Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Biosynthetic Gene Cluster for the Cladoniamides, Bis-Indoles with a Rearranged Scaffold

The cladoniamides are bis-indole alkaloids isolated from Streptomyces uncialis, a lichen-associated actinomycete strain. The cladoniamides have an unusual, indenotryptoline structure rarely observed among bis-indole alkaloids. I report here the isolation, sequencing, and annotation of the cladoniamide biosynthetic gene cluster and compare it to the recently published gene cluster for BE-54017, a closely related indenotryptoline natural product. The cladoniamide gene cluster differs from the BE-54017 gene cluster in gene organization and in the absence of one N-methyltransferase gene but otherwise contains close homologs to all genes in the BE-54017 cluster. Both gene clusters encode enzymes needed for the construction of an indolocarbazole core, as well as flavin-dependent enzymes putatively involved in generating the indenotryptoline scaffold from an indolocarbazole. These two bis-indolic gene clusters exemplify the diversity of biosynthetic routes that begin from the oxidative dimerization of two molecules of l-tryptophan, highlight enzymes for further study, and provide new opportunities for combinatorial engineering

How Do They Do It? – Understanding the Success of Marine Invasive Species

From the depths of the oceans to the shallow estuaries and wetlands of our coasts, organisms of the marine environment are teeming with unique adaptations to cope with a multitude of varying environmental conditions. With millions of years and a vast volume of water to call their home, they have become quite adept at developing specialized and unique techniques for survival and – given increasing human mediated transport – biological invasions. A growing world human population and a global economy drives the transportation of goods across the oceans and with them invasive species via ballast water and attached to ship hulls. In any given 24-hour period, there are about 10,000 species being transported across different biogeographic regions. If any of them manage to take hold and establish a range in an exotic habitat, the implications for local ecosystems can be costly. This review on marine invasions highlights trends among successful non-indigenous species (NIS), from vectors of transport to ecological and physiological plasticity. Apart from summarizing patterns of successful invasions, it discusses the implications of how successfully established NIS impact the local environment, economy and human health. Finally, it looks to the future and discusses what questions need to be addressed and what models can tell us about what the outlook on future marine invasions is

Sobrevida después de accidentes de tránsito: impacto de las variables clínicas y pre hospitalarias

OBJETIVO: Analisar as variáveis clínicas e pré-hospitalares associadas à sobrevivência de vítimas de acidente de trânsito. MÉTODOS: Estudo realizado no município de São Paulo, SP, de 1999 a 2003. Foram analisados dados de 175 pacientes, entre 12 e 65 anos, vitimados por acidente de trânsito. A Análise de Sobrevivência de Kaplan-Meier foi utilizada na abordagem dos resultados na cena do acidente com as vítimas de escore <11 segundo o Revised Trauma Score. As variáveis analisadas foram: sexo, idade, mecanismos do acidente, procedimentos de suporte básico e avançado realizados, parâmetros e flutuações do Revised Trauma Score, tempo consumido na fase pré-hospitalar e gravidade do trauma segundo o Injury Severity Score e a Maximum Abbreviated Injury Scale. RESULTADOS: A análise identificou que as vítimas que tiveram menor probabilidade de sobrevivência durante todo período de internação hospitalar apresentaram: lesões graves no abdome, tórax ou membros inferiores, com flutuação negativa da freqüência respiratória e do Revised Trauma Score na fase pré-hospitalar e necessitaram de intervenções avançadas ou compressões torácicas. As lesões encefálicas foram associadas ao óbito tardio. CONCLUSÕES: O reconhecimento das variáveis envolvidas na sobrevivência de vítimas de acidentes de trânsito pode auxiliar na determinação de protocolos e na tomada de decisão para a realização de intervenções pré e intra-hospitalares e conseqüentemente maximizar a sobrevivência.OBJECTIVE: To assess clinical and prehospital variables associated with survival of motor vehicle crash victims. METHODS: Study carried out in the city of São Paulo (Southeastern Brazil), from 1999 to 2003. Data from 175 patients, who were aged between 12 and 65 years and had been motor vehicle crash victims, were analyzed. Kaplan-Meier Survival Analysis was used to approach the results at the accident scene with victims scoring <11, according to the Revised Trauma Score. Variables analyzed were: sex, age, injury mechanisms, basic and advanced support procedures, Revised Trauma Score parameters and fluctuations, time elapsed in the prehospital phase and trauma severity according to the Injury Severity Score and Maximum Abbreviated Injury Scale. RESULTS: Analysis revealed that victims who were less likely to survive during the hospitalization period showed serious lesions in the abdomen, thorax, or lower limbs, with negative fluctuation of respiratory frequency and Revised Trauma Score in the prehospital phase. In addition, they needed specialized interventions or thoracic compressions. Brain lesions were associated with late death. CONCLUSIONS: Recognition of variables involved in the survival of motor vehicle crash victims may help to determine protocols and to make decisions in order to perform pre- and in-hospital interventions and, consequently, maximize survival.OBJETIVO: Analizar las variables clínicas y pre hospitalarias asociadas a la sobrevida de víctimas de accidentes del tránsito. MÉTODOS: Estudio realizado en el municipio de São Paulo (Sudeste de Brasil), de 1999 a 2003. Fueron analizados datos de 175 pacientes, entre 12 y 65 años, victimas de accidentes de tránsito. El análisis de Sobrevida de Kaplan-Meier fue utilizado en el abordaje de los resultados en la escena del accidente con las víctimas de score <11 segun el Revised Trauma Score. Las variables analizadas fueron: sexo, edad, mecanismos del accidente, procedimientos de soporte básico y avanzado realizados, parámetros y fluctuaciones del Revised Trauma Score, tiempo consumido en la fase pre hospitalaria y gravedad del trauma según el Injury Severity Score y la Maximum Abbreviated Injury Scale. RESULTADOS: El análisis identificó que la víctimas que tuvieron menor probabilidad de sobre vivencia durante todo el período de interacción hospitalaria presentaron: lesiones graves en el abdomen, tórax o miembros inferiores, con fluctuación negativa de la frecuencia respiratoria y del Revised Trauma Score en la fase pre hospitalaria y necesitaron de intervenciones avanzadas o compresiones torácicas. Las lesiones encefálicas fueron asociadas al óbito tardío. CONCLUSIONES: El reconocimiento de las variables involucradas en la sobrevida de víctimas de accidentes del tránsito puede auxiliar en la determinación de protocolos y en la toma de decisiones para la realización de intervenciones pre e intra-hospitalarias y consecuentemente maximizar la sobrevida