Morphine dependence and preference. (I). Morphine preference in naive and morphine-experienced rats]

The spontnaeous morphine intake ratio (M-SIR) under free access to morphine-admixed food and quinine-admixed food conditions was measured for 3 weeks in naive and morphine-experienced rats. In the case of morphine (0.5 mg/g of food) vs. quinine (0.5 mg/g of food), naive rats gradually increased M-SIR from 17% to 77%. Using a higher level of morphine- and quinine-admixed food (1 mg/g vs. 1 mg/g of food), M-SIR was more rapidly increased than that in the lower group. Thus while on the 10 approximately 60 mg/kg/day dose range, the M-SIR was gradually increased dose dependently in naive rats due mainly to the positive reinforcing properties of morphine. Morphine-experienced rats showed a significant increase in M-SIR for the first 4 days specifically as compared with naive rats. Morphine dependent rats thus obtained morphine in sufficient amounts to maintain dependent states only after the first 2 approximately 3 days. This choice behavior revealed the psychological aspects of morphine dependence in rats and the preference for morphine was also observed after withdrawal for more than 2 weeks as secondary abstinence syndrome.     

Voluntary self-administration of both morphine and cocaine by rats

Voluntary self-administration of cocaine and/or morphine was studied in rats. Male rats were offered water bottles or bottles containing either cocaine or morphine, both cocaine and morphine (combination) or cocaine and morphine as a mixture. Alternating the three drug-containing bottles had no effect on drug choice. When offered alone, rats consumed about 12 +/- 8 mg/kg/day of cocaine or 0.3 +/- 0.3 mg/kg/day of morphine. When both drugs were offered in combination, they consumed a higher amount of cocaine (22 +/- 7), but the same amount of morphine (0.4 +/- 0.3). Availability of cocaine/morphine mixture kept morphine consumption constant (0.3 +/- 0.1), but markedly decreased cocaine intake (0.3 +/- 0.2). Addition of saccharin to the drug solutions only slightly increased consumption of both drugs, whereas saccharin added as a competitor or distracter to the drug solution reduced cocaine but not morphine self-administration. Animals showed wide interindividual variations but surprisingly small intraindividual variations in self-administration of cocaine or morphine under all conditions. No correlation between cocaine and morphine intake was apparent in the combination situation. Forcing animals first with cocaine had no effect on subsequent intake of cocaine or morphine presented in combination. However, forcing animals first with morphine subsequently increased morphine and reduced cocaine intake. In conclusion, morphine intake was the same if offered alone, in combination or as a mixture, whereas cocaine intake increased during a combination but decreased in the mixture situation. Cocaine pre-exposure had no effect on subsequent voluntary morphine or cocaine choice, whereas morphine pre-exposure increased subsequent voluntary morphine but decreased cocaine intake. These results suggest the possibility of two reward centers, one for each drug, the morphine center exerting a dominant influence over the cocaine center.     

Differential effects of morphine on food and water intake in food deprived and freely-feeding rats

In two experiments the effects of a range of doses of morphine (1, 3, 10 and 30 mg/kg) on the food and water consumption of rats were studied. The results of the first experiment showed that in 24 h food-deprived rats, morphine reduced levels of food and water intake. The duration of these actions was dependent upon dose, with only the highest dose (30 mg/kg) producing any effect persisting for longer than 4 h. In contrast a second experiment showed that morphine increased levels of food and water intake in non-deprived animals. The effect on food intake was most apparent when measurements were taken at 2 h and 4 h after drug administration, while water intake remained above control levels for over 6 h. This study shows that the actions of morphine on ingestion of food and water are affected by food deprivation, and the results are consistent with the hypothesised role of endogenous opiates in the mediation of such behaviour.     

Preference for morphine and drug-seeking behavior in morphine dependent rats

We have already reported that morphine pretreated rats prefered morphine-admixed food during choice trials with the two cup method. In the present work, we utilized both the five and two cup methods and observed the preference for morphine in rats forcedly pretreated with the drug and the increasing rate of preference for the drug in rats where the feeding time was limited. In morphine pretreated rats, preference rate for morphine was 61.2 +/- 3.0% with the five cup method and 61.8 +/- 3.3% with the two cup method during the choice trials. In rats that were limitedly treated with morphine, each preference rate for morphine during choice trials rapidly increased in the five cup method, i.e. 5.5 leads to 14.4 leads to 31.7 leads to 43.6 leads to 61.2%, and the preference rate for morphine stabilized at approximately 60 percent. Findings with the two cup method were similar. After the preference for morphine was stabilized at the 60 percent level, morphine was given subcutaneously and it was found that the preference rate was dependent on the dose injected. When the drug-admixed concentration was changed from 1 mg/g food to 0.5 and 2 mg/g food, the preference rate changed in parallel with the concentration. When the number of food cups containing morphine-admixed food was changed from 1/5 to 2/5, 3/5 and 4/5 food cup, the preference rate was not effected. These studies clearly demonstrate drug-seeking behavior in rats. In the process of preference for morphine, morphine treatment enhances spontaneous intake of morphine-admixed food.     

Aspects of abstinence after morphine ingestion

Sprague-Dawley male rats were intoxicated with morphine, using an ingestion method where exposed and control rats received equivalent amounts of calories and nutrients. The degree of physical dependence on morphine was demonstrated by studying and quantifying abstinence symptoms after withdrawal or after administration of opiate antagonists. The aims of the study were (1) to further enlighten the specificity and validity of the intoxication method concerning physical dependence, and (2) to determine whether some of the abstinence signs might be of value to facilitate quantitation of the degree of physical dependence on morphine, with diet and fluid intake being maintained under control. Withdrawn rats showed a decreased fluid diet intake and a body weight loss, the latter partly due to anorexia. Other mild abstinence signs were irritation, tremor and some motor excitation. The body weight loss during the first day of morphine withdrawal was proportional to the accumulated drug dose (between 25 and 300 mg morphine PO/kg b.wt.). However, prolonged morphine treatment on one dose (340 mg/kg b.wt.) did not reinforce the body weight changes caused by morphine withdrawal. The succeeding weight gain some days after morphine withdrawal was not entirely dependent on the amount of fluid diet intake. Methadone was shown to partially block the decrease in diet intake and the weight loss seen during morphine withdrawal. The naloxone-precipitated withdrawal symptoms were motor excitation, cholinergic signs, body weight loss, diarrhoea and decreased diet intake. The weight loss 2 hr after naloxone administration to long-term intoxicated rats was proportional to the naloxone dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Repeated social-defeat stress, cocaine or morphine

RATIONALE: Repeated social stress experiences engender "behavioral sensitization" and may also increase the potential for abuse of psychomotor stimulants, particularly cocaine use during "binges." OBJECTIVE: Experimental protocols were designed to induce behavioral sensitization through exposures to social-defeat stress or injections of cocaine or morphine. The impact of stress, cocaine or morphine sensitization on cocaine self-administration was assessed using several protocols. METHODS: Behavioral sensitization was induced in male Long-Evans rats by four social-defeat stress episodes, each separated by 72 h. Expression was assessed following a challenge of D-amphetamine (1.0 mg/kg) or cocaine (7.5 mg/kg or 10.0 mg/kg), 10-15 days after the last defeat. Sensitization to cocaine (15.0 mg/kg) or morphine (10.0 mg/kg) was induced via daily administrations for 10 days and later assessed by challenges with cocaine or morphine. Subsequently, i.v. self-administration of cocaine was analyzed for (i) rates of acquisition, (ii) sensitivity to various doses, (iii) "breaking points" during a progressive ratio schedule of cocaine reinforcement, and (iv) patterns of intake during a 24-h binge, in sensitized and control rats. RESULTS: Social-defeat stress, cocaine or morphine administrations increased the locomotor response to stimulant challenges. During 24-h cocaine self-administration binges, sensitization to social-defeat stress or to cocaine prolonged responding, resulting in more cocaine intake. In addition, cocaine sensitization increased the rate of acquisition to cocaine self-administration and the breaking point during a progressive ratio schedule. CONCLUSION: The process of sensitization to social-defeat stress or cocaine intensifies cocaine intake during a binge, supporting the hypothesis that sensitization may facilitate the transition to compulsive drug taking.     

Quantifiable dose-dependent withdrawal after morphine discontinuation in a rat model

We evaluated the intensity of the withdrawal symptoms after the discontinuation of the morphine infusion in rats. Opiate addiction was induced by progressively increasing intraperitoneal morphine infusion rates. The control group (Group 1) received normal saline. The initial morphine rates were 1, 4, and 16 mg kg(-1) h for Groups 2, 3, and 4, respectively. Infusion rates were gradually increased by a factor of 1.4, 2, 2.8, and 4 on the second, third, fourth, and fifth days, respectively. The last rate was used for 48 h and then infusions were disconnected. Weight reduction, food consumption, and water intake were used for evaluation of withdrawal. All morphine groups showed a significant reduction of body weight during the 4 postdiscontinuation days and a decline in food and water intake on the first postdiscontinuation day. All changes were dependent on the morphine infusion concentration. No changes were observed in the control group. We suggest that the rat model used in this study may be utilized for quantification of spontaneous withdrawal.     

Multiple opiate receptors and pharmacological response to morphine in rats maintained on diets differing in protein concentration

1. The influence of diets differing in protein concentration on the characteristics of mu, delta, and kappa-opiate receptors and on the analgesic and hyperthermic responses to morphine was examined in rats. Three groups of male Sprague-Dawley rats were maintained for four weeks on isocaloric diet containing either 4, 20 or 50% protein. 2. The animals maintained on 4% protein diet weighed 92 +/- 2% of the initial weight at the end of the fourth week, whereas animals maintained on 20% and 50% protein diet weighed 222 +/- 2% and 221 +/- 2%, respectively. The average food intake per 100 g body weight on day 1 of the study in 4, 20 and 50% protein diet group was 5.0 +/- 2.2 g, 10.4 +/- 1.4 g, and 10.0 +/- 1.2 g, respectively. This difference in food intake was not observed during rest of the period of the study. 3. Water intake was higher for the animals maintained on diet containing 50% protein as compared to the other two groups. 4. The analgesic and the hyperthermic response to morphine varied in direct relation to the concentration of protein in the diet. The concentration of morphine in the brain and plasma of animals maintained on the three diets following challenge dose of morphine did not differ. Similarly the Bmax and Kd values for the binding of [3H]naltrexone, [3H]D-Ser2-Thr6-leucine enkephalin and [3H]ethylketocyclazocine to brain membranes prepared from rats kept on 4, 20 and 50% protein concentration did not differ. 5. It is concluded that the diet differing in protein concentration can alter the responses to morphine, and that such altered effects can not be accounted for by the changes in the distribution of morphine in brain and plasma or to the changes in the characteristics of the mu, delta and kappa opiate receptors in the brain.     

Locomotor activity in morphine-treated rats: Effects of and comparisons between cocaine,procaine, and lidocaine

The effects of cocaine, procaine, and lidocaine on open field and spontaneous (actophotometer) locomotor activities were assessed and compared in rats (1) treated acutely with morphine (single injection), (2) made dependent on morphine (SC pellets), (3) implanted with morphine and withdrawn at the time of peak dependence, and (4) implanted SC with lactose-containing pellets (sham). Cocaine-induced (10 or 30 mg/kg) open field and spontaneous locomotor activities were significantly greater in each of the four groups than those of the corresponding groups administered saline. Procaine (50 or 100 mg/kg) significantly reduced open field locomotor activity in all morphine-treated rats and spontaneous locomotor activity in acute rats. Lidocaine (30 mg/kg) significantly depressed spontaneous locomotor activity in acute rats. Upon comparison of the activities induced by the three local anesthetics, open field locomotor activity of sham-implanted rats was greater following cocaine (10 or 30 mg/kg) than following procaine (50 or 100 mg/kg). Only morphine withdrawn rats manifested greater activity following cocaine (10 mg/kg) than following either procaine (50 mg/kg) or lidocaine (10 mg/kg); activities were equivalent in dependent and acute rats. In contrast, cocaine-induced (30 mg/kg) open field locomotor activity of all morphine-treated rats was greater than either procaine- (100 mg/kg) or lidocaine- (30 mg/kg) induced activities. Spontaneous locomotor activity of all groups except acute morphine was greater following both doses of cocaine than following both doses of either procaine or lidocaine. In acute rats, only cocaine (10 mg/kg) induced greater activity than the other local anesthetics. Thus, stimulation of locomotor activity following cocaine treatment is a pharmacological property unique to cocaine and not shared by either procaine or lidocaine. Further, the data indicate that the methods selected for assessing locomotor activity may not give comparable results.     

A new ingestion method for long-term morphine intoxication in rat

A new method for long-term morphine intoxication in rat was developed. It was designed to deal with the nutritional imbalance and body weight loss that generally occurs using conventional techniques for morphine treatment. The morphine is administered in a nutritionally complete diet. Also pair-feeding is used to deal with intoxicated rats that do not eat the same amount of food as controls. The technique was validated during the study of different intoxication conditions, using different initial doses, dose increments and final doses. An initial dose of 25 mg morphine/kg b.w., raised exponentially up to 340 mg/kg b.w. in 8 days, made the rats dependent, as tested by withdrawal signs, precipitated by excluding morphine from the diet, or by administration of antagonists. A final dose of up to 715 mg morphine/kg b.w. was reached in 13 days without decreased food intake. However, initial doses of 340 or 715 mg/kg led to impaired weight gain and diet consumption. Plasma morphine levels of 3 μg/ml serum were reached on a dose of 340 mg/kg b.w. Also, preference for morphine diet over control diet was evaluated by choice tests. The technique is simple, time-saving and inexpensive, allowing the treatment of numerous animals for long periods under standardized intoxication conditions. No animals get ill or die.     

A study on drug dependence using fast acting drugs]

Physical dependence on narcotics is induced in laboratory animals by intermittent parenteral administration (2 approximately 3 times daily). However, inducing of dependence on pethidine has been unsuccessful using the parenteral method. Recently, it has been reported that physical dependence on pethidine can be induced by continuous infusion methods (5.6). In the present experiment, pethidine was administered to rats (n=5 approximately 6) by ingestion of pethidine-admixed food preparations (0.5 approximately 4.0 mg/g of feed). The results indicated that (a) when rats are allowed free access to two food preparations (0.5 mg/g vs. 1 mg/g of food) for 7 weeks, spontaneous intake ratios of food (1 mg/g of food) gradually increased from 15% to 30% after 3 weeks. (b) Abrupt withdrawal for 48 hr after a 10 day administration period (2 mg/g of food on day 1 approximately 3 and 4 mg/g of food on day 4 approximately 10) resulted in a loss of body weight in the next 24 hr, and the prewithdrawal level of body weight was recovered in 48 hr. (c) The time course of body weight and food intake during the first 24 hr withdrawal period demonstrated the characteristic pattern of abstinence syndrome of pethidine, viz. early onset (12 approximately 13 hr) and rapid recovery (within 48 hr), as compared to morphine withdrawal. (d) Suppression of pethidine abstinence of both a single injection of morphine (10 mg/kg, s.c.) and substitution for morphine-admixed food was also realized. (e) When levallorphan (5 mg/kg, s.c.) was administered to both pethidine and morphine dependence rats, the maximal decrease in body weight was less than that in morphine dependent rats. These data indicate that pethidine possesses about one fifth the dependence liability of morphine and the maximal abstinence syndrome appears within 24 hr after withdrawal. Conclusively, application of a drug-admixed food preparation in drug dependence tests in rats has proven to be a useful method, particularly in the case of pethidine-like drugs which rapidly disappear from the blood.     

A method for computer control of morphine ingestion by rats

In this paper, we describe a method for controlling the administration of liquid diet and morphine to sixteen rats using a computer. Morphine ingestion treatment was performed with 6 feeding occasions per 24 hr, all experimental animals receiving similar drug doses. The amount of drug was individual and based on body weight at each feeding occasion. Control and experimental animals were kept under isocaloric conditions. Corrections of drug doses in order to compensate for changes in body weight were made every 24 hr. Sensors registered the exact time of complete drug and diet consumption and prevented overdistribution. Rats were administered 103 mg/kg b.wt. morphine during 24 hr. In another experiment rats were administered 191 mg/kg b.wt. morphine during 48 hr, and no weight loss or decrease in fluid diet intake was registered during the time of drug administration in either of the experiments. After exclusion of morphine from the fluid diet, the body weight loss was 6.1% and 8.3%, respectively, and the liquid diet intake decreased by 12.4 ml and 13.4 ml, respectively, compared with control animal intake. This demonstrates the induction of physical drug dependence. A major advantage of using computer-aided administration of morphine-admixed, fluid diet is the stepwise, small dose increments provided several times a day, resulting in higher drug dose per unit time when compared with ingestion procedures using one feeding occasion per day. The method enables rats to rapidly ingest large morphine doses under standardized conditions.     

Voluntary consumption of amphetamine, cocaine, ethanol and morphine by rats as influenced by a preceding period of forced drug intake and clozapine.

Forced nicotine intake was previously found to decrease a subsequent free choice selection, whereas clozapine (CL) caused a marked increase in its consumption. Here these findings are extended to ethanol, cocaine, morphine and amphetamine. Forced intake of ethanol, cocaine, morphine and amphetamine had no major effect on a subsequent voluntary intake. CL, a dopamine D4 antagonist, increased the voluntary consumption of amphetamine and morphine with no effects on ethanol or cocaine intake. Only for cocaine was it found that low-consuming rats increased but high-consuming rats decreased their voluntary cocaine intake by CL. Thus, forced drug exposure per se does not lead to subsequent enhancement of voluntary intake; CL exerts differential effects on intake of these drugs, and a specific dopaminergic set point may govern the voluntary intake of cocaine by individual rats.     

Effects of acute and chronic administration of delta 9-tetrahy-drocannabinol or cocaine on ethanol intake in a rat model.

The acute and chronic administration of delta 9-tetrahydrocannabinol (delta 9-THC) or cocaine were studied in rats trained to obtain all of their daily food by lever pressing during four equally-spaced 30-min periods with water and 5% or 7.5% ethanol solutions freely available. With 5% ethanol available, rats consumed almost all of their daily fluid intake as ethanol, while with 7.5% ethanol available, rats consumed water and ethanol solution in approximately equal amounts. Rats consumed more food pellets with 7.5% ethanol available than with 5% ethanol available. Acute administration of delta 9-THC produced a dose-dependent decrease of 5% ethanol intake and food pellets consumed with a small increase in water intake, especially after the higher doses. Acute administration of delta 9-THC also depressed food intake when 7.5% ethanol was available, but decreases in ethanol solution intake were small. Chronic administration of delta 9-THC initially decreased ethanol intake, but tolerance occurred to this effect, so that during chronic delta 9-THC administration ethanol intake not only recovered, but increased above control levels. When the chronic administration of delta 9-THC was discontinued, ethanol intake was increased for 1 (5% ethanol) to 3 (7.5% ethanol) weeks. Animals with initially high, or initially low, but not with initially moderate ethanol intake, accounted for the increased ethanol intake during chronic delta 9-THC administration and withdrawal. Acute cocaine administration, at doses up to 30 mg/kg, had little effect on eating and drinking; however, during chronic cocaine administration, ethanol intake gradually increased, an increase which was sustained during cocaine withdrawal. The increased ethanol drinking was confined to the first 6-h period after cocaine administration. These data suggest that the chronic administration and withdrawal of other drugs can increase ethanol intake in this rat model.     

Eating pattern of morphine dependent rats

To analyze the drug ingestion patterns of rats in the course of dependence development while on the drug-admixed food (DAF) method, an automatic food intake measuring apparatus was developed. Rats were put on morphine-admixed food, and the food ingestion patterns were recorded with the apparatus in the course of dependence development, during drug withdrawal and at the time of challenge with levallorphan. The naive rats ate the regular diet intermittently at night, and the eating time of morphine-treated rats was longer than that of naive rats. The treated rats also exhibited a frequent eating behavior after 4--5 days on the morphine treatment. During morphine withdrawal, the animal gradually ate the regular diet at about 1-hour intervals, even after evolvement of abstinence signs. When the morphine-dependent rats were given levallorphan, they neither ate nor approached to the food for the first 2--3 hours, but after this time, showed abrupt increases in these activities. Thus, the drug intake pattern of rats in the course of morphine dependence development suggests a correlation between the stage of development of physical dependence and the stage when the animals frequently eat the drug-admixed food.     

Effect of methamphetamine on morphine preference

The effect of methamphetamine on preference for morphine was studied in rats by the drug-admixed food (DAF) method. The preference rates for morphine-admixed food gradually increased by the repetition of choice and forced trials and then became stable at the level of 70%. On the other hand, the preference rates for morphine-admixed food combined with methamphetamine did not so increase compared with the case of morphine alone. From the taste aversion test, it was assumed that combination of morphine and methamphetamine did not enhance taste aversion, although methamphetamine suppressed development of preference for morphine. In the case of combination of morphine and cocaine or caffeine, preference rates for these drugs increased like the case of morphine. This result indicated that the suppression of the preference for morphine which was induced by methamphetamine was not produced by the general effect of CNS stimulants. We found that methamphetamine suppressed the development of the preference for morphine. These findings suggest that the suppression resulted from neither taste aversion nor the general effect of CNS stimulants. Furthermore, acute toxicity and other effects were enhanced by the combination of morphine and methamphetamine, and it might participate with the suppression.     

Relapse to morphine self-administration in morphine,methadone, and levo-alpha-acetylmethadol (LAAM) post-addict rats

Adult female Sprague-Dawley rats were prepared with chronic intravenous cannulae and cortical and muscle electrodes for recording electroencephalograms and electromyograms, respectively. They were made physically dependent on morphine by automatic intravenous injections and then trained to lever press in order to self-administer morphine on a fixed ratio (FR-20) schedule of reinforcement. Upon stabilization of daily morphine self-administration, these rats were divided into three groups of eight rats each. One group continued to self-administer morphine for an additional three weeks. In the second and third groups methadone and levo-alpha-acetylmethadol (LAAM) were substituted for morphine. The dependence state was terminated by removal of the rats from the experimental cages and placement in their home cages where they underwent spontaneous withdrawal. Each rat was then returned to its experimental cage three to four weeks later and given the opportunity to lever press and to relapse to self-administration of morphine or saline with the same FR-20 schedule of reinforcement. It was found that by day six of relapse to morphine all three groups of post-addict rats had reestablished dependence; the rats had reached mean daily morphine intakes and acquired mean daily REM sleep times that were comparable to the mean values observed during the initial period of morphine dependence. In contrast, when post-addict rats were offered saline for self-administration, extinction patterns emerged; that is, high leverpressing activity and high numbers of saline self-injections were seen during the first day of relapse. Thereafter, saline self-injections continued to decline in number, and after two weeks of relapse only one or two saline self-injections were taken per day; these rats had normal daily REM sleep times during every day of relapse. These results demonstrate that even though, in earlier studies, LAAM-dependent rats had been found to experience milder withdrawal than morphine- and methadone-dependent rats, LAAM post-addict rats in the present study exhibited an analogous tendency to relapse to morphine self-administration as morphine and methadone post-addict rats.     

Physical dependence on morphine, phenobarbital and diazepam in rats by drug-admixed food ingestion.

To produce physical dependence on morphine, phenobarbital and diazepam in rats, these drugs were mixed with powder form of rat food in concentrations of 0.5 mg/g, 1 mg/g and 2 mg/g of food. One group of rats (the lower dose group) was continuously exposed for 1 week to two morphine-admixed foods with morphine to food ratios of 0.5 mg/g and 1 mg/g in a cage. The other group (the higher dose group) could choose between two morphine-admixed foods with morphine to food ratios of 1 mg/g and 2 mg/g. After 1 week, morphine-admixed foods were replaced with morphine free food for 2 days. Both groups of rats showed greatly reduced body weight and food intake after the first 24-48 hr withdrawal. The body weight decrease was greater for rats in the higher dose group. Control groups of morphine dependent rats were kept on the morphine added food diets and showed the same body weight increase as well as normal control rats during the course of these experiments. Physical dependence on phenobarbital and diazepam was produced using the same dosage schedules as with morphine. Both the lower and higher dose groups showed significant decrease in body weight due to withdrawal after 1 week of drug-food exposure. Levallorphan (0.5, 1, 3 and 5 mg/kg, s.c.) administered to morphine dependent rats had dose-dependent effects on the intensity of abstinence symptoms (e.g., diarrhea, piloerection and wet shakes phenomena), maximal decrease in body weight and duration of decreased body weight. Cross-physical dependence between phenobarbital and diazepam was demonstrated by this method.     

Dependence on and preference for morphine (II). Comparison among morphine, phenobarbital and diazepam]

Results of a previous experiment indicated that naive rats given a choice between morphine-admixed food (0.5 similar to 1mg/g of food) and quinine-admixed food (0.5 similar to 1 mg/g of food) for 3 weeks gradually and spontaneously preferred the morphine-admixed food, and this choice behavior revealed one of the psychological aspects of morphine dependent rats. In the present work, the ability of preference formation was detected for morphine, phenobarbital and diazepam by a defferent chioce test using drug dependent rats. Rats were pretreated with morpnine, phenobarbital, and/or diazepam by drug admixed food ingestion method for 12 similar to 15 weeks, and the choice test was practiced for one week at 3 intervals (4 similar to 5 trials). Control groups of rats were given the same choice testas the naive rats. Results indicated that (a) of all the drugs employed, morphine showed the most rapid and intensive preference formation (b) Phenobarbital and diazepam had almost the same degree of preference formation. (c) Phenobarbital showed no dose-dependent intensity of preference formation in the 50-90 mg/kg/day dose range, however, a more rapid development of preference was observed dose-dependently among the 80-120 mg/kg/day dose range of diazepam. Thus these studies utilizing a choice test provide a clear demonstration of drug-seeking behavior in rats. In addition, the present method is useful for drug screening tests involving weak psychological dependence liability, and moreover, the data could be analyzed statistically.     

吗啡处理大鼠的戒断症状以及血浆吗啡及其代谢物M3G含量的性别差异

本文旨在评价阿片依赖行为是否存在性别差异。纳洛酮催促戒断研究：20只大鼠,单次注射吗啡后1小时注射纳洛酮。评价大鼠戒断症状,同时应用HPLC-UV方法测定血浆中吗啡和M3G浓度。自然戒断研究：97只大鼠,吗啡组以剂量递增法给药28天,于最后一次给药后,评价大鼠自然戒断症状和血浆中吗啡以及M3G的含量。急性给药催促戒断的戒断症状未观察到性别差异。自然戒断后身体戒断症状存在性别差异,雄鼠重于雌鼠（P〈0.05）。在急性给药实验和慢性给药实验中,吗啡的Cmax雄鼠比雌鼠含量高,M3G的Cmax雌鼠比雄鼠含量高。吗啡药代动力学特征在急性给药实验和慢性给药实验中存在性别差异。成瘾大鼠自然戒断后身体戒断症状的程度和血浆中吗啡、M3G浓度以及M3G/MOR的比值相关。