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International Journal of Molecular... Jun 2020The modulation of neuronal cell firing is mediated by the release of the neurotransmitter GABA (γ-aminobuytric acid), which binds to two major families of receptors.... (Review)
Review
The modulation of neuronal cell firing is mediated by the release of the neurotransmitter GABA (γ-aminobuytric acid), which binds to two major families of receptors. The ionotropic GABAA receptors (GABARs) are composed of five distinct subunits that vary in expression by brain region and cell type. The action of GABA on GABARs is modulated by a variety of clinically and pharmacologically important drugs such as benzodiazepines and alcohol. Exposure to and abuse of these substances disrupts homeostasis and induces plasticity in GABAergic neurotransmission, often via the regulation of receptor expression. Here, we review the regulation of GABAR subunit expression in adaptive and pathological plasticity, with a focus on substance use. We examine the factors influencing the expression of GABAR subunit genes including the regulation of the 5' and 3' untranslated regions, variations in DNA methylation, immediate early genes and transcription factors that regulate subunit expression, translational and post-translational modifications, and other forms of receptor regulation beyond expression. Advancing our understanding of the factors regulating GABAR subunit expression during adaptive plasticity, as well as during substance use and withdrawal will provide insight into the role of GABAergic signaling in substance use disorders, and contribute to the development of novel targeted therapies.
Topics: Animals; Gene Expression Regulation; Humans; Protein Subunits; Receptors, GABA-A; Substance-Related Disorders; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 32580510
DOI: 10.3390/ijms21124445 -
The International Journal on Drug Policy Oct 2022People who are homeless and using substances frequently encounter barriers to accessing support. This paper aims to inform policy and practice by analysing changes in...
BACKGROUND
People who are homeless and using substances frequently encounter barriers to accessing support. This paper aims to inform policy and practice by analysing changes in the tobacco, alcohol and illicit drug use of people experiencing homelessness.
METHODS
Data derive from a qualitative longitudinal study (undertaken 2020/2021) and involving telephone interviews (n = 310) conducted with 34 people accommodated in two London hotels provided as part of a UK policy response to COVID-19. The hotels offered various supports, including opioid replacement therapy, prescribed alcohol, licensed nicotine replacement therapy, and e-cigarettes. Participants' substance use data were organised by Iterative Categorization and subjected to a content analysis to identify patterns and themes..
RESULTS
At entry to the hotel, 5/34 participants (14.7%) had never used alcohol nor illicit drugs; 10/34 (29.4%) had only ever used alcohol (mostly without a problem); 11/34 (32.4%) had ever used illicit drugs but without a problem; and 8/34 (23.5%) had ever had a problem with illicit drugs. Sub-groups had different socio-demographic characteristics, particularly regarding being/not being a UK national, sex, and homelessness duration. Tobacco smoking was common across all sub-groups (18/34; 52.9%). Participants were often anxious about living with others who were using substances, and some worried about their own substance use. Substance use was changeable, with more decreases than increases. Changes related to intrapersonal (psychological), interpersonal (social) and structural (resource-based) factors. For example, decreases were precipitated by people feeling motivated to change, separation from others who used drugs, and receiving treatment or support.
CONCLUSION
Findings indicate that various interventions and accommodation models may benefit people who are homeless and using substances. An initiative that combined shelter and basic amenities, pharmacological treatment, psychosocial support, and space where substances were not available and other people using substances could be avoided resulted in an overall reduction in substance use amongst those accommodated.
Topics: COVID-19; Electronic Nicotine Delivery Systems; Ill-Housed Persons; Humans; Illicit Drugs; Longitudinal Studies; Policy; Qualitative Research; Smoking Cessation; Substance-Related Disorders; Tobacco Use Cessation Devices
PubMed: 35961238
DOI: 10.1016/j.drugpo.2022.103818 -
Alterations of Stress-Related Glucocorticoids and Endocannabinoids in Hair of Chronic Cocaine Users.The International Journal of... Mar 2022Previous research in animals and humans has demonstrated a potential role of stress regulatory systems, such as the hypothalamic-pituitary-adrenal (HPA) axis and the...
BACKGROUND
Previous research in animals and humans has demonstrated a potential role of stress regulatory systems, such as the hypothalamic-pituitary-adrenal (HPA) axis and the endocannabinoid (eCB) system, in the development of substance use disorders. We thus investigated alterations of HPA and eCB markers in individuals with chronic cocaine use disorder by using an advanced hair analysis technique.
METHODS
We compared hair concentrations of glucocorticoids (cortisone, cortisol) and the eCBs 2-arachidonylglycerol, anandamide (AEA), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA) between 48 recreational cocaine users (RCU), 25 dependent cocaine users (DCU), and 67 stimulant-naïve controls. Self-reported substance use and hair concentrations of substances were also assessed.
RESULTS
Significantly higher concentrations of hair cortisone were found in RCU and DCU compared with controls. Hair concentrations of OEA and PEA were significantly lower in DCU compared with RCU and controls. Additionally, within cocaine users, elevated cocaine hair concentration was a significant predictor for increased glucocorticoid and decreased OEA hair levels. Moreover, higher 3,4-methylenedioxymethamphetamine hair concentration was correlated with elevated cortisone and AEA, OEA, and PEA levels in hair within cocaine users, whereas more self-reported cannabis use was associated with lower eCBs levels in hair across the total sample.
CONCLUSION
Our findings support the hypothesis that the HPA axis and eCB system might be important regulators for substance use disorders. The mechanistic understanding of changes in glucocorticoid and eCB levels in future research might be a promising pharmacological target to reduce stress-induced craving and relapse specifically in cocaine use disorder.
Topics: Animals; Cocaine; Cortisone; Endocannabinoids; Glucocorticoids; Hair; Humans; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System
PubMed: 34676867
DOI: 10.1093/ijnp/pyab070 -
Molecules (Basel, Switzerland) Jan 2022Microbial biofilms are represented by sessile microbial communities with modified gene expression and phenotype, adhered to a surface and embedded in a matrix of... (Review)
Review
Microbial biofilms are represented by sessile microbial communities with modified gene expression and phenotype, adhered to a surface and embedded in a matrix of self-produced extracellular polymeric substances (EPS). Microbial biofilms can develop on both prosthetic devices and tissues, generating chronic and persistent infections that cannot be eradicated with classical organic-based antimicrobials, because of their increased tolerance to antimicrobials and the host immune system. Several complexes based mostly on 3D ions have shown promising potential for fighting biofilm-associated infections, due to their large spectrum antimicrobial and anti-biofilm activity. The literature usually reports species containing Mn(II), Ni(II), Co(II), Cu(II) or Zn(II) and a large variety of multidentate ligands with chelating properties such as antibiotics, Schiff bases, biguanides, N-based macrocyclic and fused rings derivatives. This review presents the progress in the development of such species and their anti-biofilm activity, as well as the contribution of biomaterials science to incorporate these complexes in composite platforms for reducing the negative impact of medical biofilms.
Topics: Animals; Anti-Infective Agents; Biocompatible Materials; Biofilms; Coordination Complexes; Extracellular Polymeric Substance Matrix; Humans; Infections; Schiff Bases
PubMed: 35164021
DOI: 10.3390/molecules27030758 -
The European Journal of Neuroscience Aug 2019Drug addiction is an aberrant memory that shares the same memory processes as other memories. Brief exposure to drug-associated cues could result in reconsolidation, a... (Review)
Review
Drug addiction is an aberrant memory that shares the same memory processes as other memories. Brief exposure to drug-associated cues could result in reconsolidation, a hypothetical process during which original memory could be updated. In contrast, longer exposure times to drug-associated cues could trigger extinction, a process that decreases the conditioned responding. In this review, we discuss the pharmacological and non-pharmacological manipulations on the reconsolidation and extinction that could be used to interfere with drug reward memories. Pharmacological agents such as β-adrenergic receptor antagonist propranolol can interfere with reconsolidation to disrupt drug reward memory. Pharmacological agents such as the NMDA receptor glycine site agonists d-cycloserine and d-serine can facilitate extinction and then attenuate the expression of drug reward memory. Besides pharmacological interventions, drug-free behavioral approaches by utilizing the reconsolidation and extinction, such as 'post-retrieval extinction' and 'UCS-retrieval extinction', are also effective to erase or inhibit the recall of drug reward memory. Taken together, pharmacological modulation and non-pharmacological modulation of reconsolidation and extinction are promising approaches to regulate drug reward memory and prevent relapse.
Topics: Adrenergic beta-Antagonists; Animals; Conditioning, Classical; Extinction, Psychological; Humans; Memory; Mental Recall; Reward; Substance-Related Disorders
PubMed: 30113098
DOI: 10.1111/ejn.14072 -
Psychopharmacology Dec 2022The use of novel psychoactive substances has been steadily increasing in recent years. Given the rapid emergence of new substances and their constantly changing chemical...
RATIONALE
The use of novel psychoactive substances has been steadily increasing in recent years. Given the rapid emergence of new substances and their constantly changing chemical structure, it is necessary to develop an efficient and expeditious approach to examine the mechanisms underlying their pharmacological and toxicological effects. Zebrafish (Danio rerio) have become a popular experimental subject for drug screening due to their amenability to high-throughput approaches.
OBJECTIVES
In this study, we used methamphetamine (METH) as an exemplary psychoactive substance to investigate its acute toxicity and possible underlying mechanisms in 5-day post-fertilization (5 dpf) zebrafish larvae.
METHODS
Lethality and toxicity of different concentrations of METH were examined in 5-dpf zebrafish larvae using a 96-well plate format.
RESULTS
METH induced lethality in zebrafish larvae in a dose-dependent manner, which was associated with initial sympathomimetic activation, followed by cardiotoxicity. This was evidenced by significant heart rate increases at low doses, followed by decreased cardiac function at high doses and later time points. Levels of ammonia in the excreted water were increased but decreased internally. There was also evidence of seizures. Co-administration of the glutamate AMPA receptor antagonist GYKI-52466 and the dopamine D2 receptor antagonist raclopride significantly attenuated METH-induced lethality, suggesting that this lethality may be mediated synergistically or independently by glutamatergic and dopaminergic systems.
CONCLUSIONS
These experiments provide a baseline for the study of the toxicity of related amphetamine compounds in 5-dpf zebrafish as well as a new high-throughput approach for investigating the toxicities of rapidly emerging new psychoactive substances.
Topics: Animals; Zebrafish; Methamphetamine; Larva; Dopamine; Seizures; Excitatory Amino Acid Antagonists
PubMed: 36269378
DOI: 10.1007/s00213-022-06252-z -
Medicina (Kaunas, Lithuania) Mar 2024Synthetic cathinones are a group of novel psychoactive substances used as an alternative to classical recreational drugs. As a result of legal prohibitions on older... (Review)
Review
Synthetic cathinones are a group of novel psychoactive substances used as an alternative to classical recreational drugs. As a result of legal prohibitions on older generations of these compounds, new formulations appeared on the drug market. One of them is metaphedrone (3-methylmethcathinone, 3-MMC), a structural isomer of 4-methylmethcathinone and a psychostimulant drug. Metaphedrone became popular in a large number of countries in a short period of time. The collection, analysis, and review of relevant research on the subject of metaphedrone in order to present information about the pharmacological, clinical, and toxicological profile of this compound. An assessment of the significance and role of metaphedrone in consumption patterns of novel psychoactive substances among recreational drug users. By using search engines like Google Scholar and PubMed, the relevant literature on metaphedrone was looked for and analyzed. The search was not limited to a specific period of time. All information regarding the compound of interest was analyzed and presented. All novel psychoactive substances are abused due to their pronounced stimulatory, hallucinogenic, dissociative, and euphoric and/or relaxing characteristics. Users of 3-methylmethcathinone usually opt for this substance for recreational purposes and/or sexual stimulation. Metaphedrone has the potential to cause a psychological dependence to the users. It was determined in relevant studies that most users are from 17 to 50 years of age. Older users usually administer metaphedrone intravenously, while younger ones usually choose snorting and oral ingestion of the drug. In Serbia, metaphedrone is a legally controlled substance. The pharmacodynamic properties make metaphedrone similar to classical recreational drugs. The method of administration, mainly repeated administration in a single session, could be explained using the pharmacokinetic profile of the drug. The most reported symptoms of intoxication were those of a sympathomimetic nature, such as tachycardia, chest pain, hypertension, diaphoresis, and agitation. Most intoxications and fatal outcomes occurred to users who combined several psychoactive substances. The correlation between measured blood concentrations of the drug and outcomes of intoxication was not found. The mechanisms of metaphedrone's toxicity are not fully understood. There is an increasing trend of abuse of metaphedrone among recreational drugs users. Future studies should focus on pharmacological and toxicological effects of metaphedrone on animals and humans.
Topics: Humans; Animals; Illicit Drugs; Hypertension; Serbia; Methamphetamine
PubMed: 38541192
DOI: 10.3390/medicina60030466 -
Expert Opinion on Pharmacotherapy May 2020Opioid use disorder (OUD) and alcohol use disorder (AUD) are two highly prevalent substance-related disorders worldwide. Co-use of the substances is also quite... (Review)
Review
Opioid use disorder (OUD) and alcohol use disorder (AUD) are two highly prevalent substance-related disorders worldwide. Co-use of the substances is also quite prevalent, yet there are no pharmacological treatment approaches specifically designed to treat co-morbid OUD and AUD. Here, the authors critically summarize OUD, AUD and opioid/alcohol co-use and their current pharmacotherapies for treatment. They also review the mechanisms of action of opioids and alcohol within the brain reward circuitry and discuss potential combined mechanisms of action and resulting neuroadaptations. Pharmacotherapies that aim to treat AUD or OUD that may be beneficial in the treatment of co-use are also highlighted. Preclinical models assessing alcohol and opioid co-use remain sparse. Lasting neuroadaptations in brain reward circuits caused by co-use of alcohol and opioids remains largely understudied. In order to fully understand the neurobiological underpinnings of alcohol and opioid co-use and develop efficacious pharmacotherapies, the preclinical field must expand its current experimental paradigms of 'single drug' use to encompass polysubstance use. Such studies will provide insights on the neural alterations induced by opioid and alcohol co-use, and may help develop novel pharmacotherapies for individuals with co-occurring alcohol and opioid use disorders.
Topics: Alcohol Deterrents; Alcoholism; Animals; Brain; Comorbidity; Disease Models, Animal; Humans; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Prevalence
PubMed: 32103695
DOI: 10.1080/14656566.2020.1732349 -
Heliyon Feb 2022The skin is a complex and multifunctional organ, in which the static versus dynamic balance is responsible for its constant adaptation to variations in the external... (Review)
Review
The skin is a complex and multifunctional organ, in which the static versus dynamic balance is responsible for its constant adaptation to variations in the external environment that is continuously exposed. One of the most important functions of the skin is its ability to act as a protective barrier, against the entry of foreign substances and against the excessive loss of endogenous material. Human skin imposes physical, chemical and biological limitations on all types of permeating agents that can cross the epithelial barrier. For a molecule to be passively permeated through the skin, it must have properties, such as dimensions, molecular weight, pKa and hydrophilic-lipophilic gradient, appropriate to the anatomy and physiology of the skin. These requirements have limited the number of commercially available products for dermal and transdermal administration of drugs. To understand the mechanisms involved in the drug permeation process through the skin, the approach should be multidisciplinary in order to overcome biological and pharmacotechnical barriers. The study of the mechanisms involved in the permeation process, and the ways to control it, can make this route of drug administration cease to be a constant promise and become a reality. In this work, we address the physicochemical and biopharmaceutical aspects encountered in the pathway of drugs through the skin, and the potential added value of using solid lipid nanoparticles (SLN) and nanostructured lipid vectors (NLC) to drug permeation/penetration through this route. The technology and architecture for obtaining lipid nanoparticles are described in detail, namely the composition, production methods and the ability to release pharmacologically active substances, as well as the application of these systems in the vectorization of various pharmacologically active substances for dermal and transdermal applications. The characteristics of these systems in terms of dermal application are addressed, such as biocompatibility, occlusion, hydration, emollience and the penetration of pharmacologically active substances. The advantages of using these systems over conventional formulations are described and explored from a pharmaceutical point of view.
PubMed: 35198788
DOI: 10.1016/j.heliyon.2022.e08938 -
Journal of Clinical Medicine Feb 2022: Assessing the abuse potential of new substances with central nervous system activity is essential for preventing possible risks of misuse and addiction. The same... (Review)
Review
: Assessing the abuse potential of new substances with central nervous system activity is essential for preventing possible risks of misuse and addiction. The same methodology is recommended for the evaluation of the abuse potential of recreational drugs. This systematic review aims to assess the pharmacological effects related to the abuse potential and pharmacokinetics of cathinones, which are evaluated in both experimental and prospective observational studies in humans. : A systematic search of the published literature was conducted to retrieve studies that had administered cathinone, mephedrone, methylone, and diethylpropion to evaluate their acute pharmacological effects related to abuse potential. : The search yielded 583 results, 18 of which were included to assess the abuse potential of cathinone ( = 5), mephedrone ( = 7), methylone ( = 1), and diethylpropion ( = 5). All four substances induce stimulant and euphorigenic effects that resemble those of amphetamines and MDMA, and their different intensities may be associated with varying levels of abuse potential. : Cathinone, mephedrone, methylone, and diethylpropion induce a range of desirable and reinforcing effects that may, to some extent, result in abuse potential. Further investigation is needed to minimize and prevent their impact on society and public health.
PubMed: 35207278
DOI: 10.3390/jcm11041004