褪黑素抑制可卡因诱导的条件性位置偏爱大鼠DNMT1的下调

目的研究褪黑素拮抗大鼠可卡因诱导的条件性位置偏爱的作用和可能机制。方法建立可卡因诱导的条件性位置偏爱模型,诱导前30min给予褪黑素腹腔注射,检测实验大鼠条件性位置偏爱的变化,并应用Western blot、免疫荧光共聚焦激光扫描显微镜及real-time PCR技术,检测褪黑素对大鼠前额叶皮层中可卡因诱导的DMNT1表达的影响。结果褪黑素对可卡因诱导的大鼠条件性位置偏爱效应具有显著的抑制作用。共聚焦显微镜和Western blot结果表明,可卡因诱导大鼠前额叶皮层中DNMT1表达的减少,而褪黑素能够抑制可卡因的这种作用。Real-time PCR检测结果证明,可卡因诱导大鼠前额叶皮层中DNMT1 mRNA的下调,而褪黑素能够抑制这种作用。结论褪黑素可能通过抑制大鼠前额叶皮层中DNMT1表达的下调拮抗可卡因诱导的条件性位置偏爱。     

Peripheral Nerve Sheath Tumors

The toxic effects of myoglobin on the kidney are discussed. Pathophysiologic mechanisms involved in myoglobinuric conditions associated with renal dysfunction as well as important diagnostic laboratory and morphologic considerations are addressed. The subject is placed in proper clinicopathologic perspective by discussing the most common clinical situations involved.     

Effects of Extended Cocaine Access and Cocaine Withdrawal on Choice Between Cocaine and Food in Rhesus Monkeys

Chronic drug use may lead to sufficient drug intake to produce dependence and the emergence of abstinence signs during withdrawal. Although withdrawal can increase the reinforcing effects of some drugs (eg opioids), the impact of withdrawal on the reinforcing effects of stimulants like cocaine is less clear. This study used a novel cocaine vs food choice procedure to examine the relative reinforcing strength of cocaine before, during, and after exposure to graded levels of extended cocaine access. Responding in four rhesus monkeys was maintained by cocaine (0–0.1 mg/kg/injection) and food delivery under a concurrent-choice schedule during daily 2-h sessions. Under baseline conditions, cocaine maintained a dose-dependent increase in cocaine choice. Subsequently, subjects were exposed to and withdrawn from periods of extended cocaine access, which was accomplished by implementing daily 21-h supplemental sessions of cocaine self-administration in addition to daily choice sessions. During supplemental sessions, cocaine (0.1 mg/kg/injection) was available under a fixed-ratio 10/time-out X schedule, and the duration of the time-out was varied from 30 to 7.5 min. Cocaine intake increased 10-fold to >11 mg/kg/day during exposure to supplemental sessions with the shortest post-injection time-out. However, parameters of cocaine choice were not significantly affected either during or after extended cocaine access. These results do not support the hypothesis that cocaine withdrawal increases the reinforcing strength of cocaine. This differs from results with the opioid agonist heroin and suggests that withdrawal may have different functions in the maintenance of opioid and stimulant abuse.     

Cardiac calcification

We present a case of sudden cardiac death (SCD) due to accelerated atheroma in a young man. Histological specimens revealed chronic myocardial ischaemia with severe calcification. The causes of myocardial calcification are reviewed and we summarise the key learning points relating to cocaine use and heart disease. Trainees should appreciate that in cases of accelerated coronary atheroma there may be multiple risk factors involved and that family history of myocardial ischaemia is often a key contributor.     

The Effect of Hyperglycemia on Cocaine Neurotoxicity and Death in Mice

OBJECTIVE: Cocaine toxicity frequently manifests as seizures and status epilepticus. Frequently, dextrose is administered to patients with cocaine-induced seizures. The objective of this study was to examine the effect of pre-existing hyperglycemia on cocaine neurotoxicity and death in mice. METHODS: Swiss albino mice received intraperitoneal dextrose at a dose of 1 g/kg (12.5%) (hyperglycemic group, n = 98). The euglycemic group (n = 98) received an equal volume of 0.9% saline. After 60 minutes, all the animals received intraperitoneal cocaine at a dose of 90 mg/kg. The times to onset of ataxia, seizure, and death were recorded in seconds. Times to events were compared using a Kaplan-Meier method and results were compared using the logrank test. The overall percentage outcomes were compared using chi-square. RESULTS: The ataxia rates (hyperglycemic 97%, euglycemic 97%, chi(2) = 0, p = 1), seizure rates (hyperglycemic 85%, euglycemic 82%, chi(2) = 0.292, p = 0.589), and survival rates (hyperglycemic 62%, euglycemic 51%, chi(2) = 0.2514, p = 0.113) were similar between the groups. The survival following a seizure was significantly higher in the hyperglycemic group (hyperglycemic 57%, euglycemic 41%, chi(2) = 4.439, p = 0.035). The median ataxia time was earlier in the hyperglycemic group (190 sec) than in the euglycemic group (166 sec) (p = 0.031). Seizures occurred no earlier in the hyperglycemic group (331 sec) than in the euglycemic group (342 sec) (p = 0.207). Survival times were not different for the hyperglycemic group (9,133 sec) and the euglycemic group (7,593 sec) (p = 0.394). Survival times following seizures were not different for the hyperglycemic group (8,095 sec) and the euglycemic group (5,816 sec) (p = 0.0752). CONCLUSIONS: In mice with pre-existing hyperglycemia, ataxia occurred earlier and survival following cocaine-induced seizures was longer than for euglycemic mice. No significant difference in the overall percentage of seizures and death was detected. Pre-existing hyperglycemia had minimal effect on worsening cocaine toxicity in mice.     

Animal studies trigger new insights on the use of methadone maintenance

Background: Although steady-state methadone (SSM) treatment is mainly used for opioid addiction, some clinical studies indicate that it also reduces cocaine abuse in opioid-dependent individuals. Objective/methods: To present evidence suggesting that SSM may be useful in the treatment of cocaine addiction without pre-existing opioid dependence. We review studies in animals investigating the effects of SSM on behaviors motivated by cocaine and on cocaine-induced alterations of genes expression in the rat brain. Conclusion: SSM reduces cocaine intake, blocks cocaine seeking and normalizes expression of genes known to regulate cocaine seeking. These findings suggest that SSM could be an effective pharmacological agent to assist cocaine detoxification and prevention of relapse to cocaine abuse in individuals not co-dependent on opioid.     

Contingency Management to Reduce Substance Use in Individuals Who are Homeless with Co-Occurring Psychiatric Disorders

Homeless shelters provide a unique opportunity to intervene with occupants who have substance abuse problems, as not addressing these issues may lead to continuation of problems playing a contributing role in homelessness. Attempts to implement Contingency Management (CM) with this population have often been complex, costly, and not straightforward to replicate in community settings. We conducted a randomized trial evaluating a simple, low-cost 4-week CM program for 30 individuals seeking shelter in a community-based homeless shelter who had both current substance and psychiatric disorders. Behavioral assessments were performed at baseline, weekly, and termination of the study. Overall retention in the trial was high; participants assigned to CM reduced their cocaine and alcohol use more than those in assessment-only. This pilot trial suggests that application of low-cost CM procedures is feasible within this novel setting and may decrease substance use.     

Behaviour of hygrine and cuscohygrine in illicit cocaine production establishes their use as markers for chewing coca leaves in contrast with cocaine abuse

Hygrine (HYG) and cuscohygrine (CUS) are natural alkaloids of coca leaves but are not found in illicit cocaine seizures. Therefore, they were proposed as markers for coca chewing in contrast to cocaine abuse in urine and hair testing. In order to examine at which step of the illegal cocaine production these compounds are lost, coca leaves were processed according to an authentic procedure by extraction with lime and kerosene, re‐extraction with sulphuric acid, and precipitation of coca paste with ammonia. Non‐extracted and extracted coca leaves, acidic extract and coca paste were analyzed by gas chromatography‐mass spectrometry (GC‐MS) and liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) for cocaine, ecgonine methyl ester (EME), cinnamoylcocaine (CIN), HYG, and CUS. It follows from the results that under these conditions, HYG and CUS are extracted only to a minor extent by kerosene and are not precipitated from the acidic re‐extract in the coca paste. Due to this behaviour in illegal cocaine production, they fulfil the conditions as markers for coca chewing in an optimal way. However, for unambiguous discrimination between coca chewing and cocaine abuse in human samples, additional markers of manufactured cocaine are required. Copyright © 2016 John Wiley & Sons, Ltd.     

Adenovirus Capsid-Based Anti-Cocaine Vaccine Prevents Cocaine from Binding to the Nonhuman Primate CNS Dopamine Transporter

Cocaine addiction is a major problem for which there is no approved pharmacotherapy. We have developed a vaccine to cocaine (dAd5GNE), based on the cocaine analog GNE linked to the capsid proteins of a serotype 5 adenovirus, designed to evoke anti-cocaine antibodies that sequester cocaine in the blood, preventing access to the CNS. To assess the efficacy of dAd5GNE in a large animal model, positron emission tomography (PET) and the radiotracer [¹¹C]PE2I were used to measure cocaine occupancy of the dopamine transporter (DAT) in nonhuman primates. Repeat administration of dAd5GNE induced high anti-cocaine titers. Before vaccination, cocaine displaced PE2I from DAT in the caudate and putamen, resulting in 62±4% cocaine occupancy. In contrast, dAd5GNE-vaccinated animals showed reduced cocaine occupancy such that when anti-cocaine titers were >4 × 10⁵, the cocaine occupancy was reduced to levels of <20%, significantly below the 47% threshold required to evoke the subjective ‘high'' reported in humans.