysis. Most research has focused on understanding and treating monogenic familial forms, most frequently caused by mutations in SOD1, FUS, TARDBP and C9orf72, although ALS is mostly sporadic and without a clear genetic cause. Rodent models have been developed to study monogenic ALS, but despite numerous pre-clinical studies and clinical trials, few disease-modifying therapies are available. ALS is a heterogeneous disease with complex underlying mechanisms where several genes and molecular pathways appear to play a role. One reason for the high failure rate of clinical translation from the current models could be oversimplification in pre-clinical studies. Here, we review advances in pre-clinical models to better capture the heterogeneous nature of ALS and discuss the value of novel model systems to guide translation and aid in the development of precision medicine.
RNP granules in ALS and neurodegeneration: From multifunctional membraneless organelles to therapeutic opportunities.
Shelkovnikova TA, Hautbergue GM
Int Rev Neurobiol · 2024 · PMID 38802180 · Publisher ↗
Amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases are characterised by dysfunction of a host of RNA-binding proteins (RBPs) and a severely disrupted RNA metabolism. Recently, RBP-harbouring phase...
Amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases are characterised by dysfunction of a host of RNA-binding proteins (RBPs) and a severely disrupted RNA metabolism. Recently, RBP-harbouring phase-separated complexes, ribonucleoprotein (RNP) granules, have come into the limelight as "crucibles" of neuronal pathology in ALS. RNP granules are indispensable for the multitude of regulatory processes underlying cellular RNA metabolism and serve as critical organisers of cellular biochemistry. Neurons, highly specialised cells, heavily rely on RNP granules for efficient trafficking, signalling and stress responses. Multiple RNP granule components, primarily RBPs such as TDP-43 and FUS, are affected by ALS mutations. However, even in the absence of mutations, RBP proteinopathies represent pathophysiological hallmarks of ALS. Given the high local concentrations of RBPs and RNAs, their weakened or enhanced interactions within RNP granules disrupt their homeostasis. Thus, the physiological process of phase separation and RNP granule formation, vital for maintaining the high-functioning state of neuronal cells, becomes their Achilles heel. Here, we will review the recent literature on the causes and consequences of abnormal RNP granule functioning in ALS and related disorders. In particular, we will summarise the evidence for the network-level dysfunction of RNP granules in these conditions and discuss considerations for therapeutic interventions to target RBPs, RNP granules and their network as a whole.
The role of glial cells in amyotrophic lateral sclerosis.
Pandya VA, Patani R
Int Rev Neurobiol · 2024 · PMID 38802179 · Publisher ↗
Amyotrophic lateral sclerosis (ALS) has traditionally been considered a neuron-centric disease. This view is now outdated, with increasing recognition of cell autonomous and non-cell autonomous contributions of central a...
Amyotrophic lateral sclerosis (ALS) has traditionally been considered a neuron-centric disease. This view is now outdated, with increasing recognition of cell autonomous and non-cell autonomous contributions of central and peripheral nervous system glia to ALS pathomechanisms. With glial research rapidly accelerating, we comprehensively interrogate the roles of astrocytes, microglia, oligodendrocytes, ependymal cells, Schwann cells and satellite glia in nervous system physiology and ALS-associated pathology. Moreover, we highlight the inter-glial, glial-neuronal and inter-system polylogue which constitutes the healthy nervous system and destabilises in disease. We also propose classification based on function for complex glial reactive phenotypes and discuss the pre-requisite for integrative modelling to advance translation. Given the paucity of life-enhancing therapies currently available for ALS patients, we discuss the promising potential of harnessing glia in driving ALS therapeutic discovery.
Current neuroprotective therapies and future prospects for motor neuron disease.
Evans LJ, O'Brien D, Shaw PJ
Int Rev Neurobiol · 2024 · PMID 38802178 · Publisher ↗
Four medications with neuroprotective disease-modifying effects are now in use for motor neuron disease (MND). With FDA approvals for tofersen, relyvrio and edaravone in just the past year, 2022 ended a quarter of a cent...
Four medications with neuroprotective disease-modifying effects are now in use for motor neuron disease (MND). With FDA approvals for tofersen, relyvrio and edaravone in just the past year, 2022 ended a quarter of a century when riluzole was the sole such drug to offer to patients. The acceleration of approvals may mean we are witnessing the beginning of a step-change in how MND can be treated. Improvements in understanding underlying disease biology has led to more therapies being developed to target specific and multiple disease mechanisms. Consideration for how the pipeline of new therapeutic agents coming through in clinical and preclinical development can be more effectively evaluated with biomarkers, advances in patient stratification and clinical trial design pave the way for more successful translation for this archetypal complex neurodegenerative disease. While it must be cautioned that only slowed rates of progression have so far been demonstrated, pre-empting rapid neurodegeneration by using neurofilament biomarkers to signal when to treat, as is currently being trialled with tofersen, may be more effective for patients with known genetic predisposition to MND. Early intervention with personalized medicines could mean that for some patients at least, in future we may be able to substantially treat what is considered by many to be one of the most distressing diseases in medicine.
Evidence of mitochondrial dysfunction in ALS and methods for measuring in model systems.
Lee J, Pye N, Ellis L … +2 more , Vos K, Mortiboys H
Int Rev Neurobiol · 2024 · PMID 38802177 · Publisher ↗
Metabolic dysfunction is a hallmark of multiple amyotrophic lateral sclerosis (ALS) models with a majority of ALS patients exhibiting hypermetabolism. The central sites of metabolism in the cell are mitochondria, capable...
Metabolic dysfunction is a hallmark of multiple amyotrophic lateral sclerosis (ALS) models with a majority of ALS patients exhibiting hypermetabolism. The central sites of metabolism in the cell are mitochondria, capable of utilising a multitude of cellular substrates in an array of ATP-generating reactions. With reactive oxygen species (ROS) production occurring during some of these reactions, mitochondria can contribute considerably to oxidative stress. Mitochondria are also very dynamic organelles, interacting with other organelles, undergoing fusion/fission in response to changing metabolic states and being turned over by the cell regularly. Disruptions to many of these mitochondrial functions and processes have been reported in ALS models, largely indicating compromised mitochondrial function, increased ROS production by mitochondria, disrupted interactions with the endoplasmic reticulum and reduced turnover. This chapter summarises methods routinely used to assess mitochondria in ALS models and the alterations that have been reported in these models.
From use of omics to systems biology: Identifying therapeutic targets for amyotrophic lateral sclerosis.
Castelli L, Vasta R, Allen SP … +4 more , Waller R, Chiò A, Traynor BJ, Kirby J
Int Rev Neurobiol · 2024 · PMID 38802176 · Publisher ↗
Amyotrophic lateral sclerosis (ALS) is a heterogeneous progressive neurodegenerative disorder with available treatments such as riluzole and edaravone extending survival by an average of 3-6 months. The lack of highly ef...
Amyotrophic lateral sclerosis (ALS) is a heterogeneous progressive neurodegenerative disorder with available treatments such as riluzole and edaravone extending survival by an average of 3-6 months. The lack of highly effective, widely available therapies reflects the complexity of ALS. Omics technologies, including genomics, transcriptomic and proteomics have contributed to the identification of biological pathways dysregulated and targeted by therapeutic strategies in preclinical and clinical trials. Integrating clinical, environmental and neuroimaging information with omics data and applying a systems biology approach can further improve our understanding of the disease with the potential to stratify patients and provide more personalised medicine. This chapter will review the omics technologies that contribute to a systems biology approach and how these components have assisted in identifying therapeutic targets. Current strategies, including the use of genetic screening and biosampling in clinical trials, as well as the future application of additional technological advances, will also be discussed.
Use of biomarkers in clinical trials and future developments that will help identify novel biomarkers.
Malaspina A
Int Rev Neurobiol · 2024 · PMID 38802175 · Publisher ↗
Engineering new solutions for therapeutic benefit in Amyotrophic Lateral Sclerosis (ALS) has proved a difficult task to accomplish. This is largely the reflection of complexities at multiple levels, that require solution...
Engineering new solutions for therapeutic benefit in Amyotrophic Lateral Sclerosis (ALS) has proved a difficult task to accomplish. This is largely the reflection of complexities at multiple levels, that require solutions to improve cost-effectiveness and outcomes. The main obstacle related to the condition's clinical heterogeneity, chiefly the broad difference in survival observed among ALS patients, imposes large populations studies and long follow-up to evaluate any efficacy. The emerging solution is composite clinical and biological parameters enabling prognostic stratification into homogeneous phenotypes for more affordable studies. From a therapeutic development perspective, the choice of a medicinal product requires the availability of treatment-specific biomarkers of target engagement to identify off-target effects based on the compound's putative modality of action. More importantly, there are no established biomarkers of treatment response that can complement clinical outcome measures and support futility and end of treatment analyses of efficacy. Ultimately the onus rests on the development of biomarkers encompassing the unmet needs of clinical trial design, from inclusion to efficacy. These readouts of the pathological process may be used in combination with clinical and paraclinical outcome measured, significantly reducing the time and financial burden of clinical studies. Progress towards a biomarker-driven clinical trial design in ALS has been possible thanks to the accurate detection of neurofilaments and of other immunological mediators in biological fluids with the disease progression, a step change enabling the testing of novel therapeutic agents in a new clinical trial setting. However, further progress remains to be made to find treatment specific target engagement biomarkers along with readouts of treatment response that can be reliably applied to all emerging therapies and clinical studies. Here we will cover the basic notions of biomarker development in ALS clinical trials, the most crucial unanswered questions and the unmet needs in the ALS biomarkers space.
Advances in symptom management and in monitoring disease progression in motor neuron disease.
Hobson E, McDermott C
Int Rev Neurobiol · 2024 · PMID 38802174 · Publisher ↗
The aim of supportive management of motor neuron disease is to improve survival, promote good quality of life and patient independence and autonomy whilst preparing for future progression and the end of life. Multidiscip...
The aim of supportive management of motor neuron disease is to improve survival, promote good quality of life and patient independence and autonomy whilst preparing for future progression and the end of life. Multidisciplinary specialist care aims to address the multifaceted and interacting biopsychosocial problems associated with motor neuron disease that leads to proven benefits in both survival and quality of life. This chapter will explore principles, structure and details of treatment options, and make recommendations for practice and for future research.
Amyotrophic lateral sclerosis; clinical features, differential diagnosis and pathology.
Van Es MA
Int Rev Neurobiol · 2024 · PMID 38802173 · Publisher ↗
Amyotrophic lateral sclerosis (ALS) is a late-onset syndrome characterized by the progressive degeneration of both upper motor neurons (UMN) and lower motor neurons (LMN). ALS forms a clinical continuum with frontotempor...
Amyotrophic lateral sclerosis (ALS) is a late-onset syndrome characterized by the progressive degeneration of both upper motor neurons (UMN) and lower motor neurons (LMN). ALS forms a clinical continuum with frontotemporal dementia (FTD), in which there are progressive language deficits or behavioral changes. The genetics and pathology underlying both ALS and FTD overlap as well, with cytoplasmatic misvocalization of TDP-43 as the hallmark. ALS is diagnosed by exclusion. Over the years several diagnostic criteria have been proposed, which in essence all require a history of slowly progressive motor symptoms, with UMN and LMN signs on neurological examination, clear spread of symptoms through the body, the exclusion of other disorder that cause similar symptoms and an EMG that it is compatible with LMN loss. ALS is heterogeneous disorder that may present in multitude ways, which makes the diagnosis challenging. Therefore, a systematic approach in the diagnostic process is required in line with the most common presentations. Subsequently, assessing whether there are cognitive and/or behavioral changes within the spectrum of FTD and lastly determining the cause is genetic. This chapter, an outline on how to navigate this 3 step process.
GABAergic mechanisms in alcohol dependence.
Uusi-Oukari M, Korpi ER
Int Rev Neurobiol · 2024 · PMID 38555121 · Publisher ↗
The target of alcohol's effect on the central nervous system has been sought for more than 50 years in the brain's GABA system. The behavioral and emotional effects of alcohol in humans and rodents are very similar to th...
The target of alcohol's effect on the central nervous system has been sought for more than 50 years in the brain's GABA system. The behavioral and emotional effects of alcohol in humans and rodents are very similar to those of barbiturates and benzodiazepines, and GABA receptors have been shown to be one of the sites of alcohol action. The mechanisms of GABAergic inhibition have been a hotspot of research but have turned out to be complex and controversial. Genetics support the involvement of some GABA receptor subunits in the development of alcohol dependence and in alcohol use disorders (AUD). Since the effect of alcohol on the GABA system resembles that of a GABAergic positive modulator, it may be possible to develop GABAergic drug treatments that could substitute for alcohol. The adaptation mechanisms of the GABA system and the plasticity of the brain are a big challenge for drug development: the drugs that act on GABA receptors developed so far also may cause adaptation and development of additional addiction. Human polymorphisms should be studied further to get insight about how they affect receptor function, expression or other factors to make reasonable predictions/hypotheses about what non-addictive interventions would help in alcohol dependence and AUD.
Phosphatidylethanol (B-PEth) and other direct and indirect biomarkers of alcohol consumption.
de Bejczy A
Int Rev Neurobiol · 2024 · PMID 38555120 · Publisher ↗
When identifying, preventing and treating alcohol use disorder, a correct estimation of alcohol intake is essential. An objective marker is preferred as self-reported alcohol intake suffers from bias, and the use of alco...
When identifying, preventing and treating alcohol use disorder, a correct estimation of alcohol intake is essential. An objective marker is preferred as self-reported alcohol intake suffers from bias, and the use of alcohol biomarkers is increasing globally. An easy-to-use blood biomarker to correctly assess alcohol consumption is an invaluable asset in alcohol treatment strategies, as well as in alcohol research studies. The specific, cumulative, biomarker phosphatidylethanol, mirroring the past two weeks of consumption, has shown superiority over traditional biomarkers and is an attractive choice of proxy for alcohol intake.
Designing and testing treatments for alcohol use disorder.
Witkiewitz K, Tuchman FR
Int Rev Neurobiol · 2024 · PMID 38555119 · Publisher ↗
This chapter provides a succinct overview of several recommendations for the design and analysis of treatments for AUD with a specific focus on increasing rigor and generalizability of treatment studies in order to incre...
This chapter provides a succinct overview of several recommendations for the design and analysis of treatments for AUD with a specific focus on increasing rigor and generalizability of treatment studies in order to increase the reach of AUD treatment. We recommend that researchers always register their trials in a clinical trial registry and make the protocol accessible so that the trial can be replicated in future work, follow CONSORT reporting guidelines when reporting the results of the trial, carefully describe all inclusion and exclusion criteria as well as the randomization scheme, and always use an intent to treat design with attention to analysis of missing data. In addition, we recommend that researchers pay closer attention to recruitment and engagement strategies that increase enrollment and retention of historically marginalized and understudied populations, and we end with a plea for more consideration of implementation science approaches to increase the dissemination and implementation of AUD treatment in real-world settings.
Reducing the harms of alcohol: nutritional interventions and functional alcohol alternatives.
Belelli D, Riva A, Nutt DJ
Int Rev Neurobiol · 2024 · PMID 38555118 · Publisher ↗
The health risks and harm associated with regular alcohol consumption are well documented. In a recent WHO statement published in The Lancet Public Health alcohol consumption has been estimated to contribute worldwide to...
The health risks and harm associated with regular alcohol consumption are well documented. In a recent WHO statement published in The Lancet Public Health alcohol consumption has been estimated to contribute worldwide to 3 million deaths in 2016 while also being responsible for 5·1% of the global burden of disease and injury. The total elimination of alcohol consumption, which has been long imbedded in human culture and society, is not practical and prohibition policies have proved historically ineffective. However, valuable strategies to reduce alcohol harms are already available and improved alternative approaches are currently being developed. Here, we will review and discuss recent advances on two main types of approaches, that is nutritional interventions and functional alcohol alternatives.
Alcohol and the dopamine system.
Söderpalm B, Ericson M
Int Rev Neurobiol · 2024 · PMID 38555117 · Publisher ↗
The mesolimbic dopamine pathway plays a major role in drug reinforcement and is likely involved also in the development of drug addiction. Ethanol, like most addictive drugs, acutely activates the mesolimbic dopamine sys...
The mesolimbic dopamine pathway plays a major role in drug reinforcement and is likely involved also in the development of drug addiction. Ethanol, like most addictive drugs, acutely activates the mesolimbic dopamine system and releases dopamine, and ethanol-associated stimuli also appear to trigger dopamine release. In addition, chronic exposure to ethanol reduces the baseline function of the mesolimbic dopamine system. The molecular mechanisms underlying ethanol´s interaction with this system remain, however, to be unveiled. Here research on the actions of ethanol in the mesolimbic dopamine system, focusing on the involvement of cystein-loop ligand-gated ion channels, opiate receptors, gastric peptides and acetaldehyde is briefly reviewed. In summary, a great complexity as regards ethanol´s mechanism(s) of action along the mesolimbic dopamine system has been revealed. Consequently, several new targets and possibilities for pharmacotherapies for alcohol use disorder have emerged.
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