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Sedatives of the central nervous system CNS are the most commonly used, abused, and prescribed drugs. It is now apparent that withdrawal of these drugs, particularly if done in a precipitous fashion, can lead to seizures that are usually generalized. Victor and Brausch demonstrated, in a large series of alcoholics presenting to a hospital, that alcohol withdrawal was frequently associated with seizures. Benzodiazepine withdrawal Fialip et al. There is a paucity of data concerning the cellular electrophysiological mechanisms associated with sedative drug withdrawal seizures. Investigations by this laboratory over the past few years are summarized and discussed in this chapter. These studies were performed in neurons of adult rat or guinea pig hippocampal brain slices, which were recorded intracellularly using standard voltage recording techniques Blaxter et al. This is a preview of subscription content, log in via an institution to check access. Institutional subscriptions. Unable to display preview. Download preview PDF. Alger, B. Google Scholar. Belknap, J. Article Google Scholar. Bergamaschi, A. Blaxter, T. Brailowsky, S. Browne, T. Carlen, P. Davis Co. Davidson, M. Davies, M. Dolin, S. Eckert, R. Fialip, J. Fraser, H. Gaustaut, H. Mercier ed. II, Pergamon Press, Oxford, pp. Gurevich, N. Hillbom, M. Hotson, J. Krnjevic, K. Lambert, J. Lovinger, D. Porter, R. Michaelis, M. Miljkovic, Z. Mody, I. Naquet, I. Niesen, C. Reynolds, J. Rougier-Naquet, I. Neuro sci. Spigelman, I. Winter Conf. Tsien, R. Victor, M. Download references. You can also search for this author in PubMed Google Scholar. Massimo Avoli M. Reprints and permissions. In: Avoli, M. Print ISBN : Online ISBN : Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Policies and ethics. Skip to main content. Generalized Epilepsy. Abstract Sedatives of the central nervous system CNS are the most commonly used, abused, and prescribed drugs. Access this chapter Log in via an institution. Chapter EUR Softcover Book EUR Tax calculation will be finalised at checkout Purchases are for personal use only. Preview Unable to display preview. Differential effects of sodium channel blockers on in vitro induced epileptiform activities Article 29 October Effects of anti-epileptic drugs on spreading depolarization-induced epileptiform activity in mouse hippocampal slices Article Open access 19 September References Alger, B. Google Scholar Belknap, J. Article Google Scholar Belknap, J. Article Google Scholar Bergamaschi, A. Article Google Scholar Blaxter, T. Google Scholar Blaxter, T. Google Scholar Brailowsky, S. Article Google Scholar Browne, T. Article Google Scholar Carlen, P. Google Scholar Davidson, M. Article Google Scholar Davies, M. Google Scholar Dolin, S. Article Google Scholar Eckert, R. Article Google Scholar Fialip, J. Article Google Scholar Fraser, H. Article Google Scholar Gaustaut, H. Google Scholar Gurevich, N. Google Scholar Hillbom, M. Article Google Scholar Hotson, J. Google Scholar Krnjevic, K. Google Scholar Lambert, J. Article Google Scholar Lovinger, D. Google Scholar Michaelis, M. Article Google Scholar Michaelis, M. Article Google Scholar Miljkovic, Z. Article Google Scholar Mody, I. Google Scholar Naquet, I. Google Scholar Niesen, C. Article Google Scholar Reynolds, J. Google Scholar Spigelman, I. Google Scholar Tsien, R. Google Scholar Victor, M. Google Scholar Download references. Authors P. Carlen View author publications. View author publications. Rights and permissions Reprints and permissions. About this chapter Cite this chapter Carlen, P. Copy to clipboard. Publish with us Policies and ethics. Search Search by keyword or author Search. Navigation Find a journal Publish with us Track your research.

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Substance abuse has become a global problem due to drug-induced addiction and neurotoxicity, which causes a huge physical, social, and financial burden. To summarize recent scientific advances on drug abuse, we reviewed relevant publications to analyze research progress and such trends through bibliometric ways. Based on retrieval strategies, a total of scientific records published from to were screened and included in the Web of Science WoS database. Further scientometric analysis revealed that annual publication output increased across this period, with the United States of America USA contributing a significant number of reasons. Research has focused on neurotransmitter, oxidative stress, mitochondrial system injury, and other neurotoxic mechanisms. Neuroimmune, neurotoxic targets, and new psychoactive substances have been hot topics in recent years, which deserve continued research in the future. Specific research on molecular mechanisms has progressed across this period, with an emphasis on the root cause of toxicity and molecular targets for therapy. Moreover, collaborations of international multi-disciplinary research teams have been efficient and need to be encouraged for addiction research and the development of appropriate therapeutic processes. Substance abuse, including relapse, refers to excessive consumption of stimulants, cannabis, amphetamines, cocaine, and hallucinogens, according to ICD WHO, and DSM-5 Quinn et al. According to the report of the European Monitoring Centre for Drugs and Drug Addiction EMCDDA in , both the number of drug-related deaths and the number of addicts, across the European Union EU , are increasing, which aggravates the global burden on public health systems, resulting in huge worldwide economic costs, including law enforcement resources Rehm et al. Studies have shown that abused drugs activate the mesolimbic dopaminergic system, orbitofrontal cortex, and extended amygdala Cunha-Oliveira et al. Specifically, substance abuse alters intracellular signaling pathways, transcription factors, and levels of gene expression in these reward circuits Nestler, ; Hyman et al. To provide an international description of scientific activities examining substance abuse, a bibliometric analysis is needed to quantify the influences of scientific literature sets, academic characteristics e. The visible technology that provides an overview of programmatic research and its developmental trends will provide researchers with a clearer understanding of relative research breakthroughs and their expected future dynamics Kamdem et al. With this in mind, we review the research on the neurotoxicity of substance abuse and relapse with the goal of deepening our understanding of this progress as well as trends for future research, and molecular targets for therapeutic development. The Web of Science WoS Core Collection database is a global academic database indexing more than 20, authoritative and high-impact academic journals, covering natural science, engineering technology, biomedicine, social science, and arts and humanities. We retrieved 1, records published between January and December , and excluded 25 non-English records, narrowing the list to 1, English manuscripts for further analysis. A total of 1, original articles were identified, and studies, including review, meeting abstract, letter, proceedings paper, editorial materials, early access, notes, book chapters, news items, and corrections, were excluded. Two investigators screened all of the original data, eliminated noise, respectively, and reached a consensus via discussion and re-evaluation by a third investigator when discrepancies were observed. Finally, articles were assembled for scientometric mining Figure 1. We used CiteSpace 5. Overall, annual publication outputs had a generally positive growth rate, except for a few fluctuations, since ; for this period, the peak annual publication count was 45 in Figure 2. In line with an increasing number of annual publications, substance abuse and its neurotoxicity remained an important research topic across this time period. Remarkably, according to the categorization of the topics, publications were focused on molecular mechanisms, while the rest were almost all on behavior or neuropsychology. Accordingly, the proportion of articles on molecular mechanisms also increased year by year, with its highest level in at Figure 2. Annual number and accumulated number of articles on neurotoxicity of substance abuse, and number of publications on molecular mechanisms from to The United States Besides this, other Asian Among these top 10 productive countries, United States had the greatest number of publications devoted to studies on molecular mechanisms of neurotoxicity and substance abuse Figure 3 also depicts bilateral cooperation between contributing countries; the United States cooperated with 22 countries, making it the most collaborative country, followed by Germany and Canada, each, respectively, cooperating with 6 other countries. The articles received a total of 22, citations according to the WoS, giving an average citation of Without a defined conservative cutoff of time limit for citation, Germany Other than this, the average H-index of the retrieved papers queried on the WoS was 71; and the top 3 countries were the United States with the highest H-index of 61, followed by Spain 24 and Germany Furthermore, the core institutions in the countries, such as Portugal Table 2 lists the top 10 most-cited articles, which were regarded as high-quality scientific research published in authoritative journals categorized in psychiatry No. These most cited papers examined the mechanisms of psychomotor impairment and neurotoxicity, and eight of the top 10 papers examined neurotoxic molecular mechanisms, like a role of the dopamine transporter Volkow et al. More than authoritative journals published articles on the neurotoxicity of substance abuse. Among these, the top 10 of these active journals contained Table 3. The 10 most active journals that published articles on substance abuse and its neurotoxicity research. After excluding irrelevant and repeated keywords, we analyzed, merged, and visualized the network maps of keyword co-occurrence by CiteSpace Figure 4 , which illustrated the relevance and frequency of keywords using circle link and size. Figure 4. Network of keywords co-occurrence. The circle size and the link illustrated the frequency and relevance of keywords, respectively. After clustering and mapping co-cited literatures Figure 5 , we analyzed the timeline of developing trends of specific research fields, the observed shift of research focus, and the formal professional structures of these research systems Niazi and Hussain, According to an in-depth analysis of the top ten clusters, we identified that most were distributed in the period from to The earlier studies have focused on methamphetamine 3 , drug abuse 1 , and dopamine 5 ; then, the research hotspots shifted to heat shock protein 7 , synaptic plasticity 8 , NMDA receptor 6 , oxidative stress 0 , and neurotoxicity 2 , which are all involved in neurotoxic molecular mechanisms of substance abuse. Figure 5. Co-cited references timeline map of neurotoxicity of substance abuse. Nodes represent referenced documents. The size of nodes represents the frequencies of cited references, and the location reflects the present time. Years are arranged horizontally at the top. The clusters are performed based on the themes of co-cited references and the label of each cluster is shown at the end of the timeline. We found that keywords could reveal research topics and contents, which play an apparent and updated role in tracking the transition of research hotspots. We obtained a keyword burst map to visualize shifts in focus and emergence across time on the basis of the strongest burst of keywords in scientific research articles Figure 6. In addition, burst keywords could summarize outstanding research topics over any period of time by indicating the duration and intensity of these hot issues Kleinberg, ; Chen, , ; Chen et al. According to the top 24 keywords with the strongest citation bursts, the earlier research hotspots were neurotoxic target-organs and animal models dismutase transgenic mice, rat brain, and central serotonergic neuron , examination positron emission tomography , and commonly abused drugs cocaine. Then, the burst keywords shifted to molecular mechanism-related items e. Figure 6. Top 24 keywords with the strongest citation bursts. Each blue or red short line represents a year, and a red line stands for a burst detected year. Our study performed a visualized bibliometric analysis of substance abuse and its neurotoxicity from to using CiteSpace. More and more research has focused on the neurotoxic progression of substance abuse, especially the complexities of molecular mechanisms. These fields of research have needed a review to map the publications providing new ideas for the treatment and prevention of drug abuse and relapse i. Drug abuse has brought a tremendous socioeconomic burden to the whole world, especially in recent decades Hagemeier, ; this dreadful situation needs more research to expose the severity of drug addiction and drug-induced neurological disorders. Encouragingly, from to , the total amount of related publications reached a total of , with an average of 27 per year; and an annual number of publications had a generally rising trend with a peak in Over the past 25 years, the United States, contributing more than half of the total publications, has played a leading significant role in productivity in this field, and Asian and European countries came followed with far less production. Regarding the reason for this status, in the United States, various types of smuggled drugs have flooded its streets; meanwhile, classic opiates, cocaine, and amphetamines were pursued by a large number of substance abusers. Except for such a severe social landscape, the United States government offered abundant research funds to support high-level research activity, which resulted in a high academic reputation and characteristic H-index value in scientific research e. Based on legalized marijuana policies in the United States and Canada, similar domestic and international situations and potential cooperative opportunities increased exponentially; additionally, the United States provides attractive financial grants to facilitate efficient cooperation and productivity Goundar et al. Under a shared global concern of drug abuse, worldwide scientific cooperation should be further strengthened to highlight research quality, and the outcomes should be noted to more deeply illustrate the harm of substance abuse and drug-induced toxicity Rahim et al. The 10 most active journals, as shown in Table 3 , were of high quality and rational JCR quartile on neuroscience and neuropsychiatry, published nearly one-third of the total publications. Of the molecular mechanisms of neurotoxicity of substance abuse, the understanding has reached unprecedented depth, and significant advances are laudable over the past few decades. The neurotoxic effects of drug abuse are associated with oxidative stress, mitochondrial dysfunction, apoptosis, and neurogenesis inhibition, directly or indirectly affecting neurotransmitter systems, including but not limited to dopaminergic and glutamatergic neurons, and causing irreversible neuronal damage Cunha-Oliveira et al. The bibliometric indicators, including publication numbers, citations per article, journal impact factors, crown indicators, H-index, and its variants, can manifest high-quality scientific results Joshi, Our results indicated that the average citation per article on the neurotoxicity of substance abuse was Furthermore, six of these articles focused on studies related to methamphetamine, while the remaining four articles analyzed the neurotoxicity mechanisms of 3,4-methylenedioxymethamphetamine MDMA , nitrous oxide laughing gas , and neuronal apoptosis associated with morphine tolerance. Among the methamphetamine abusers, the aforementioned neurotoxicity is significantly more severe in men than in women; nevertheless, no significant molecular differences were observed between the sexes Munro et al. Moreover, the 10 most-cited articles were all published from through , which suggest that these results have primarily progressed and verified the mechanisms of neurotoxicity of substance abuse in this decade and enlightened more research afterward. According to the presented keyword co-occurrence network, the core direction of the specific research topics was examined. The neurotoxic effects of abused substances could be described as inhibiting e. Besides, studies also proved that tachykinins, especially substance P SP , are linked to the terminal degeneration of dopamine through NK-1 receptor activity in substantia nigra for chronic methamphetamine abusers Yu et al. Of note, drug participatory induced the release of monoamines from neuronal storage vesicles, metabolism by monoamine oxidase or catechol-O-methyltransferase COMT , and reactive oxygen species ROS generation da Silva et al. It is worth noting that drug-induced mitochondrial metabolism dysfunction promotes oxidative stress by inhibiting oxidative phosphorylation and ATP production, triggering apoptotic signaling pathways, and then causing neuronal damage Burrows et al. It has been shown that methamphetamine and cocaine, interfering with all electron transport chain ETC complexes, producing excess ROS, further aggravate mitochondrial disintegration, while mephedrone affects the activity of mitochondrial complex II and IV Yang et al. Besides the above, the highly cited articles demonstrated that abused drugs could increase microglial reactivity and lead to neuroinflammation, which has shown a strong link to neurotoxicity Lacagnina et al. Amphetamine compounds, acting on dopamine D1-like receptors, microglia, and relevant signaling proteins, exacerbated neuroinflammation responses and promoted macrophage polarization from M0 to M1, which provides a potential basis of long-term neurotoxicity Li et al. Cannabis could impair the activation of Toll-like receptors 4 TLR4 by inhibiting cytokine production and interfering with TLR-induced immune responses Sexton, Moreover, synthetic cathinone and ketamine have been confirmed to induce the release of pro-inflammatory cytokines and microglial activation Li et al. These referenced molecular mechanisms may provide valid and reliable therapy potential for substance abuse and relapse in the future. As a prominent feature of bibliometrics, the research topic clustering technology categorizes all retrieved records with similar topics and generates a timeline map Waltman et al. According to the clustering of the co-cited literatures, NMDA receptor 6, N -methyl- D -aspartic acid receptor has been a significant focus for a long time. Based on glutamatergic neurotransmission involved in several substances of abuse, activated NMDA receptors would increase intracellular calcium concentration, which increases extracellular glutamate with positive feedback Rego and Oliveira, ; Tzschentke and Schmidt, Methamphetamine increased glutamate by exocytosis of astrocytes through TNF production and calcium mobilization, which thereby promoted microglial reactivity to neuroinflammation, and neuronal death Canedo et al. In addition, other psychoactive substances e. Therefore, further research on NMDA receptor activities may provide new strategies to treat substance abuse. Similar to traditional drugs, synthetic cathinones also act on monoaminergic terminal functional markers, increasing ROS, activating apoptotic signaling pathways, and causing cytotoxicity Leyrer-Jackson et al. According to the bibliometrics analysis, we found that research on poly drug abuse often co-occurred recently. As quite a few drug abusers may prefer multi-substances of abuse Gerostamoulos et al. Other proportionately interesting findings on the neurotoxicity of substance abuse were also retrieved. Curcumin, a natural polyphenol extracted from the rhizome of Curcuma longa L, and Melissa officinalis , an antioxidant plant, both scavenge oxygen free radicals and inhibit monoamine oxidase to antagonize drug-induced neuronal apoptosis Hassanzadeh et al. This suggests a potential neuroprotective role of natural plant extracts for the treatment of substance abuse. A number of pharmacological interventions for drug-related memory deficits have shown significant benefits in preventing relapse at the preclinical level, such as propranolol interfering with heroin memory consolidation and reducing subsequent drug-seeking, making it an attractive treatment candidate for opioid addiction and relapse prevention Chen et al. Moreover, mTOR mammalian target of rapamycin interferes with cocaine-related memory consolidation, reduces cocaine-seeking behavior, and prevents relapse, and these effects are extract-dependent and time-specific Zhang et al. Besides, 5-hydroxytryptamine receptor 1F 5-HT1F receptor agonist, LY , and cannabidiol showed a therapeutic prevention of relapse to drug addiction Shahidi et al. While there has been an exponential increase in substance abuse harm and corresponding research, there is still a paucity of studies examining systematic bibliometric progress. With the included visualized illustration, we constructed this assessment to elucidate interdisciplinary information of research on psychoactive substances. Based on the studies of neurotoxicity, pharmacological effects, and epidemiology, this update on research evidence suggests greater scientific therapeutic predictability to combat addiction to psychoactive substances. The overall findings of this study suggest that research hotspots have focused on molecular mechanisms, and more scientific priority should be given to allocate research resources for these studies with the greatest potential to investigate therapeutic applications. There were inevitable limitations to our study. First, since the scientific literature database WoS keeps dynamic publishing, the interval lag between the publication and the retrieval would affect the time sensitivity of studies. Second, to comply with the software condition of CiteSpace, only English studies were analyzed for the function of co-occurrence and co-citation analysis methods incompatibility of multiple languages. ML and ZL contributed to the conception, design of the study, reviewed, and edited the manuscript. AZ organized the database and performed the statistical analysis. AZ and ML wrote the first draft of the manuscript. All authors contributed to the manuscript revision, read, and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. We thank the reviewers for their insightful comments on the manuscript, as their remarks led to an improvement of the work. Altun, B. Psychoactive bath salts and neurotoxicity risk. Barbosa, D. Pro-oxidant effects of ecstasy and its metabolites in mouse brain synaptosomes. Baumann, M. Burrows, K. Rapid and transient inhibition of mitochondrial function following methamphetamine or 3,4-methylenedioxymethamphetamine administration. Forensic Pathology Reviews. Cadet, J. Molecular bases of methamphetamine-induced neurodegeneration. Canedo, T. Astrocyte-derived TNF and glutamate critically modulate microglia activation by methamphetamine. Neuropsychopharmacology 46, — Cassel, E. Chen, C. Searching for intellectual turning points: progressive knowledge domain visualization. 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Neurokinin-1 NK-1 receptor antagonists abrogate methamphetamine-induced striatal dopaminergic neurotoxicity in the murine brain. Zhang, F. Disrupting reconsolidation by systemic inhibition of mtor kinase via rapamycin reduces cocaine-seeking behavior. Zuo, D. Alcohol amplifies ketamine-induced apoptosis in primary cultured cortical neurons and PC12 cells through down-regulating CREB-related signaling pathways. Keywords : scientometric analysis, visualization, molecular mechanism, substance abuse, neurotoxicity. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Top bar navigation. About us About us. Sections Sections. About journal About journal. Article types Author guidelines Editor guidelines Publishing fees Submission checklist Contact editorial office. Figure 1. The flowchart of methodology. Table 1. The top 10 productive countries and institutions. Figure 3. Cooperation between contributed countries. Table 2. The characteristics of highly cited articles.

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