Several dopamine (DA) indirect agonists have been proposed as potential medications for treating cocaine abuse. The objective of the present study was to quantify the interactions among cocaine and DA uptake inhibitors or DA releasers to better understand how these drugs may be working when administered in combination. The DA uptake inhibitors GBR 12909 [1-{2-[bis-(4-fluorophenyl)methoxy]-ethyl}-4-(3-phenylpropyl)piperazine], WIN 35,428 [2␤-carbomethoxy-3␤-(4-fluorophenyl)tropane], methylphenidate, indatraline, nomifensine, and mazindol and DA releasers methamphetamine, d-amphetamine, methcathinone, cathinone, fencamfamine, and phentermine were examined alone and in combination with cocaine in rats trained to discriminate cocaine (10 mg/kg i.p.) from saline injections. All of the DA indirect agonists dose-dependently substituted for cocaine and shifted the cocaine dose-effect curve leftward. Isobolographic analysis indicated the interactions were generally additive, although both methamphetamine and d-amphetamine were quantitatively determined to be more potent than DA uptake inhibitors in shifting the cocaine dose-effect function to the left. The potential of d-amphetamine as an effective treatment for cocaine abuse and negative clinical results with dopamine uptake inhibitors suggest that differences in shifts in dose-effect curves should be further examined with emerging clinical data as a predictive index of potential treatments for cocaine abuse.

Dopaminergic (DA) agonist-induced yawning in rats seems to be mediated by DA D3 receptors, and low doses of several DA agonists decrease locomotor activity, an effect attributed to presynaptic D2 receptors. Effects of several DA agonists on yawning and locomotor activity were examined in rats and mice. Yawning was reliably produced in rats, and by the cholinergic agonist, physostigmine, in both the species. However, DA agonists were ineffective in producing yawning in Swiss–Webster or DA D2R and DA D3R knockout or wild-type mice. The drugs significantly decreased locomotor activity in rats at one or two low doses, with activity returning to control levels at higher doses. In mice, the drugs decreased locomotion across a 1000–10 000-fold range of doses, with activity at control levels (U-91356A) or above control levels [(±)-7-hydroxy-2-dipropylaminotetralin HBr, quinpirole] at the highest doses. Low doses of agonists decreased locomotion in all mice except the DA D2R knockout mice, but were not antagonized by DA D2R or D3R antagonists (L-741 626, BP 897, or PG01037). Yawning does not provide a selective in-vivo indicator of DA D3R agonist activity in mice. Decreases in mouse locomotor activity by the DA agonists seem to be mediated by D2 DA receptors.

Rationale Dopamine transporter (DAT) conformation plays a role in the effectiveness of cocaine-like and other DAT-inhibitors. Cocaine-like stimulants are intolerant to DAT conformation changes having decreased potency in cells transfected with DAT constructs that face the cytosol compared to wild-type DAT. In contrast, analogs of benztropine (BZT) are among compounds that are less affected by DAT conformational change. Methods We compared the displacement of radioligand binding to various mammalian CNS sites, acute stimulation of accumbens shell dopamine levels, and place-conditioning in rats among cocaine and four BZT analogs with Cl-substitutions on the diphenyl-ether system including two with carboalkoxy substitutions at the 2-position of the tropane ring. Results Binding assays confirmed high-affinity and selectivity for the DAT with the BZT analogs which also produced significant stimulation of mesolimbic dopamine efflux. Because BZT analogs produced temporal patterns of extracellular dopamine levels different from those by cocaine (3-10 mg/kg, IP), the place conditioning produced by BZT analogs and cocaine was compared at doses and times at which both the increase in dopamine levels and rates of increase were similar to those produced by an effective dose of cocaine. Despite this equilibration, none of the BZT analogs tested produced significant place conditioning. Conclusions The present results extend previous findings suggesting that cocaine-like actions are dependent on a binding equilibrium that favors the outward conformational state of the DAT. In contrast BZT analogs with reduced dependence on DAT conformation have reduced cocaine-like behavioral effects and may prove useful in development of medications for stimulant abuse.

It is an important precondition and basis for the design of tailings reservoir and its safety facilities by reasonably judging and estimating the mud-sand flow hazard due to dam-break. In this paper, the mud-sand flow hazard scope, extent and spatial state after dam-broken of heightened Mawuqing tailing dam were simulated and analyzed through a flood and debris flow numerical simulation approach, and the hazard risk grade of different spatial locations of downstream Xiaoqingkou(XQK) village was obtained from the simulation. Then the spatial simulation of sand flow hazard under different preventive measures was carried out, and the variation of hazard risk grade at different spatial locations in XQK was obtained. The result of spatial simulation and analysis has shown that if the retaining wall or detention dam is set at the edge of the village, the risk hazard of the village due to dam-break can be reduced after the tailing dam is heightened. At the same time, it can be concluded that to reduce dam break hazard the above local engineering measures are more effective than an overall engineering measures to control the mud-sand flow. The spatial simulation and analysis have provided the basis to make more reasonable engineering decision and protection measures for XQK after the reconstruction of the tailing dam, and also provided the technical support for tailing dam-break accident prevention, the safety management of tailing dam and the mine production safety.

In order to evaluate the risk degree of the tailings pond’s dam-break disaster reasonably, according to statistical analysis of the tailings pond’s dam-break failure and "the tailings major hazards classification method" of our country, the improved "index weight method" is worked out, and the index partition method and weight assignment of the "index weight method" are analyzed and researched detailed. Combining with an engineering example to verify the improved "index weight method", and the sensitivity of index weight is discussed. The results of the analysis show that "index weight method" for the judgment of the risk degree of the tailings pond’ s dam-break disaster is more reasonable. It is more feasible for safety department to make division of attention to supervision level of the tailings pond according to the determination results.

The core of economical and intensive land-use in tourism industry is the land for construction(LC). The paper studied the evaluation system about the economical and intensive land-use of the LC in the tourism industry. And made the cites as the evaluation unit of Yunnan Province, selected seven factors, such as the received tourist of units construction from abroad, the investment of units construction, the income of tourism and so on as the evaluation factors, analyzed and evaluated the status of intensive use of the LC, which provided the basis for the land-use planning of tourism industry in Yunnan Province.