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.     

Role of cytokines in drug dependence]

Methamphetamine (MAP) is a drug of abuse that has steadily gained in popularity. Repeated use of MAP can cause drug dependence that may lead to serious psychiatric and neurologic signs and symptoms in users. It has recently become accepted that multidirectional communication exists among the immune, hormonal, and central nervous systems. Thus, it is suggested that these communications play an important role in drug dependence. Here we review the role of cytokines in drug dependence.     

Overview of the progress in drug dependence studies--mainly focussing on psychic dependence]

The technical term 'drug dependence' was officially adopted by WHO's Expert Committee on Addiction in 1964. Until this, to describe a state of dependence, terms such as 'poisoning', 'habit', 'ism', and 'addiction' had been used from time to time. Until the 1950's, investigators were mainly focussed on the phenomena of physical dependence. However, once the concept of psychic dependence had been introduced, behavioral and neuropharmacological studies on the modes of drug action that produce psychic dependence were activated and have progressed in the last two decades, and among the points clarified by these studies are the following: 1. The critical drug properties that produce psychic dependence are those of rewarding subjective and reinforcing effects of drugs but these effects are not the properties that produce physical dependence, although the development of physical dependence on particular drugs such as opiates may substantially enhance craving for the drugs. 2. The mesolimbic and mesocortical dopamine systems in the brain and also the N. Accumbens play a primary or at least a partial role in producing the subjective and reinforcing effects of major dependence-producing drugs such as cocaine, opiates, barbiturates, benzodiazepines, and ethanol. 3. Many drugs such as naltrexone, methadone, and some dopamine antagonists and serotonin reuptake inhibitors or antagonists were found to be effective in the pharmacotherapy of the dependence on opiates, cocaine, or ethanol.     

Gene expression by addictive drugs and drug dependence]

Drug dependence is developed by repeated administration of addictive drugs. This phenomenon resembles to learning and memory, although input stimuli are different. Pur alpha is abundant in the brain and binds to a single stranded DNA with (GGN)n sequence. The DNA-binding activity was enhanced by calmodulin and decreased in the brain treated with chronic morphine. The data suggest that morphine stimulates gene expression by a pathway different from that of cAMP. Arc protein is an "effector protein" and markedly induced by convulsion or methamphetamine. A novel protein, Amida, was isolated as an Arc-binding protein. Amida was transported into the nuclei and induced apoptosis and the inhibition of cell growth. The functions of these protein and the involvement of them in the development of drug dependence were discussed.     

药物筛选的发展与现状

随着人类对自身健康的关注和对生命质量要求的不断提高，对医学和药物的要求也越来越高。我国人口众多，药物需求量大，对新药研究的要求更为强烈。新药研究可分为两个步骤：一是药物作用的发现，二是药物应用的研究。药物作用发现过程的一个重要环节就是药物筛选。国际上...     

Personality dependence in drug dependence

Is drug dependence more likely to establish itself in persons whose personality structure is already characterized by a psychological dependence which can be looked at from two aspects: cognitive field dependence and emotional dependence? Three groups of 21 subjects each, multiple drug users, users of cannabis and non-users, are studied with the expectation that the first group is more psychologically dependent than the second one, the latter being in turn more dependent than the group of non-users. The situation is not so simple. Hard-drug users appear to be more active than users of cannabis, whereas non-users are even more dynamic individuals. However, in such a study the duration of consumption exercises an important influence because, in this regard, different personality profiles of the two drug-using groups come into play, the users of cannabis presenting a more incoherent picture. The multiple drug addict selected from his natural environment seems to acquire, through his prolonged consumption, a greater perceptual independence and emotional maturity owing to the clandestine nature of his habit, and a more acute and articulate general way of functioning in order to avoid mishaps.     

Micturition in naive and morphine-dependent rats.

Voiding responses were recorded in conscious water-loaded rats. Morphine sulphate (5 mg kg-1) elevated the volume threshold for micturition (MV); the group mean MV of 16 rats after morphine was 40% larger than control. Micturition was nevertheless complete since no urine remained in the bladder afterwards. The implantation of 2 or 4 morphine-base pellets (150 or 300 mg morphine) elevated for 12 days the MV in water-loaded rats. On the 3rd to the 10th day following implantation the group mean was approximately twice that of untreated controls. After micturition was over no residual urine was found in the bladder. Within 3 days the rats became tolerant to the antinociceptive action of the morphine-base pellets but little apparent tolerance developed to their action on micturition. On the 1st day after the pellets were removed, the mean MV was reduced. When withdrawal was precipitated by the administration of naloxone the MV was often too small to measure. This component of a withdrawal syndrome could be elicited in the rats throughout the 12 days of morphine pellet implantation. The administration of 20 mg kg-1 morphine sulphate to anaesthetized rats did not decrease the contractions of the urinary bladder to repetitive stimulation of its motor nerves at 1 and 20 Hz.     

Nitroglycerin inhibits the development of morphine tolerance and dependence in rats

The development of tolerance to and physical dependence on opioids remains a significant barrier to their clinical use. N-Methyl-D-aspartate (NMDA) receptor antagonists inhibit tolerance and dependence. However, many NMDA antagonists have undesirable side effects. It has been shown that nitroglycerin (NTG) can antagonize NMDA receptor activity. This study was designed to determine whether NTG could inhibit the development of morphine tolerance and dependence. Rats were anesthetized and implanted with either morphine or placebo pellets, and pumps infusing vehicle or NTG (doses from 0.1 microg/kg/day to 10 mg/kg/day). Tolerance development was assessed by tail-flick latency (TFL). After 6 days, withdrawal was precipitated by subcutaneous injection of 2 mg/kg naloxone. Withdrawal signs were observed for 15 min. Placebo-pelleted rats showed no changes in TFL over the course of the study and no withdrawal signs. Morphine-pelleted rats developed tolerance. The 0.1 mg/kg/day NTG dose significantly attenuated tolerance development, while the other doses had no significant effect. The 0.1 mg/kg/day dose also attenuated some withdrawal signs. Higher or lower doses were not effective, possibly because of competing biochemical effects.     

An assessment of the individual sensitivity of Wistar rats to the development of morphine dependence]

A search was made for behavioral and physiological indicators which could serve predictors of the individual sensitivity of Wistar rats to the development of physical morphine dependence. Animals with high sensitivity to the development of dependence initially demonstrated intensive ambulation and low motor rearing in the "open field" and had low nociception. Stable animals exhibited high ambulation and motor rearing with insignificant grooming activity as compared to other rats. It has been revealed that rats sensitive to the development of dependence demonstrate higher anxiety in the Vogel test as compared to the stable ones. The findings obtained allowed one to derive a number of equations to predict Wistar rats' individual sensitivity to the development of physical morphine dependence.     

Neuropharmacological studies on drug dependence (I). Effects due to the difference in strain, sex and drug administration time on physical dependence development and characteristics of withdrawal signs in CNS-affecting drug dependent rats (author's transl)

We studied the influence of differences in strain, sex and drug administration time on physical dependence of morphine and phenobarbital in rats and also whether or not pole climbing avoidance is useful as an indicator of physical dependence. We then compared the behavioral characteristics seen with morphine-dependence with those of other CNS-affecting drugs. Withdrawal signs involving weight loss in morphine and phenobarbital groups were different in JCL-Wistar, SLC-Wistar, JCL-Sprague Dawley and HOS-Donryu strain rats. Withdrawal signs in males were generally more marked than in females. Withdrawal signs due to the difference of drug administration time were different with the sex and/or kinds of drugs. After administration of morphine-type and barbiturate-type drugs, withdrawal signs of sedation and weight loss, also excitability together with weight loss appeared 24 and 40 hours later, respectively. These signs were generally greatly increased by antagonist-induced withdrawal. Abrupt withdrawal of methamphetamine and cocaine caused no withdrawal signs. Rectal temperature was unchanged on abrupt withdrawal in the case of each drug, though temperatures did decrease with morphine-type drugs, and increased with phenobarbital and chlordiazepoxide groups, on antagonist-induced withdrawal. Inhibition of the avoidance was mild with the abrupt withdrawal of morphine, codeine, phenobarbital chlordiazepoxide and cocaine, but was marked on antagonist-induced withdrawal of morphine and codeine.     

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.