自身给药实验

自身给药实验王桂林，郑继旺（北京医科大学中国药物依赖性研究所，北京１０００８３）自身给药实验是用来研究药物的强化效应，进而评价其精神依赖性潜力的一种方法。早在６０年代，Ｗｅｅｋｓ［１］和Ｙａｎａｇｉｔａ［２］等就分别建立了大鼠和猴的自身给药模型，此后...     

大白鼠固定比率连续自身给药实验动物模型的建立

本实验采用固定比率为1：1的4h连续自身给药实验模型，药物是经典的具有较强精神依赖性的盐酸吗啡。在低于形成身体依赖性的阈下剂量，大白鼠经过一定的训练后能形成主动的觅药行为。改变每次响应注射剂量后，大白鼠均能通过调整踏板次数来控制药物的摄入量，组间t检验踏板次数有显著性差异，而日剂量无明显差异，说明精神依赖性已经形成。大白鼠自身给药实验形成稳定模型的周期短，且药物进入大鼠静脉时不延期、不打扰动物，给药的剂量准确，影响因素少，所得到的实验结果稳定可靠。     

大白鼠固定比率连续自身给药实验动物模型的建立

本实验采用固定比率为1:1的4h连续自身给药实验模型,药物是经典的具有较强精神依赖性的盐酸吗啡。在低于形成身体依赖性的阈下剂量,大白鼠经过一定的训练后能形成主动的觅药行为。改变每次响应注射剂量后,大白鼠均能通过调整踏板次数来控制药物的摄入量,组间t检验踏板次数有显著性差异,而日剂量无明显差异,说明精神依赖性已经形成。大白鼠自身给药实验形成稳定模型的周期短,且药物进入大鼠静脉时不延期、不打扰动物,给药的剂量准确,影响因素少,所得到的实验结果稳定可靠。     

大鼠静脉自身给药法观察盐酸二氢埃托啡的自身给药行为

本文用大鼠自身给药法评价了盐酸二氢埃托啡（ＤＨＥ）的精神依赖性，结果表明：在１．０，２．０和４．０μｇ．ｋｇ＾－１三个剂量下，ＤＨＥ均能形成稳定的自身给药行为，与吗啡相比，具有潜伏期短，反应阳性率高，踏板频率高等特点，提示ＤＨＥ的精神依赖性较强。     

大鼠静脉自身给药法观察盐酸二氢埃托啡的自身给药行为

本文用大鼠自身给药法初步评价了盐酸二氢埃托啡（ＤＨＥ）的精神依赖性，结果表明：在１．０，２．０和４．０μｇ·ｋｇ－１三个剂量下，ＤＨＥ均能形成稳定的自身给药行为，与吗啡相比，具有潜伏期短，反应阳性率高，踏板频率高等特点；提示ＤＨＥ的精神依赖性较强。     

东莨菪碱对猕猴吗啡静脉自身给药及反应恢复的影响

目的：研究M胆碱能受体阻滞剂东莨菪碱对猕猴吗啡静脉自身给药及反应恢复行为的影响。方法：建立猕猴吗啡静脉自身给药模型（固定比率1，给药期4h)以及反应恢复模型。观察不同浓度东莨菪碱急性处理对吗啡静脉自身给药模型、踏板反应率、吗啡用药量以及自由活动度的影响。同时观察慢性和急性东莨菪碱处理对静脉自身给药行为淬灭后反应恢复行为的影响。结果：东莨菪碱急性处理（0．025，0．075，0．25，0．75mg/kg)可以减弱FR1程序控制下吗啡静脉自身给药行为，不仅表现为总用药量和反应速率的降低，而且还可延迟自身给药行为的起动，同时对自身给药行为模式有较大的影响，小剂量东莨菪碱可使急促的用药行为变为缓慢，大剂量时几乎可完全阻断动物的踏板反应。反应恢复实验结果显示，东莨菪碱急性处理可延迟淬灭后踏板反应的恢复，而慢性处理可降低动物的踏板反应率及总的强化次数。结论，提示东莨菪碱对复吸行为可能有一定的治疗作用。     

东莨菪碱对猕猴吗啡静脉自身给药及反应恢复的影响

目的研究M胆碱能受体阻滞剂东莨菪碱对猕猴吗啡静脉自身给药及反应恢复行为的影响。方法建立猕猴吗啡静脉自身给药模型(固定比率1 ,给药期4h)以及反应恢复模型。观察不同浓度东莨菪碱急性处理对吗啡静脉自身给药模式、踏板反应率、吗啡用药量以及自由活动度的影响。同时观察慢性和急性东莨菪碱处理对静脉自身给药行为淬灭后反应恢复行为的影响。结果东莨菪碱急性处理(0.025,0.075,0.25,0.75mg/kg)可以减弱FR1程序控制下吗啡静脉自身给药行为 ,不仅表现为总用药量和反应速率的降低 ,而且还可延迟自身给药行为的起动 ,同时对自身给药行为模式有较大的影响 ,小剂量东莨菪碱可使急促的用药行为变为缓慢 ,大剂量时几乎可完全阻断动物的踏板反应。反应恢复实验结果显示 ,东莨菪碱急性处理可延迟淬灭后踏板反应的恢复 ,而慢性处理可降低动物的踏板反应率及总的强化次数。结论提示东莨菪碱对复吸行为可能有一定的治疗作用     

固定比率为10的大鼠吗啡静脉注射自身给药模型建立

目的:建立固定比率为10(FR10)的大鼠吗啡静脉注射(iv)自身给药模型。方法:先对20只雄性SD大鼠进行2种条件刺激程序下的食物训练,比较2种程序下训练效果差异,大鼠学会踏板后进行颈静脉插管手术,手术恢复期过后以吗啡训练剂量(0.5 mg·kg^-1·injection^-1)进行FR1模式下静脉注射自身给药的建立,2 h·d^-1,随后进行消退测试证明动物已经吗啡成瘾,接着恢复FR1自身给药行为后提升难度至FR10,FR10自身给药稳定后依次替换吗啡剂量为0.125,0.25,0.5和1.0 mg·kg^-1·injection^-1,每个剂量连续替换3 d,进行剂量反应关系的测试。结果:20只雄性大鼠,在食物训练阶段的2种条件刺激程序下均有8只动物食物训练成功,但2种程序训练效果无明显差别;FR1自身给药阶段有13只动物成功建立FR1静脉注射自身给药行为和消退测试,并呈现出了明显的消退特点;FR10自身给药阶段有5只动物成功建立FR10静脉注射自身给药稳定行为并呈现出典型的"倒U...     

甲氧氯普胺对小鼠吗啡身体依赖性的影响

目的·· :观察甲氧氯普胺对吗啡身体依赖性的影响。方法·· :皮下注射盐酸吗啡建立吗啡依赖小鼠模型,以纳洛酮催促戒断症状。分别在建立吗啡依赖模型前或后给予不同剂量的甲氧氯普胺,观察其预防性给药和急性给药产生的影响。结果·· :甲氧氯普胺急性给药(20 -80mg·kg-1,ip)吗啡依赖小鼠跳跃次数显著减少 ,体重下降加剧 ;预防性给药 (5-20mg·kg-1,ip)小鼠跳跃次数减少 ,但无统计学意义 ,体重下降有显著性改善。结论·· :甲氧氯普胺可缓解吗啡依赖小鼠的部分戒断症状,在一定程度上抑制吗啡身体依赖的形成。     

大鼠吗啡精神依赖动物模型的建立

建立吗啡依赖大鼠模型是研究阿片类药物依赖机制,评价药物脱毒和药物成瘾型治疗的必要手段。条件性位置偏爱（conditioned place preference,CPP）是评价药物精神依赖、建立大鼠吗啡精神依赖的常用方法。但目前许多研究多采用剂量递增的方法诱导大鼠CPP,建立模型所需时间较长。因此我们采用连续6天等剂量注射的方法建立大鼠吗啡精神依赖模型,并对不同给药剂量进行了位置偏爱效应的比较,获得了理想的实验结果。     

An investigation of nalorphine and perphenazine as negative reinforcers in an escape paradigm.

Rhesus monkeys were trained to self-administer morphine intravenously at dose levels sufficient to develop physical dependence. The monkeys were then trained to press a lever to escape a continuous infusion of the morphine antagonist, nalorphine. When saline was substituted for the nalorphine, escape responding extinguished. After morphine self-administration was eliminated, responding to escape from nalorphine was maintained in the postdependent monkeys, showing no difference from escape responding during morphine dependence. Finally, perphenazine was substituted for the nalorphine and the monkeys reliably escaped continuous infusions of this phenothiazine. The escape procedure appears useful for analyzing the aversive properties of drugs.     

猴自身给药方法评价盐酸二氢埃托啡的精神依赖性潜力

本实验采用4个实验对盐酸二氢埃托啡(DHE)的精神依赖性潜力进行了较系统的评价 ,并与其他阿片类药物进行了比较。在FR1程序下 ,未接触过药物的恒河猴可学会踏板觅药并维持对DHE的自身给药行为 ,潜伏期较短。在交叉替代实验中 ,DHE与其他阿片类药物有良好的交叉耐受性。在可变比率实验中 ,最高的稳定比率值为VR100。在累进比率实验中 ,断点达到2022 ,而海洛因只有911。结果证明 ,盐酸二氢埃托啡具有很强的精神依赖性潜力 ,其精神依赖性潜力比海洛因强得多 ,且具有成瘾潜伏期较短 ,相邻两次注射间隔短等特点。虽然镇痛作用较强 ,但作为临床用药仍有很大的危险性。     

Discrimination among morphine, saline and naltrexone in rhesus monkeys receiving morphine subchronically

Discriminative control was established among morphine, saline and naltrexone in rhesus monkeys receiving morphine every other day. Three hours prior to sessions subjects received saline or 3.2mg/kg morphine; immediately prior to sessions they received saline or 0.01mg/kg of naltrexone. There were dose-related generalizations to each training condition: morphine generalized to the morphine plus saline lever; small doses of naltrexone reversed effects of morphine and larger doses occasioned responding on the morphine plus naltrexone lever; in one monkey still larger doses occasioned responding on the saline plus saline lever. When saline was administered 3h earlier, naltrexone had no effect in one subject and occasioned responding on the morphine plus naltrexone lever in a second subject. Nalbuphine substituted for morphine plus saline in one monkey and for morphine plus naltrexone in a second monkey; ketamine did not substitute for either training drug. That stimulus control was established between no drug and a combination of morphine and naltrexone suggests the latter condition did not represent the absence of morphine. In addition to demonstrating stimulus control for three conditions in rhesus monkeys, the current study suggests opioid antagonists might have novel discriminative stimulus effects at opioid receptors even under conditions where signs of withdrawal are not evident.     

Morphine-like stimulus effects in the monkey: opioids with antagonist properties

The discriminative stimulus properties of opioids with a wide spectrum of agonist and antagonist properties were evaluated in squirrel monkeys trained to discriminate between morphine and saline in a two-choice discrete-trial avoidance task. Stimulus control was considered to be established when the monkeys reliably completed at least 22 trials of a 25-trial session on the lever appropriate for the drug state. Tests of stimulus generalization were conducted with compounds that were previously shown in the rat to produce discriminative stimulus effects that are: (a) morphine-like (profadol, WY-16,225, pentazocine, butorphanol, nalmexone); (b) cyclazocine-like (cyclazocine, ketocyclazocine, levallorphan); (c) neither morphine-like nor cyclazocine-like (nalbuphine and nalorphine). Profadol and WY-16,225 were equipotent with morphine in producing morphine-like stimulus effects. Naloxone antagonized the morphine-appropriate responding produced by all three compounds, but 10 times more naloxone was needed to block the stimulus effects of WY-16,225 than to block those of either morphine or profadol consistent with the known antagonist properties of WY-16,225. None of the other drugs produced complete morphine-like stimulus control of behavior but, with the exception of nalorphine, the highest dose of each resulted in about half of the trials being completed on the morphine-appropriate choice lever. These results confirm the heterogeneous nature of the discriminative stimulus effects of opioids with mixed agonist and antagonist properties and indicate the importance of interspecies comparisons.     

Behavioral effects of morphine and naloxone following chronic morphine administration

The effects of morphine, naloxone, and combinations of these drugs were examined in squirrel monkeys under shock-postponement schedules. In the absence of a lever press, shocks could be presented every 4s, and each response postponed shock for 20s. Acutely, morphine (0.10–3.00 mg/kg) produced not only overall response-rate decreases, but also increases in the number of shocks, whereas naloxone (0.10–30.00 mg/kg) had little effect on responding. When given in combination with morphine, several doses of naloxone antagonized the rate-reducing and shock-increasing effects of morphine. Daily administration of morphine resulted in a substantial decrease in the number of shocks received and a moderate attenuation of the rate-decreasing effects of morphine (tolerance). Lower doses substituted for the fixed daily dose resulted in a smaller effect on behavior than under acute administration. Naloxone given in combination with the daily morphine dose or substituted for the daily administration of morphine, produced effects similar to those seen prior to chronic drugging. Thus, behavioral effects of naloxone were not altered even though tolerance to morphine was observed. Larger doses of naloxone continued to antagonize the effects of morphine for at least 24h. No signs of physical dependence were noted when naloxone was administered or when administration of morphine ended.     

Spontaneous vs. naloxone-induced abstinence in dependent rats self-administering L-alpha-acetylmethadol (LAAM) or morphine.

Rats maintained dependence by the self-administration of LAAM or morphine. Following the substitution of saline for LAAM, REM sleep was not disrupted, and the frequency of lever pressing for saline self-injections peaked at about 24 hr. In contrast, following the substitution of saline for morphine, REM sleep was suppressed for 24 hr while the frequency of lever pressing for saline self-injections peaked within 8 hr. When abstinence was induced by hourly iv naloxone injections, REM sleep occurrences were suppressed to a similar degree and for similar durations during naloxone-induced abstinence from both morphine and LAAM. These results suggest that the level of physical dependence maintained during self-administration of LAAM and morphine was similar. The relatively mild abstinence syndrome that was seen during saline substitution in LAAM-dependent rats was most likely related to the long plasma half-lives of the pharmacologically active N-demethylated metabolites of LAAM.     

The pharmacology of azidomorphine and azidocodeine

From a series of newly synthesized morphine derivatives 6-deoxy-6-azidodihydroisomorphine (azidomorphine) and 6-deoxy-6-azidodihydroisocodeine (azidocodeine) were selected for detailed pharmacological study. In the hot plate test in rats, azidomorphine proved to be about 300 times and azidocodeine about 13 times more potent than morphine. Azidomorphine given over ten weeks was significantly less toxic in the rat than morphine or fentanyl. A total dose 40 times that of the analgesic ED50 dose of morphine (200 mg kg^?1) produced the highest grade physical dependence in mice as measured by naloxone-precipitated jumping. However, even a total dose of 2800 times the analgesic ED50 dose of azidomorphine (70 mg kg^?1) was less effective in producing physical dependence. Treatment on every second day with increasing doses of morphine led to the development of high grade tolerance and chronic physical dependence in rats and monkeys (Rhesus macacus). Severe abstinence syndrome was precipitated after the administration of nalorphine in rats pretreated for 24 days with rapidly increasing doses of morphine and grave symptoms of abstinence were elicited in pretreated monkeys on withdrawal of morphine on the 55th, 175th and 300th days of treatment. In parallel experiments neither the development of tolerance nor that of physical dependence was demonstrable in rats and monkeys pretreated with increasing equi-analgesic doses of azidomorphine.     

Discriminative stimulus effects of etorphine in rhesus monkeys

Two rhesus monkeys were trained to discriminate the IM injection of etorphine (0.001 mg/kg) from saline in a task in which 20 consecutive responses on one of two levers resulted in food delivery. In both monkeys, etorphine (0.0001–0.0018), meperidine (0.1–1.0 mg/kg), morphine (0.1–3.2 mg/kg), and codeine (0.3–3.2) produced dose-related increases in the percentage of total session responses that occurred on the etorphine-appropriate lever. In contrast, ethylketazocine, SKF-10047, and pentazocine, at doses up to and including those that suppressed response rates, produced responses primarily on the saline-appropriate lever. Thus, etorphine-like narcotics, including morphine, have discriminative stimulus effects in rhesus monkeys which can be distinguished from those produced by narcotics with nonmorphine-like actions such as ethylketazocine, SKF-10047, and pentazocine.     

Comparison of naltrexone, 6α-naltrexol, and 6β-naltrexol in morphine-dependent and in nondependent rhesus monkeys

Rationale Some opioid receptor ligands that appear to be neutral antagonists can have inverse agonist activity under conditions of increased constitutive activity (e.g., agonist treatment). Objectives This study compared the opioid receptor antagonist naltrexone and its metabolites 6α-naltrexol and 6β-naltrexol in nondependent and morphine-dependent monkeys to see whether their potencies varied according to drug treatment and, presumably, to differences in constitutive activity of μ opioid receptors. Results In monkeys (n = 4) receiving 3.2 mg/kg per day of morphine and discriminating 0.0178 mg/kg naltrexone, naltrexone and each metabolite increased responding on the naltrexone lever in a dose-related manner with naltrexone being 8- and 71-fold more potent than 6α- and 6β-naltrexol, respectively. After 27 h of no-morphine treatment, monkeys responded on the naltrexone lever, and this effect was reversed by morphine. Naltrexone and each metabolite prevented morphine reversal of naltrexone-lever responding, and their rank order potency was the same as their substitution for naltrexone; however, the potency between naltrexone and each metabolite was slightly greater in morphine-dependent as compared to morphine-deprived monkeys. In a separate group (n = 3) of nondependent monkeys discriminating 1.78 mg/kg of morphine, all three compounds antagonized morphine with the same potency as in the reversal study (morphine-dependent monkeys), with Schild analyses showing no difference in apparent affinities (pA ₂) between nondependent and morphine-dependent monkeys. Conclusion Naltrexone and 6α- and 6β-naltrexol have qualitatively similar effects, and their potencies do not vary markedly with opioid treatment, suggesting that under these conditions, they do not vary with regard to inverse agonism.     

Factors affecting voluntary morphine intake in self-maintained addicted rats

Summary Self-maintained morphine addicted rats were prepared by implanting chronic venous cannulas and fitting the rats with a device permitting relatively free movement and also enabling them to obtain morphine injections at will by pressing a lever. Three factors modifying voluntary morphine intake were studied. 1. Using a continuous reinforcement schedule, progressively decreasing the size of the morphine dose led to a greater number of doses daily. Compensation was incomplete in that the total daily morphine intake decreased. 2. Progressively increasing a fixed ratio reinforcement schedule up to about FR-75, caused rats to continue responding on the lever until the dose was obtained. Above FR-75 responding became intermittent and daily morphine decreased as the time interval between doses increased. 3. Continuous intravenous infusion of a second drug, leaving voluntary access to morphine at FR-10, led to decreased morphine intake following infusion of morphine itself, codeine and meperidine. Nalorphine infusion increased morphine intake. Effectiveness of infusions varied with the infusion rate.A preliminary account of this work was presented at the 25th Meeting of the Committee on Drug Addiction and Narcotics, Natl. Res. Council, Natl. Acad. Sci., Ann Arbor, Michigan, 15–17 February 1963.