International review of neurobiology最新文献

Repurposing drugs for the treatment of alcohol dependence involves the use of drugs that were initially developed for other conditions, but have shown promise in reducing alcohol use or preventing relapse. This approach can offer a more cost-effective and time-efficient alternative to developing new drugs from scratch. Currently approved medications for alcohol use disorder (AUD) include acamprosate, disulfiram, naltrexone, nalmefene, baclofen, and sodium oxybate. Acamprosate was developed specifically for AUD, while disulfiram's alcohol-deterrent effects were discovered incidentally. Naltrexone and nalmefene were originally approved for opioids but found secondary applications in AUD. Baclofen and sodium oxybate were repurposed from neurological conditions. Other drugs show promise. Topiramate and zonisamide, anticonvulsants, demonstrate efficacy in reducing alcohol consumption. Another anticonvulsant, gabapentin has been disappointing overall, except in cases involving alcohol withdrawal symptoms. Varenicline, a nicotinic receptor agonist, benefits individuals with less severe AUD or concurrent nicotine use. Ondansetron, a 5-HT3 antagonist, has potential for early-onset AUD, especially when combined with naltrexone. Antipsychotic drugs like aripiprazole and quetiapine have limited efficacy. Further investigation is needed for potential repurposing of α1 adrenergic receptor antagonists prazosin and doxazosin, glucocorticoid receptor antagonist mifepristone, the phosphodiesterase inhibitor Ibudilast, the cysteine prodrug N-acetylcysteine, and the OX1R and OX2R blocker Suvorexant. This review supports repurposing drugs as an effective strategy for expanding treatment options for AUD.

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.

Alcohol use disorder (AUD) is a multifactorial disorder arising from a complex interplay of various genetic, environmental, psychological, and social factors. Environmental factors influence alcohol misuse and can lead to AUD. While stress plays a crucial role in the onset and progression of this disorder, environmental enrichment (EE) also influences ethanol-induced behavioral and neurobiological responses. These alterations include reduced ethanol consumption, diminished operant self-administration, attenuated behavioral sensitization, and enhanced conditioned place preference. EE exerts modulatory effects on multiple neurobiological processes, such as the brain-derived neurotrophic factor/TrkB signaling pathway, the oxytocinergic system, and the hypothalamic-pituitary-adrenal axis. EE, which includes stimulating activities to counteract ethanol effects in animal studies, has parallels in human intervention that have shown potential benefits. Physical activity, cognitive behavioral therapy, and meditation, alongside techniques involving cognitive stimulation, social interaction, and recreational activities, may lead to more effective therapeutic outcomes in treatments of AUD.

Peripheral neuropathic pain, which occurs after a lesion or disease affecting the peripheral somatosensory nervous system, is a complex and challenging condition to treat. This chapter will cover molecular mechanisms underlying the pathophysiology of peripheral neuropathic pain, focusing on (1) sensitization of nociceptors, (2) neuro-immune crosstalk, and (3) axonal degeneration and regeneration. The chapter will also emphasize the importance of identifying novel therapeutic targets in non-neuronal cells. A comprehensive understanding of how changes at both neuronal and non-neuronal levels contribute to peripheral neuropathic pain may significantly improve pain management and treatment options, expanding to topical application that bypass the side effects associated with systemic administration.

Cannabidiol (CBD) has been investigated as a pharmacological approach for treating a myriad of neurological and psychiatric disorders, the most successful of them being its use as an antiseizure drug (ASD). Indeed, CBD has reached the clinics for the treatment of certain epileptic syndromes. This chapter aims to overview the pharmacology of CBD and its potential mechanisms of action as an ASD. First, we give an outline of the concepts, mechanisms and pharmacology pertaining to the field of study of epilepsy and epileptic seizures. In the second section, we will summarize the effects of CBD as an ASD. Next, we will discuss its potential mechanisms of action to alleviate epileptic seizures, which seem to entail multiple neurotransmitters, receptors and intracellular pathways. Finally, we will conclude and present some limitations and perspectives for future studies.

Peptides of the gut-brain axis have gained recent attention as potential treatment targets for addiction. While the number of gut-brain peptides is vast, ghrelin and glucagon-like peptide-1 (GLP-1) have been suggested as important players. Ghrelin is traditionally considered an orexigenic peptide, but recent studies found that it increases alcohol intake in rodents and craving for alcohol in humans. Additionally, suppression of the ghrelin receptor attenuates alcohol-related responses in animal models reflecting alcohol use disorder (AUD). For instance, a lower alcohol intake, suppressed motivation to consume alcohol, and attenuated reward from alcohol is observed after ghrelin receptor antagonism treatment. On a similar note, a partial ghrelin receptor agonist prevents hangover symptoms in humans. When it comes to the anorexigenic peptide GLP-1, agonists of its receptor are approved to treat diabetes type 2 and obesity. Extensive preclinical studies have revealed that these GLP-1 receptor agonists reduce alcohol intake, suppress the motivation to consume alcohol, and prevent relapse drink, with effects tentatively associated with a reduced alcohol-induced reward. These preclinical findings have to some extent been varied in humans, as GLP-1 receptor agonists decrease alcohol intake in overweight patients with AUD. Furthermore, genetic variations in either the genes encoding for pre-pro-ghrelin, GHSR, GLP-1, or its receptor, are associated with AUD and heavy alcohol drinking. While central mechanisms appear to modulate the ability of either ghrelin or GLP-1 to regulate alcohol-related responses the exact mechanisms have not been defined. Taken together these preclinical and clinical data imply that gut-brain peptides participate in the addiction process and should be considered as potential targets for AUD treatment.

Development and maintenance of alcohol use disorders have been proposed to recruit critical mechanisms involving Corticotropin Releasing Factor and Urocortins (CRF/Ucns). The CRF/Ucns system is comprised of a family of peptides (CRF, Ucn 1, Ucn 2, Ucn 3) which act upon two receptor subtypes, CRFR1 and CRFR2, each with different affinity profiles to the endogenous peptides and differential brain distribution. Activity of CRF/Ucn system is further modulated by CRF binding protein (CRF-BP), which regulates availability of CRF and Ucns to exert their actions. Extensive evidence in preclinical models support the involvement of CRF/Ucn targets in escalated alcohol drinking, as well as point to changes in CRF/Ucn brain function as a result of chronic alcohol exposure and/or withdrawal. It highlights the role of CRF and CRFR1-mediated signaling in conditions of excessive alcohol taking and seeking, including during various stages of withdrawal and relapse to alcohol. Besides its role in the hypothalamic-pituitary-adrenal (HPA) axis, the importance of extra-hypothalamic CRF pathways, especially in the extended amygdala, in the neurobiology of alcohol abuse and dependence is emphasized. Emerging roles for other targets of the CRF/Ucn system, such as CRF2 receptors, CRF-BP and Ucns in escalated alcohol drinking is also discussed. Finally, the limited translational value of CRF/Ucn interventions in stress-related and alcohol use disorders is discussed. So far, CRFR1 antagonists have shown little or no efficacy in human clinical trials, although a range of unexplored conditions and possibilities remain to be explored.

The heterogeneity of non-motor features observed in people with Parkinson's disease (PD) is often dominated by one or more symptoms belonging to the neuropsychiatric spectrum, such as cognitive impairment, psychosis, depression, anxiety, and apathy. Due to their high prevalence in people with PD (PwP) and their occurrence in every stage of the disease, from the prodromal to the advanced stage, it is not surprising that PD can be conceptualised as a complex neuropsychiatric disorder. Despite progress in understanding the pathophysiological mechanisms underlying the neuropsychiatric signs and symptoms in PD, and better identification and diagnosis of these symptoms, effective treatments are still a major unmet need. The impact of these symptoms on the quality of life of PwP and caregivers, as well as their contribution to the overall non-motor symptom burden can be greater than that of motor symptoms and require a personalised, holistic approach. In this chapter, we provide a general clinical overview of the major neuropsychiatric symptoms of PD.

Non-motor symptoms (NMS) of Parkinson's disease (PD) are well described in both clinical practice and the literature, enabling their management and enhancing our understanding of PD. NMS can dominate the clinical pictures and NMS subtypes have recently been proposed, initially based on clinical observations, and later confirmed in data driven analyses of large datasets and in biomarker-based studies. In this chapter, we provide an update on what is known about three common subtypes of NMS in PD. The pain (Park-pain), sleep dysfunction (Park-sleep), and autonomic dysfunction (Park-autonomic), providing an overview of their individual classification, clinical manifestation, pathophysiology, diagnosis, and potential treatments.

The absence of blood flow in cerebral ischemic conditions triggers a multitude of intricate pathophysiological mechanisms, including excitotoxicity, oxidative stress, neuroinflammation, disruption of the blood-brain barrier and white matter disarrangement. Despite numerous experimental studies conducted in preclinical settings, existing treatments for cerebral ischemia (CI), such as mechanical and pharmacological therapies, remain constrained and often entail significant side effects. Therefore, there is an imperative to explore innovative strategies for addressing CI outcomes. Cannabidiol (CBD), the most abundant non-psychotomimetic compound derived from Cannabis sativa, is a pleiotropic substance that interacts with diverse molecular targets and has the potential to influence various pathophysiological processes, thereby contributing to enhanced outcomes in CI. This chapter provides a comprehensive overview of the primary effects of CBD in in vitro and diverse animal models of CI and delves into some of its plausible mechanisms of neuroprotection.