Effects of MPEP on locomotion, sensitization and conditioned reward induced by cocaine or morphine

Exposure to environmental cues is considered a major cause of relapse in detoxified addicts. Recent findings showed an involvement of glutamate in cue-induced relapse and suggest that subtype 5 of metabotropic glutamate receptors (mGluR5) is involved in conditioned drug-reward. The present study applied the conditioned place preference (CPP) paradigm to examine the involvement of mGluR5 in cocaine- and morphine-induced behaviours. Results of previous mice-studies were extended into rats by using the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP). As a result, the evaluated behavioural parameters were dose-relatedly affected by MPEP. Low-dosed MPEP (10 mg/kg, i.p.) did not affect spontaneous locomotion, reduced cocaine-induced hyperlocomotion and produced sensitized locomotion, while showing no effect on sensitized locomotion induced by repeated cocaine or morphine. Low-dosed MPEP did not genuinely block development of cocaine- and morphine-CPP, but rendered CPP expression state-dependent. The medium MPEP-dose (30 mg/kg) was most effective in reducing spontaneous locomotion. The high MPEP-dose (50 mg/kg) was most effective in reducing both body-weight and morphine-CPP expression. Cocaine-CPP expression was not affected by any MPEP-dose. In conclusion, mGluR5 are involved in modulation of spontaneous and cocaine-induced locomotion, in state-dependent learning and in expression of morphine-CPP. Thus, MPEP may be beneficial for relapse prevention in morphine-addicts.     

Relevance of MDMA ("ecstasy")-induced neurotoxicity to long-lasting psychomotor stimulation in mice

Rationale. Although many studies have focused on the mechanisms underlying MDMA-induced neurotoxicity, little is known about the subsequent long-term response to psychostimulants following exposure to a neurotoxic dose of MDMA. Objectives. We investigated the effect of pre-exposure to neurotoxic and non-neurotoxic doses of MDMA on the response of mice to the psychomotor stimulating effects of MDMA and cocaine. Methods. To investigate MDMA-induced neurotoxicity, male Swiss Webster mice were subjected to three regimens of MDMA: i) 40 mg/kg×2, ii) 30 mg/kg×2, and iii) 15 mg/kg×2 for 2 days. On day 5 following the last exposure to MDMA, the levels of dopaminergic and serotonergic markers were determined. For the behavioral experiments, mice received either a single injection of 10 mg/kg MDMA [MDMA(L)] or one of the following doses of MDMA: 30 mg/kg×2 or 15 mg/kg×2 for 2 days [MDMA (H)]. A third group received saline as a control. On day 5 after the last pretreatment injection, the first MDMA (10 mg/kg) challenge was given, and on day 12, cocaine (20 mg/kg) was administered. Subsequently, mice were re-challenged with MDMA on days 35, 50 and 80, after which locomotor activity was monitored by infrared beam-interrupts. On day 83, mice were killed to detect the levels of dopaminergic and serotonergic markers. Results. MDMA-induced mortality and depletion of dopaminergic and serotonergic markers were dose-dependent. MDMA (H) mice endured a sensitized response to MDMA challenge from days 5 through 80, e.g. a persistent 3-fold increase in locomotor activity compared to the response of mice that were not pretreated with a neurotoxic dose of MDMA. The depletion of DAT and 5-HTT binding sites was sustained throughout this time period (64–68% of control). The MDMA (L) mice showed a sensitized response to MDMA only on day 5. Both MDMA (L) and MDMA (H) mice were sensitized to the cocaine challenge. Conclusions. The induction of sensitization to the locomotor stimulating effects of MDMA and cocaine was independent of MDMA-induced neurotoxicity. However, the long-lasting maintenance of the sensitized response to MDMA may be related to the enduring neurotoxicity caused by MDMA. Electronic Publication     

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.     

Morphine and amphetamine sensitization in rats demonstrated under moderate- and high-dose NMDA receptor blockade with MK-801 (dizocilpine)

Rationale: It has been inferred from indirect tests that MK-801, an NMDA receptor antagonist, blocks sensitization to amphetamine and to morphine. These inferences were made from studies where behavioral scores were not recorded after each drug treatment in the sensitization protocol. Objectives: We reinvestigated the role of NMDA receptors in sensitization to amphetamine or morphine more directly by taking locomotor and stereotypy scores after each of several treatments with MK-801 and amphetamine or morphine. Methods: Each male Long Evans rat was administered intraperitoneal injections of MK-801 (0.1 or 0.25 mg/kg) or saline followed 30 minutes later by amphetamine (0.75 mg/kg), morphine (1.25 mg/kg) or saline and placed immediately in a photocell chamber. Locomotion and stereotypy were measured simultaneously by photobeam breaks and direct observation, respectively. This procedure was repeated on days 1, 2, 3, 4, 5, 8, 11 and 27 for rats receiving amphetamine or saline as the second injection and on days 1–10, 13, 16 and 32 for rats receiving morphine or saline as their second injection (with no testing or treatment on intervening days). Results: The animals treated in the amphetamine condition and animals treated in the morphine condition all showed progressively greater locomotion and stereotypy over the first 5 (amphetamine) or 10 (morphine) test days; the sensitized response was seen regardless of whether the animals were pretreated with saline or with MK-801. Thus MK-801 failed to block the development of psychomotor sensitization seen with these treatment regimens. When, following initial sensitization, amphetamine or morphine was given in the absence of MK-801 (days 8 and 13 for amphetamine and morphine rats, respectively), there was no expression of the sensitized response; the sensitized response of animals previously treated in the MK-801 drug state was expressed only when the animal was tested in the MK-801 drug state. The sensitized response was still expressed, in animals tested in the appropriate drug condition, after a 2-week period in which no drugs were given, confirming that the changes underlying this form of sensitization were long-lasting and thus probably a consequence of some form of synaptic plasticity. Conclusions: Our data provide evidence that behavioral sensitization to amphetamine and to morphine can occur despite the presence of NMDA receptor blockade. These and previous findings suggest that the failure of expression of sensitization seen when MK-801 is withdrawn from a given psychomotor stimulant treatment regimen reflects, at least in part, the dependency of sensitization on the various conditions of training rather than dependency on some essential function of NMDA receptor activation. Received: 14 October 1999 / Accepted: 7 March 2000     

Interactions between iboga agents and methamphetamine sensitization: studies of locomotion and stereotypy in rats

Rationale: The phenomenon of sensitization has been theoretically implicated in mediating various aspects of drug addiction. Recent dose-response studies demonstrated that pretreatment with the putative anti-addictive agent, ibogaine (IBO), and a synthetic iboga alkaloid congener, 18-methoxycoronaridine (18-MC), increase the potency of cocaine to elicit behavioral sensitization, an effect proposed to contribute, in part, to their ability to attenuate drug self-administration. Objectives: As abuse of the methylated amphetamine derivative, methamphetamine (METH), is a growing public health concern, the present study determined the interactions between IBO and 18-MC and the expression of METH-induced behavioral sensitization. Methods: The effects of pretreatment with 18-MC (40 mg/kg, IP, 19 h earlier) on the expression of METH-induced locomotion (0, 0.25, 0.5, 1 and 2 mg/kg, IP) and the effects of pretreatment with either IBO or 18-MC on the expression of METH-induced stereotypy (2 and 4 mg/kg, IP) were assessed in rats treated chronically with either METH (4 mg/kg daily for 7 days) or saline. Results: Compared to vehicle-pretreated controls, 18-MC produced an overall enhancement in METH-induced locomotion in rats treated chronically, but not acutely, with METH. In addition, both iboga agents increased the stereotypic response to METH. Conclusions: Iboga agents augment both the locomotor and stereotypic effects of METH in a manner consistent with previous reports for cocaine. Thus, it appears that iboga agents interact in a similar manner with the neural mechanisms mediating motor hyperactivity induced by the chronic administration of stimulant drugs. Received: 17 December 1999 / Accepted: 26 April 2000     

Modulation of morphine sensitization in the rat by contextual stimuli

Rationale: The repeated administration of addictive drugs, such as amphetamine, cocaine, and morphine, produces a progressive enhancement (sensitization) of their psychomotor activating effects. We have previously shown that administration of amphetamine or cocaine in a distinct test environment promotes more robust psychomotor sensitization than if they are given at home. No information is available, however, on whether this environmental manipulation has a similar effect on sensitization to morphine, a drug that enhances dopamine (DA) release in the striatum indirectly by disinhibiting midbrain DA neurons. Objectives: The main goal of present study was to determine whether exposure to a distinct environmental context facilitates morphine sensitization. Methods: As an index of psychomotor activation, we used rotational behavior in rats with a uni- lateral 6-hydroxydopamine lesion of the mesostriatal DA system. There are inconsistencies in the literature regarding the ability of morphine to elicit rotational behavior. Therefore, in experiment 1 we determined the effect of 2.0, 3.0, 4.0, 6.0, and 8.0 mg/kg, IP, of morphine on rotational behavior. In experiment 2, we studied the effect of five consecutive IV infusions of saline or morphine (2.0 mg/kg) in rats treated either in their home cage or in a distinct and relatively novel test environment. After 5 days of withdrawal, all rats received an IV infusion of 2.0 mg/kg morphine (Morphine challenge). The following day all rats received an IV infusion of saline (Saline challenge). Results: Morphine produced a dose-dependent increase in rotational behavior. Environmental novelty enhanced both the acute psychomotor response to morphine and its ability to induce psychomotor sensitization. Furthermore, a conditioned rotational response was seen only in animals treated in the novel environment. Conclusions: Environmental novelty can facilitate the development of sensitization to the psychomotor activating effects of major addictive drugs, such as amphetamine, cocaine, and morphine. Received: 29 November 1999 / Accepted: 14 March 2000     

Locomotor sensitization to quinpirole in rats: effects of drug abstinence and sex

RATIONALE: Behavioral sensitization, induced by the chronic administration of psychomotor stimulants, serves as an experimental model for the development of behavioral pathology. Although many factors are known to influence the sensitization produced by indirect dopamine agonists, such as cocaine and the amphetamines, less is known about factors that influence the behavioral sensitization produced by direct dopamine receptor agonists. OBJECTIVE: As the extent to which behavioral sensitization is expressed following the repeated administration of indirect dopamine agonists can depend upon a period of drug abstinence, the present study determined the effects of drug abstinence on the expression of locomotor sensitization to the D2/D3 receptor agonist, quinpirole (QNP). METHODS: Male and female rats were administered ten, twice weekly, injections of 0.5 mg/kg QNP or saline (SAL), and then received one of five QNP doses (0-1.0 mg/kg; n=7-10/dose) in two dose-response tests for locomotor sensitization, conducted at 3 and 15 days following the cessation of chronic treatment. RESULTS: The sensitized locomotor response of QNP-treated animals was similar on the 2 test days in both male and female subjects. Compared to males, female rats displayed greater locomotor responding to QNP, both during chronic treatment and on the dose-response tests for sensitization. CONCLUSIONS: QNP locomotor sensitization is (a) not influenced by 2 weeks of QNP abstinence and (b) can be influenced by the sex of the animal. It is suggested that direct and indirect dopamine agonists produce locomotor sensitization via distinct mechanisms that differ in sensitivity to the passage of time but are both influenced by sex-specific variables.     

Alterations in BDNF and trkB mRNAs following acute or sensitizing cocaine treatments and withdrawal

In the present study, we used in situ hybridization to examine the influence of acute or repeated cocaine administrations and withdrawal from repeated cocaine treatment on the level of brain-derived neurotrophic factor (BDNF) and its receptor trkB mRNAs in rat brain. Cocaine (10 mg/kg i.p.) injected acutely produced locomotor hyperactivation, while repeated (single injection for 5 days) administrations of cocaine (10 mg/kg) induced a two-fold increases in the locomotor activity in rats in response to a challenge cocaine dose (10 mg/kg) on day 10, as compared to the saline-treated animals (sensitization). Cocaine treatments induced a brain-region-specific decrease in the levels of trkB mRNA. On the other hand, BDNF mRNA in the rat hippocampus was increased only in the group of rats subjected to cocaine withdrawal. Animals under cocaine withdrawal demonstrated a significant increase in the immobility time measured by the use of modified forced swimming test. Therefore, the increases in the levels of BDNF mRNA in the rat hippocampus seem to be correlated with "depressive-like" behavioral effects during withdrawal from repeated cocaine treatment. In the shell (but not in the core) of the nucleus accumbens, the levels of BDNF mRNA were significantly increased following acute and repeated cocaine treatment as well as during cocaine withdrawal, which indicates that the alterations in the neurotrophin level in the brain region important for the expression of cocaine-induced sensitization involve other mechanisms.     

海南省海口市气传花粉调查

目的调查海口市空气中花粉种类分布及其飘散情况,为本地区防治花粉症及城市绿化品种的选择提供有效资料. 方法在海口市秀英区设点,取5.5米、20米两个高度放置花粉采样器,将涂有软凡士林黏附剂的25.4mm×76.2mm×1mm载玻片,分别放在两个采样器内曝光,24小时更换载玻片,曝片用甘油胶染色,20mm×20mm盖玻片覆盖,光镜下观察花粉种类、数量.并记录当日天气情况. 结果全年共曝片713张,其中5.5米高度357张,丢失8张,无破损.20米高度356张,丢失9张,无破损.曝片结果显示:全年均有花粉飘散,曝片见花粉26种,13891粒.2～4月为高峰期,曝片见10970粒,占全年总数的78.97%.1月、8月、12月最少,仅占全年1.65%.木麻黄花粉曝片见到最多,8724粒,占总数62.80%,高峰期在3月,禾本科花粉位居第二,1912粒,占13.76%全年曝片均可见到,9月为高峰期.结论海口市空气中气传花粉飘散种类、数量及季节分布规律的调查结果,可以为本地区花粉症防治及绿化品种的选择提供可靠依据.     

声反射的高频敏化作用

目的　探讨正常人和感音性聋患者声反射敏化作用特点及其作用机制。方法　选用 30名 ( 6 0耳 )正常人和 15耳早期梅尼埃病患者、34耳老年性聋、2 7耳突发性聋患者作为测试对象 ,以单耳双声高频敏化低频方法测试声反射敏化反应。结果　正常人 6 0耳均能引出声反射敏化作用 ,单耳双声敏化法敏化值为 11.4 8± 7.6 9dB ,双耳双声敏化值为 6 .2 7± 6 .32dB ;15耳早期梅尼埃病敏化值为 6 .5 3± 5 .77dB ;34耳老年性聋敏化值为 5 .35± 5 .77dB ;2 7耳突发性聋敏化值为 5 .6 3± 5 .0 8dB。病变组与正常听力组间比较P <0 .0 1,病变组间比较P >0 .0 5。结论　正常人均可引出声反射敏化作用 ,感音性聋敏化值较正常人为小 ,敏化作用机制和耳蜗功能损害相关