Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" medications for cocaine dependence: studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys

Monoamine releasers constitute one class of drugs under investigation as candidate medications for the treatment of cocaine abuse. Promising preclinical and clinical results have been obtained with amphetamine, which has high selectivity for releasing dopamine/norepinephrine versus serotonin. However, use of amphetamine as a pharmacotherapy is complicated by its high abuse potential. Recent preclinical studies suggest that nonselective monoamine releasers or serotonin-selective releasers have lower abuse liability and may warrant evaluation as alternatives to amphetamine. To address this issue, the present study evaluated the effects of five monoamine releasers in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. The releasers varied along a continuum from dopamine/norepinephrine-selective to serotonin-selective [m-fluoroamphetamine (PAL-353), methamphetamine, m-methylamphetamine (PAL-314), 1-napthyl-2-aminopropane (PAL-287), fenfluramine]. In drug discrimination studies, rhesus monkeys were trained to discriminate saline from cocaine (0.4 mg/kg i.m.) in a two-key, food-reinforced drug discrimination procedure. Substitution for cocaine was positively associated with selectivity for dopamine/norepinephrine versus serotonin release. In drug self-administration studies, rhesus monkeys responded for cocaine (0.01 and 0.032 mg/kg/injection) and food (1-g pellets) under a second-order fixed-ratio 2 (variable-ratio 16:S) schedule. In general, monoamine releasers produced dose-dependent and sustained decreases in cocaine self-administration. However, the dopamine/norepinephrine-selective releasers decreased cocaine self-administration with minimal effects on food-maintained responding, whereas the more serotonin-selective releasers produced nonselective reductions in both cocaine- and food-maintained responding. These results are consistent with the conclusion that dopamine/norepinephrine-selective releasers retain cocaine-like abuse-related effects but may also be capable of producing relatively selective reductions in the reinforcing effects of cocaine.     

Incidence and mortality of venous thrombosis: a population-based study

Background: Estimates of the incidence of venous thrombosis (VT) vary, and data on mortality are limited. Objectives: We estimated the incidence and mortality of a first VT event in a general population. Methods: From the residents of Nord‐Trøndelag county in Norway aged 20 years and older (n = 94 194), we identified all cases with an objectively verified diagnosis of VT that occurred between 1995 and 2001. Patients and diagnosis characteristics were retrieved from medical records. Results: Seven hundred and forty patients were identified with a first diagnosis of VT during 516 405 person‐years of follow‐up. The incidence rate for all first VT events was 1.43 per 1000 person‐years [95% confidence interval (CI): 1.33–1.54], that for deep‐vein thrombosis (DVT) was 0.93 per 1000 person‐years (95% CI: 0.85–1.02), and that for pulmonary embolism (PE) was 0.50 per 1000 person‐years (95% CI: 0.44–0.56). The incidence rates increased exponentially with age, and were slightly higher in women than in men. The 30‐day case‐fatality rate was higher in patients with PE than in those with DVT [9.7% vs. 4.6%, risk ratio 2.1 (95% CI: 1.2–3.7)]; it was also higher in patients with cancer than in patients without cancer [19.1% vs. 3.6%, risk ratio 3.8 (95% CI 1.6–9.2)]. The risk of dying was highest in the first months subsequent to the VT, after which it gradually approached the mortality rate in the general population. Conclusions: This study provides estimates of incidence and mortality of a first VT event in the general population.     

对QT离散度实质的探讨

为探讨ＱＴ离散度（ＱＴｄ）的真实意义，观察１３９例急性心肌梗死（ＡＭＩ，ＡＭＩ组）及１０９例正常人（对照组）的最长ＱＴ间期（ＱＴｍａｘ）、校正ＱＴｍａｘ（ＱＴｃｍａｘ）及ＱＴｄ的变化。结果：①ＡＭＩ组的ＱＴｍａｘ、ＱＴｃｍａｘ和ＱＴｄ均显著高于对照组（分别为４２２．６０±３０．５１ｍｓｖｓ３８２．４６±２３．４０ｍｓ、４６０．２１±２８．９６ｍｓｖｓ３８８．５１±２０．１５ｍｓ、５９．８０±２８．４０ｍｓｖｓ３９．４３±１２．２１ｍｓ，Ｐ均＜０．００１）。②ＡＭＩ组中发生严重室性心律失常（ＶＡ）患者（１１４例）的ＱＴｍａｘ、ＱＴｃｍａｘ、ＱＴｄ与无ＶＡ的患者（２５例）相比，均有显著差异（分别为４４８．５８±３３．４０ｍｓｖｓ４１６．１０±３５．３０ｍｓ、４８１．４３±３５．１７ｍｓｖｓ４３９．６０±２７．１０ｍｓ、６６．９０±２０．７２ｍｓｖｓ４８．３２±２３．６１ｍｓ，Ｐ均＜０．００１）。认为ＡＭＩ时ＱＴｄ系Ｔ向量环在不同导联上的“投影”差异所引起的，其异常的本质是ＱＴ间期延长     

Role of µ-opioid receptor reserve and µ-agonist efficacy as determinants of the effects of µ-agonists on intracranial self-stimulation in rats

The net effect of μ-opioid receptor agonists on intracranial self-stimulation (ICSS) in rats reflects an integration of rate-increasing and rate-decreasing effects. Previous opioid exposure is associated with tolerance to rate-decreasing effects and the augmented expression of abuse-related rate-increasing effects. This finding was replicated here with morphine. Subsequent studies then tested the hypothesis that opioid agonist-induced rate-decreasing effects require the activation of a larger relative fraction of μ receptors, and hence are more vulnerable to tolerance-associated reductions in receptor density than rate-increasing effects. Two sets of experiments were conducted to test this hypothesis. First, the effects of morphine on ICSS were examined after pretreatment with the irreversible μ antagonist β-funaltrexamine to reduce the density of available μ receptors. Second, effects were examined for a range of μ opioids that varied in relative efficacy at μ receptors. The hypothesis predicted that (a) morphine, after β-funaltrexamine treatment, or (b) low-efficacy μ agonists would mimic the effects of morphine tolerance to produce the reduced expression of rate-decreasing effects and enhanced expression of rate-increasing effects. Neither of these predictions were supported. These results indicate that μ agonist-induced facilitation and depression of ICSS may be mediated by distinct populations of μ receptors that respond differently to regimens of opioid exposure.     

The effects of heroin on prolactin levels in male rhesus monkeys: use of cumulative-dosing procedures

There is considerable evidence that mu opioid receptors are involved in the regulation of anterior pituitary function. For example, in nonhuman primates and humans, mu agonists generally increase prolactin (PRL) levels. In contrast, mu antagonists decrease or have no effect on PRL levels. The goal of this study was to assess the potential utility of cumulative-dosing procedures to evaluate the endocrine effects of mu opioid receptor ligands. The effects of single and multiple, cumulative doses of the mu agonist heroin and the mu-selective antagonist quadazocine on PRL levels were investigated in four male rhesus monkeys. Cumulative dose-response curves were determined by infusing increasing drug doses at 60 min intervals over 290 min. Blood samples for PRL analysis were collected at 25 and 50 min after each cumulative infusion. Samples were collected at similar time points following single drug dose administration. Heroin (0.01-0.32 mg/kg, IV) administration dose-dependently increased PRL levels. Maximum levels of heroin-induced PRL levels were equivalent after single and cumulative doses. Quadazocine alone (0.032-1.0 mg/kg, IM) did not alter PRL levels significantly. However, quadazocine (0.1 mg/kg, IM) antagonized heroin-stimulated increases in PRL levels and produced a significant rightward shift in the heroin dose-effect curve. These data suggest that a cumulative-dosing procedure similar to that used in behavioral pharmacology may be useful to study the endocrine pharmacology of mu opioids in rhesus monkeys.     

Effects of dopamine D(1-like) and D(2-like) agonists in rats that self-administer cocaine.

The reinforcing effects of D(1-like) and D(2-like) agonists, and their capacity to modify cocaine self-administration, were compared in rats with extensive cocaine self-administration experience. Cocaine (0.01-1.0 mg i.v.) dose-dependently maintained responding under a fixed ratio (FR) 5 schedule of reinforcement, and an inverted U-shaped function characterized the relationship between unit dose and self-administration behavior. When substituted for cocaine, the D(1-like) agonists SKF 82958 (0.001-0.032 mg i.v.) and SKF 77434 (0.001-0.1 mg i.v.) did not maintain responding above levels observed during saline substitution. In contrast, the D(2-like) agonists quinelorane (0.001-0.1 mg i.v.) and 7-hydroxy-dipropylaminotetralin (7-OH-DPAT; 0.01-0.32 mg i.v.) reliably maintained i.v. self-administration behavior that was characterized by inverted U-shaped dose-effect functions. Pretreatment with the D(1-like) agonists SKF 82958 and SKF 77434 (0.1-1.0 mg/kg i.p.) shifted the dose-effect function for cocaine self-administration downward, whereas pretreatment with the D(2-like) agonists quinelorane (0.01 mg/kg i.p.) and 7-OH-DPAT (0.32-1.0 mg/kg i.p.) shifted the cocaine dose-effect function to the left. Effects of D(1-like) and D(2-like) agonists on patterns of responding maintained by cocaine (0.32 mg i.v.) also differed: D(1-like) agonists increased the latency to the first response but did not otherwise alter patterns of cocaine self-administration, whereas D(2-like) agonists increased the intervals between self-administered cocaine injections. The results suggest that D(2-like) agonists, but not D(1-like) agonists, have prominent reinforcing effects and enhance the effects of self-administered cocaine in rats with extensive cocaine self-administration experience. Consequently, D(2) receptor-related neuronal mechanisms may be especially important in mediating the abuse-related effects of cocaine.