Novel pharmacotherapeutic treatments for cocaine addiction

Cocaine is a stimulant that leads to the rapid accumulation of catecholamines and serotonin in the brain due to prevention of their re-uptake into the neuron that released the neurotransmitter. Cocaine dependence is a public health concern and cause of significant morbidity and mortality worldwide. At present, there are no approved medications for the treatment of this devastating illness, and behavioral interventions have proven to be of limited use. However, there have been a number of recent trials testing promising agents including dopamine agonists, GABAergic medications and the cocaine vaccine. Here we discuss the most recent human clinical trials of potential medications for treatment of cocaine dependence, as well as pre-clinical studies for another promising agent, levo tetrahydropalmatine. Examination of these recent findings shows promise for GABAergic medications and the cocaine vaccine, as well as unique medications such as disulfiram, whose mechanism remains to be determined. Future work may also confirm specific subgroups of patients for treatment response based on clinical characteristics, biomarkers and pharmacogenetics. This review highlights the need for further, bigger studies in order to determine optimal clinical usage

Opioid dependence treatment: options in pharmacotherapy.

The development of effective treatments for opioid dependence is of great importance given the devastating consequences of the disease. Pharmacotherapies for opioid addiction include opioid agonists, partial agonists, opioid antagonists, and alpha-2-adrenergic agonists, which are targeted toward either detoxification or long-term agonist maintenance. Agonist maintenance therapy is currently the recommended treatment for opioid dependence due to its superior outcomes relative to detoxification. Detoxification protocols have limited long-term efficacy, and patient discomfort remains a significant therapy challenge. Buprenorphine\u27s effectiveness relative to methadone remains a controversy and may be most appropriate for patients in need of low doses of agonist treatment. Buprenorphine appears superior to alpha-2 agonists, however, and office-based treatment with buprenorphine in the USA is gaining support. Studies of sustained-release formulations of naltrexone suggest improved effectiveness for retention and sustained abstinence; however, randomized clinical trials are needed

Noradrenergic α1 Receptor Antagonist Treatment Attenuates Positive Subjective Effects of Cocaine in Humans: A Randomized Trial

Preclinical research implicates dopaminergic and noradrenergic mechanisms in mediating the reinforcing effects of drugs of abuse, including cocaine. The objective of this study was to evaluate the impact of treatment with the noradrenergic α(1) receptor antagonist doxazosin on the positive subjective effects of cocaine.Thirteen non-treatment seeking, cocaine-dependent volunteers completed this single-site, randomized, placebo-controlled, within-subjects study. In one study phase volunteers received placebo and in the other they received doxazosin, with the order counterbalanced across participants. Study medication was masked by over-encapsulating doxazosin tablets and matched placebo lactose served as the control. Study medication treatment was initiated at 1 mg doxazosin or equivalent number of placebo capsules PO/day and increased every three days by 1 mg. After receiving 4 mg doxazosin or equivalent number of placebo capsules participants received masked doses of 20 and 40 mg cocaine IV in that order with placebo saline randomly interspersed to maintain the blind.Doxazosin treatment was well tolerated and doxazosin alone produced minimal changes in heart rate and blood pressure. During treatment with placebo, cocaine produced dose-dependent increases in subjective effect ratings of "high", "stimulated", "like cocaine", "desire cocaine", "any drug effect", and "likely to use cocaine if had access" (p<.001). Doxazosin treatment significantly attenuated the effects of 20 mg cocaine on ratings of "stimulated", "like cocaine", and "likely to use cocaine if had access" (p<.05). There were trends for doxazosin to reduce ratings of "stimulated", "desire cocaine", and "likely to use cocaine if had access" (p<.10).Medications that block noradrenergic α₁ receptors, such as doxazosin, may be useful as treatments for cocaine dependence, and should be evaluated further.Clinicaltrials.gov NCT01062945

A regime shift from macrophyte to phytoplankton dominance enhances carbon burial in a shallow, eutrophic lake

Ecological regime shifts and carbon cycling in aquatic systems have both been subject to increasing attention in recent years, yet the direct connection between these topics has remained poorly understood. A four-fold increase in sedimentation rates was observed within the past 50 years in a shallow eutrophic lake with no surface in- or outflows. This change coincided with an ecological regime shift involving the complete loss of submerged macrophytes, leading to a more turbid, phytoplankton- dominated state. To determine whether the increase in carbon (C) burial resulted from a comprehensive transformation of C cycling pathways in parallel to this regime shift, we compared the annual C balances (mass balance and ecosystem budget) of this turbid lake to a similar nearby lake with submerged macrophytes, a higher transparency, and similar nutrient concentrations. C balances indicated that roughly 80% of the C input was permanently buried in the turbid lake sediments, compared to 40% in the clearer macrophyte-dominated lake. This was due to a higher measured C burial efficiency in the turbid lake, which could be explained by lower benthic C mineralization rates. These lower mineralization rates were associated with a decrease in benthic oxygen availability coinciding with the loss of submerged macrophytes. In contrast to previous assumptions that a regime shift to phytoplankton dominance decreases lake heterotrophy by boosting whole-lake primary production, our results suggest that an equivalent net metabolic shift may also result from lower C mineralization rates in a shallow, turbid lake. The widespread occurrence of such shifts may thus fundamentally alter the role of shallow lakes in the global C cycle, away from channeling terrestrial C to the atmosphere and towards burying an increasing amount of C

Microrna-Mrna Networks Are Dysregulated in Opioid Use Disorder Postmortem Brain: Further Evidence for Opioid-Induced Neurovascular Alterations

INTRODUCTION: To understand mechanisms and identify potential targets for intervention in the current crisis of opioid use disorder (OUD), postmortem brains represent an under-utilized resource. To refine previously reported gene signatures of neurobiological alterations in OUD from the dorsolateral prefrontal cortex (Brodmann Area 9, BA9), we explored the role of microRNAs (miRNA) as powerful epigenetic regulators of gene function. METHODS: Building on the growing appreciation that miRNAs can cross the blood-brain barrier, we carried out miRNA profiling in same-subject postmortem samples from BA9 and blood tissues. RESULTS: miRNA-mRNA network analysis showed that even though miRNAs identified in BA9 and blood were fairly distinct, their target genes and corresponding enriched pathways overlapped strongly. Among the dominant enriched biological processes were tissue development and morphogenesis, and MAPK signaling pathways. These findings point to robust, redundant, and systemic opioid-induced miRNA dysregulation with a potential functional impact on transcriptomic changes. Further, using correlation network analysis, we identified cell-type specific miRNA targets, specifically in astrocytes, neurons, and endothelial cells, associated with OUD transcriptomic dysregulation. Finally, leveraging a collection of control brain transcriptomes from the Genotype-Tissue Expression (GTEx) project, we identified a correlation of OUD miRNA targets with TGF beta, hypoxia, angiogenesis, coagulation, immune system, and inflammatory pathways. DISCUSSION: These findings support previous reports of neurovascular and immune system alterations as a consequence of opioid abuse and shed new light on miRNA network regulators of cellular response to opioid drugs

Exenatide as an Adjunct to Nicotine Patch for Smoking Cessation and Prevention of Postcessation Weight Gain Among Treatment-Seeking Smokers With Pre-Diabetes and/or Overweight: Study Protocol for a Randomised, Placebo-Controlled Clinical Trial

INTRODUCTION: Obesity and smoking are the two leading causes of preventable death in the USA. Unfortunately, most smokers gain weight after quitting. Postcessation weight gain (PCWG) is frequently cited as one of the primary barriers to a quit attempt and a common cause of relapse. Further, excessive PCWG may contribute to the onset or progression of metabolic conditions, such as hyperglycaemia and obesity. The efficacy of the current treatments for smoking cessation is modest, and these treatments have no clinically meaningful impact on mitigating PCWG. Here, we outline a novel approach using glucagon-like peptide 1 receptor agonists (GLP-1RA), which have demonstrated efficacy in reducing both food and nicotine intake. This report describes the design of a double-blind, placebo-controlled, randomised clinical trial that evaluates the effects of the GLP-1RA exenatide as an adjunct to nicotine patches on smoking abstinence and PCWG. METHODS AND ANALYSIS: The study will be conducted at two university-affiliated research sites in Houston, Texas, the UTHealth Center for Neurobehavioral Research on Addiction and Baylor College of Medicine Michael E. DeBakey VA Medical Centre. The sample will consist of 216 treatment-seeking smokers with pre-diabetes (haemoglobin A1c of 5.7%-6.4%) and/or overweight (body mass index of 25 kg/m ETHICS AND DISSEMINATION: The study has been approved by the UTHealth Committee for the Protection of Human Subjects (HSC-MS-21-0639) and Baylor College of Medicine Institutional Review Board (H-50543). All participants will sign informed consent. The study results will be disseminated via peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT05610800

Factors influencing submerged macrophyte presence in fresh and brackish eutrophic waters and their impact on carbon emissions

In agricultural landscapes of North-Western Europe, the majority of water bodies do not meet the targets set by the European Water Framework Directive due to a lack of submerged macrophytes and associated biodiversity. These eutrophic waters can also be a substantial source of methane (CH4) and carbon dioxide (CO2) to the atmosphere. Here we present a two-year field experiment on the island of Goeree-Overflakkee (southwest Netherlands), conducted in six drainage ditches varying in salinity, where we monitored four permanent plots per ditch and varied the presence of both fish and macrophytes. We aimed to: 1) investigate factors limiting submerged macrophyte growth, focussing on exclusion of grazing pressure and bioturbation by fish; and 2) quantify the CO2 and CH4 emission under these conditions. Even in highly eutrophic, semi turbid ditches with fluctuating salinity levels and sulphide presence in the root zone, submerged macrophytes established successfully after introduction when the influence of grazing and bioturbation by fish was excluded. In the exclosures, diffusive CH4 and CO2 emissions, but not ebullitive CH4 emissions were significantly reduced. The spontaneous development of submerged macrophytes in the exclosures without macrophyte introduction underlined the effect of grazing and bioturbation by fish and suggest that abiotic conditions did not hamper submerged macrophyte development. Our results provide important insights into the influential factors for submerged macrophyte development and potential for future management practices. Large-scale fish removal may stimulate submerged macrophyte growth and reduce methane emissions, albeit that the macrophyte diversity will likely stay low in our study region due to fluctuating salinity and eutrophic conditions.</p

Sequence variation and linkage disequilibrium in the GABA transporter-1 gene (SLC6A1) in five populations: implications for pharmacogenetic research

<p>Abstract</p> <p>Background</p> <p>GABA transporter-1 (GAT-1; genetic locus <it>SLC6A1</it>) is emerging as a novel target for treatment of neuropsychiatric disorders. To understand how population differences might influence strategies for pharmacogenetic studies, we identified patterns of genetic variation and linkage disequilibrium (LD) in <it>SLC6A1 </it>in five populations representing three continental groups.</p> <p>Results</p> <p>We resequenced 12.4 kb of <it>SLC6A1</it>, including the promoters, exons and flanking intronic regions in African-American, Thai, Hmong, Finnish, and European-American subjects (total n = 40). LD in <it>SLC6A1 </it>was examined by genotyping 16 SNPs in larger samples. Sixty-three variants were identified through resequencing. Common population-specific variants were found in African-Americans, including a novel 21-bp promoter region variable number tandem repeat (VNTR), but no such variants were found in any of the other populations studied. Low levels of LD and the absence of major LD blocks were characteristic of all five populations. African-Americans had the highest genetic diversity. European-Americans and Finns did not differ in genetic diversity or LD patterns. Although the Hmong had the highest level of LD, our results suggest that a strategy based on the use of tag SNPs would not translate to a major improvement in genotyping efficiency.</p> <p>Conclusion</p> <p>Owing to the low level of LD and presence of recombination hotspots, <it>SLC6A1 </it>may be an example of a problematic gene for association and haplotype tagging-based genetic studies. The 21-bp promoter region VNTR polymorphism is a putatively functional candidate allele for studies focusing on variation in GAT-1 function in the African-American population.</p