Angiotensin converting enzyme inhibitor captopril modifies conditioned place preference induced by morphine and morphine withdrawal signs in rats.

Angiotensin II and angiotensin converting enzyme (ACE) inhibitors have analgesic, anticonvulsant and antidepressive effects and in some cases they can antagonize morphine. In the present study effects of angiotensin II and ACE inhibitor captopril administered intracerobroventricularily (icv) on conditioned place preference induced by morphine as well as on morphine withdrawal signs has been evaluated in rats. Icv canullas were implanted in anesthetized male rats. Rats were allowed to recover from the surgery and conditioned place preference was induced by morphine, and the time spent in morphine compartment was compared in saline, morphine, captopril and Ang II groups. Morphine withdrawal signs were compared in three other groups of rats: morphine alone, captopril+morphine and Ang II+morphine 4 days after morphine injections (three times in each day) with naloxone injection on 4th day. Results with rats conditioned place preference induced by morphine showed that icv captopril decreased significantly the time in morphine compartment (P<0.01) while Ang II had no effect. In morphine dependent rats captopril decreased some withdrawal signs after naloxone precipitation (P<0.05 and P<0.01). Ang II administration augmented some of withdrawal signs than in the morphine group (P<0.01 and P<0.001). In conclusion captopril reduced conditioned place preference induced by morphine and some withdrawal signs in morphine dependent rats.     

Tramadol induces conditioned place preference in rats: interactions with morphine and buprenorphine

It is well established that under fasting conditions the expression of the orexigenic neuropeptide agouti-related peptide (AGRP) is up-regulated in the hypothalamic arcuate nucleus (ARC), while inconsistent data exist regarding fasting regulation of the anorexigenic neurohormone proopiomelanocortin (POMC). Inconsistencies might have methodological reasons, especially concerning neuromorphological and/or experimental (nutritional) specificity. We analyzed the expression of both neuropeptides in ARC neurons, using lasercapture microdissection (LMD) and real-time PCR in 12h fasted vs. fed Wistar rats as well as after a standardized glucose load, i.e., under clinically relevant conditions in terms of diagnosing glucose intolerance in the human. Under fasting conditions, clear up-regulation of AGRP was observed, with increasing magnitude in ARC single neurons (SNP) as compared to ARC cell layers (+125% vs. +23%, resp.), closely correlated to hypoinsulinemia and hypoleptinemia. Surprisingly, in the fasting state POMC was not found to be down-regulated, neither in ARC cell layers nor in ARC single neurons (+9% vs. +6%). However, glucose-refeeding under diagnostically relevant conditions led to strong neuronal up-regulation of POMC expression in ARC SNP (+128%), and AGRP down-regulation (-50%). In conclusion, experimentally, topographically, and analytically specific and standardized conditions confirmed AGRP in ARC neurons as being neuronally up- and down-regulated, resp., depending on the general nutritional state, while POMC was found to be (up-) regulated only after peripheral glucose load. Findings suggest that POMC in ARC neurons acts glucose-mediated as an "anti-orexigenic" neurohormone, specifically responding to hyperglycemia.     

Tramadol induces conditioned place preference in rats: Interactions with morphine and buprenorphine

Surveys and drug surveillance have demonstrated that the abuse liability of tramadol is considerably low in the general population but appears to be higher in opiate addicts, and this difference could attribute to the poly-drug abuse of opioid addicts, although this hypothesis has not been tested in the laboratory. The present study examined the interactions between tramadol and a full μ opioid receptor agonist morphine or a partial μ opioid receptor agonist buprenorphine in a conditioned place preference (CPP) paradigm in rats. Rats were conditioned with tramadol (2–54 mg/kg, i.p.), morphine (0.125–8 mg/kg, s.c.), buprenorphine (0.01–0.316 mg/kg, s.c.) or a combination of a subeffective dose of tramadol (2 mg/kg) with a subeffective dose of morphine or buprenorphine and the CPP effect was measured. The retention of CPP effect was also examined. Tramadol, morphine and buprenorphine all produced a dose-dependent and significant CPP. A smaller dose of tramadol (2 mg/kg) enhanced morphine- and buprenorphine-induced CPP and shifted the dose-effect curves of both drugs leftward. In addition, the combination of tramadol with morphine or buprenorphine prolonged the retention of CPP. These findings indicate that tramadol potentiates the rewarding effects of morphine or buprenorphine largely in an additive manner and support the general contention that tramadol has relatively low abuse liability.     

Reward value of intromissions and morphine in male rats evaluated by conditioned place preference

The present experiment was designed to determine if intromissions alone could induce a reward state as evaluated by conditioned place preference (CPP). We also compared the rewarding properties of one ejaculation and a morphine injection. We evaluated if intromissions alone could induce CPP in males with one or three ejaculations as previous sexual experience. Different groups of males were allowed to display 5, 10, and 15 intromissions or an ejaculation with a sexually receptive female before being placed in the originally non-preferred compartment of a CPP cage. On alternate days they were placed in the preferred compartment. The groups that displayed 5 or 10 intromissions did not modify their original preference, regardless of whether they had experienced 1 or 3 ejaculations before the conditioning procedure. The groups that had experienced 1 ejaculations that were allowed to display 15 intromissions or one ejaculation modified their original preference indicating the induction of a reward state. These results suggest that male rats displaying sexual behavior require a minimum amount of stimulation, 15 intromissions or an ejaculation, in order for sex to be sufficiently rewarding to induce CPP. In a separate experiment we evaluated if a morphine injection (1 mg/kg) has the same reward value that one ejaculation in male rats has. Two groups of sexually active males were used, in one group ejaculation was paired with the initially non-preferred compartment and morphine administration was paired with the initially preferred compartment. In the other group morphine injection was paired with the non-preferred compartment and ejaculation with the preferred compartment. None of the groups changed their originally preferred compartment suggesting that morphine and one ejaculation have the same reward value in male rats.     

Naloxone attenuates the conditioned place preference induced by wheel running in rats

Pairings, during which an episode of wheel running is followed by confinement in a distinctive place, produce conditioned place preference (CPP) in rats. This finding indicates that wheel running has a rewarding effect that outlasts the activity itself. In two similar experiments, we tested the hypothesis that this rewarding effect of wheel running is mediated by endogenous opioids. During a paired trial, the rats in the naloxone group were first allowed to wheel run for 2 h, then injected with naloxone (0.5 or 0.1 mg/kg in Experiments 1 and 2, respectively), and 10 min later placed in a distinctive chamber. During an unpaired trial, these rats were confined in an adjoining chamber without wheel running. Naloxone was injected before placement in both chambers, so that if naloxone-induced conditioned place aversion occurred, it would have counteracting effects on performance during the preference test. The rats in the saline group were similarly treated, except that saline was injected instead of naloxone. CPP occurred in the saline group, but not in the naloxone group. Thus, naloxone attenuated the CPP induced by wheel running. This finding supports the hypothesis that the rewarding effect of wheel running is mediated by endogenous opioids.     

Anti-craving drugs acamprosate and naloxone do not reduce expression of morphine conditioned place preference in isolated and group-housed rats

Relapse prevention in clean addicts is a great challenge for addiction-therapy. As strong cravings often precede relapse, anti-craving drugs seem to be a promising way for addicts to stay clean. Naloxone and acamprosate are two candidates for anti-craving drugs that are already used for relapse prevention in alcoholic patients. However, it has to be figured out if both drugs are also effective in opiate-addicts. In order to evaluate their effectiveness, a conditioned place preference (CPP) paradigm was used in rats conditioned to 10 mg/kg, i.p., morphine. As acamprosate and naloxone have been suggested to selectively affect different types of craving (withdrawal-craving versus reward-craving), we have tried to modulate craving-behaviour by maintaining two groups of rats under different conditions (isolated versus group-housed). Thereafter, the effectiveness of acamprosate (200 mg/kg, i.p.) and naloxone (2 mg/kg, i.p.) in reducing morphine-CPP expression was evaluated. As a result, isolation produced a weak reduction in morphine-CPP development. Furthermore, acamprosate and naloxone had no effect on morphine-CPP expression. Based on the present results, we assume that the anti-craving drugs acamprosate and naloxone may not be effective for relapse prevention in opiate-addicts.     

褪黑素抑制可卡因诱导的条件性位置偏爱大鼠DNMT1的下调

目的研究褪黑素拮抗大鼠可卡因诱导的条件性位置偏爱的作用和可能机制。方法建立可卡因诱导的条件性位置偏爱模型,诱导前30min给予褪黑素腹腔注射,检测实验大鼠条件性位置偏爱的变化,并应用Western blot、免疫荧光共聚焦激光扫描显微镜及real-time PCR技术,检测褪黑素对大鼠前额叶皮层中可卡因诱导的DMNT1表达的影响。结果褪黑素对可卡因诱导的大鼠条件性位置偏爱效应具有显著的抑制作用。共聚焦显微镜和Western blot结果表明,可卡因诱导大鼠前额叶皮层中DNMT1表达的减少,而褪黑素能够抑制可卡因的这种作用。Real-time PCR检测结果证明,可卡因诱导大鼠前额叶皮层中DNMT1 mRNA的下调,而褪黑素能够抑制这种作用。结论褪黑素可能通过抑制大鼠前额叶皮层中DNMT1表达的下调拮抗可卡因诱导的条件性位置偏爱。     

Different roles of dopamine receptor subtypes in footshock stress-induced enhancement of morphine conditioned place preference

The ability to identify safety and danger is critical to survival. However, not much is known about human somatic body reactions in these contexts. We performed a posturographic study comparing body reactions to the sight of pictures of smiling babies and families (affiliative) versus matched neutral people, and to pictures depicting body envelope violations (mutilation) versus matched neutral people. The participants stood on a force platform and heart rate and displacement of the center of pressure were recorded while the pictures were presented. Pictures of mutilation induced a freezing-like reaction consisting of a medial-lateral (M-L) decrease in the amplitude of sway (immobility) and increase of the mean power frequency (rigidity), associated with bradycardia. Affiliative stimuli also induced an immobility and rigidity behavior but in the anterior-posterior (A-P) axis. This resembles the "immobility-without-fear reaction" proposed to occur when, upon detection of safety cues, mammals including humans are involved in pro-social activities. We conclude that the sight of visual cues of affiliation and danger produce distinct body somatic reactions.     

Different roles of dopamine receptor subtypes in footshock stress-induced enhancement of morphine conditioned place preference

The present study investigated the involvement of dopamine mechanism in the effect of intermittent footshock stress on the morphine-induced place preference. A single intermittent footshock session significantly enhanced the place preference induced by 3.0 mg/kg morphine. This enhancing effect was inhibited by selective D₁ receptor antagonist SCH23390 and selective D₂ receptor antagonist sulpiride pretreatment 20 min before footshock session, suggesting dopamine D₁ and D₂ receptors are required for the development of intermittent footshock stress-induced enhancement of morphine-associated place preference. However, different from D₁ and D₂ receptors this enhancing effect was blocked by stimulation of dopamine D₃ receptor with selective D₃ receptor agonist 7-OH-DPAT pretreatment 20 min before footshock session which suggest dopamine D₃ receptor play a negative mediation effect on the intermittent footshock stress-induced this enhancement. These results indicate that dopamine D₁, D₂, and D₃ receptor subtypes play different roles in footshock stress-induced enhancement of morphine conditioned place preference.     

Nicotine-induced conditioned place preference in adolescent and adult rats

About 1 million American adolescents start smoking every year. Adolescents may be unusually sensitive to certain consequences of nicotine, demonstrating, for instance, significantly higher rates of dependence than adults at the same level of nicotine use. To explore whether adolescents may be more sensitive to rewarding properties of nicotine than adults, the present study used an animal model to assess the rewarding effects of a low nicotine dose (0.6 mg/kg) in a conditioned place preference (CPP) paradigm. Locomotor activity during conditioning and testing was also evaluated. Nicotine was observed to induce place preference conditioning in adolescent Sprague-Dawley rats, whereas the training dose of 0.6 mg/kg failed to produce convincing place preference in their adult counterparts. Age differences were also apparent in terms of nicotine influences on motor activity, with adults being more sensitive to nicotine-suppressant effects and only adolescents showing an emergence of nicotine-stimulatory effects upon repeated exposures. An increased predisposition to stimulatory nicotine effects during adolescence may contribute to age-specific rewarding properties of the drug as revealed using the CPP paradigm in this experiment. Increased sensitivity to stimulatory and rewarding effects during adolescence could potentially contribute to the high rate of nicotine use and dependence among human adolescents.     

脊髓内NMDA受体NR2B在胍丁胺拮抗吗啡耐受中的作用

目的:探讨脊髓N-甲基-D-天门冬氨酸(N-methyl-D-aspartate,NMDA)受体NR2B亚单位在胍丁胺抗吗啡耐受中的作用.方法:给大鼠皮下注射吗啡(10 mg/kg,Bid)建立慢性吗啡耐受大鼠模型.应用热水甩尾法测定甩尾潜伏期观察吗啡的镇痛效果.应用免疫印迹法(Western blot)检测脊髓NR2B蛋白表达.结果:皮下注射吗啡的第9 d,大鼠对吗啡镇痛已产生明显的耐受.此时,吗啡耐受大鼠脊髓NMDA受体NR2B蛋白表达显著增多.胍丁胺(10 mg/kg)不仅拮抗吗啡耐受,而且明显地抑制脊髓NR2B蛋白表达上调.结论:抑制慢性吗啡注射引起脊髓NMDA受体NR2B亚单位增多可能是胍丁胺抗吗啡耐受的作用机制之一.     

Differential involvement of enkephalins in analgesic tolerance, locomotor sensitization, and conditioned place preference induced by morphine

In this study, the authors investigated the role of enkephalins in morphine-induced conditioned place preference, locomotor sensitization, and analgesic tolerance. Both preproenkephalin wild type (ppENK [+/+]) and knockout (ppENK [-/-]) mice showed similar preference for the morphine-paired chamber over the vehicle-paired chamber, indicating morphine induced comparable conditioned place preference in ppENK (+/+) and ppENK (-/-) mice. Sensitization developed to the motor stimulatory action of morphine after its repeated administration, but the magnitude of this response was not altered in ppENK (-/-) mice. However, as shown previously, ppENK (-/-) mice displayed blunted morphine analgesic tolerance. Taken together, the results suggest that enkephalins may be important for the development of analgesic tolerance but not for conditioned place preference or behavioral sensitization induced by morphine.     

Obesity-resistant S5B rats showed greater cocaine conditioned place preference than the obesity-prone OM rats

Background

Dopamine (DA) and the DA D2 receptor (D2R) are involved in the rewarding and conditioned responses to food and drug rewards. Osborne-Mendel (OM) rats are genetically prone and S5B/P rats are genetically resistant to obesity when fed a high-fat diet. We hypothesized that the differential sensitivity of these two rat strains to natural rewards may also be reflected in sensitivity to drugs of abuse. Therefore, we tested whether OM and S5B/P rats showed a differential preference to cocaine using conditioned place preference (CPP). To also evaluate whether there is specific involvement of the D2R in this differential conditioning sensitivity, we then tested whether the D2R agonist bromocriptine (BC) would differentially affect the effects of cocaine in the two strains.

Methods

OM and S5B/P rats were conditioned with cocaine (5 or 10 mg/kg) in one chamber and saline in another for 8 days. Rats were then tested for cocaine preference. The effects of BC (0.5, 1, 5, 10, 20 mg/kg) on cocaine preference were then assessed in subsequent test sessions.

Results

OM rats did not show a significant preference for the cocaine-paired chamber on test day. Only the S5B/P rats showed cocaine CPP. Later treatment with only the highest dose of BC resulted in reduced cocaine CPP in S5B/P rats when treated with 5 mg/kg cocaine and in OM rats treated with 10 mg/kg cocaine.

Conclusion

Our results indicated that obesity-resistant S5B rats showed greater cocaine CPP than the obesity-prone OM rats. These findings do not support a theory of common vulnerability for reinforcer preferences (food and cocaine). However, they show that BC reduced cocaine conditioning effects supporting at least a partial regulatory role of D2R in conditioned responses to drugs.     

大鼠听皮质NMDA受体亚单位NR2B蛋白质的年龄-依赖性表达

目的：研究sD大鼠生后发育过程中,听皮质神经元NMDA受体亚单位NR2B蛋白质的表达规律。方法：采用免疫组织化学反应和蛋白质印迹技术,分别检测生后1、2、3周和成年动物听皮质神经元NMDA受体亚单位NR2B蛋白质的表达。结果：NR2B阳性神经元在生后第1周密度最高,随着生后周龄增长,NR2B阳性神经元密度递减．3周龄后降至成年动物的低表达水平。结论：大鼠生后发育过程巾．听皮质NR2B亚单位蛋白质呈现年龄-依赖性表达,此结果与mRNA水平上的表达趋势一致。     

Baclofen facilitates the extinction of methamphetamine-induced conditioned place preference in rats

The powerful, long-lasting association between the rewarding effects of a drug and contextual cues associated with drug administration can be studied using conditioned place preference (CPP). The GABA(B) receptor agonist baclofen facilitates the extinction of morphine-induced CPP in mice. The current study extended this work by determining if baclofen could enhance the extinction of methamphetamine (Meth) CPP. CPP was established using a six-day conditioning protocol wherein Meth-pairings were alternated with saline-pairings. Rats were subsequently administered baclofen (2 mg/kg i.p. or vehicle) immediately after each daily forced extinction session, which consisted of a saline injection immediately prior to being placed into the previously Meth- or saline-paired chamber. One extinction training cycle, consisted of six once-daily forced extinction sessions, mimicking the alternating procedure established during conditioning, followed by a test for preference (Ext test). CPP persisted for at least four extinction cycles in vehicle-treated rats. In contrast, CPP was inhibited following a single extinction training cycle. These data indicate that Meth-induced CPP was resistant to extinction, but extinction training was rendered effective when the training was combined with baclofen. These findings converge with the prior demonstration of baclofen facilitating the extinction of morphine-induced CPP indicating that GABA(B) receptor actions are independent of the primary (unconditioned) stimulus (i.e., the opiate or the stimulant) and likely reflect mechanisms engaged by extinction learning processes per se. Thus, baclofen administered in conjunction with extinction training may be of value for addiction therapy regardless of the class of drug being abused.     

Valproic acid sodium inhibits the morphine-induced conditioned place preference in the central nervous system of rats

The present study was performed to investigate the effects of valproic acid sodium (VPA), a widely utilized antiepileptic drug, on the establishment of chronic morphine-induced conditioned place preference (CPP). The rat model of morphine-induced CPP was conditioned with alternating intracerebroventricular (i.c.v.) injections of morphine (60 microg/6 microl) and saline for 5 days. To investigate the influence of VPA on morphine-induced CPP, rats received chronic pretreatment of i.c.v. VPA (500 microg/rat) 10 min previous to the daily morphine injection. The results demonstrated that the morphine-induced CPP was significantly attenuated by VPA pretreatment, while the VPA itself could not induce any CPP or conditioned place aversion (CPA) effects. The results of the present study not only confirmed the reliability of establishing morphine-induced CPP model by i.c.v. injection, but also suggest that the antiepileptic drug VPA may be utilized as potential therapeutic medications for drug abuse in the future.     

Ethanol‐induced locomotor activity in adolescent rats and the relationship with ethanol‐induced conditioned place preference and conditioned taste aversion

Adolescent rats exhibit ethanol‐induced locomotor activity (LMA), which is considered an index of ethanol's motivational properties likely to predict ethanol self‐administration, but few studies have reported or correlated ethanol‐induced LMA with conditioned place preference (CPP) by ethanol at this age. The present study assessed age‐related differences in ethanol's motor stimulating effects and analyzed the association between ethanol‐induced LMA and conventional measures of ethanol‐induced reinforcement. Experiment 1 compared ethanol‐induced LMA in adolescent and adult rats. Subsequent experiments analyzed ethanol‐induced CPP and conditioned taste aversion (CTA) in adolescent rats evaluated for ethanol‐induced LMA. Adolescent rats exhibit a robust LMA after high‐dose ethanol. Ethanol‐induced LMA was fairly similar across adolescents and adults. As expected, adolescents were sensitive to ethanol's aversive reinforcement, but they also exhibited CPP. These measures of ethanol reinforcement, however, were not related to ethanol‐induced LMA. Spontaneous LMA in an open field was, however, negatively associated with ethanol‐induced CTA. © 2012 Wiley Periodicals, Inc. Dev Psychobiol 55: 429–442, 2013     

Facilitation of ejaculation induced by 8-OH-DPAT does not produce conditioned place preference in male rats

The serotonin 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) produces a drastic facilitation of ejaculation characterized by a significant reduction in the number of pre-ejaculatory intromissions and a shortening of ejaculation latency. In the present study, the authors evaluated whether this facilitation of ejaculation can induce a reward state assessed by conditioned place preference. Males treated with 0.1 or 1.0 mg/kg of 8-OH-DPAT showed a clear facilitation of ejaculation but did not develop conditioned place preference. These results clearly indicate that the pharmacological facilitation of ejaculation and the reduction of the number of intromissions does not necessarily make sex rewarding.     

Dopamine antagonists do not block conditioned place preference induced by paced mating behavior in female rats

The authors assessed the behavioral effects of dopamine (DA) receptor antagonists, Cis (Z) flupentixol and S(+)-raclopride L-tartrate, on conditioned place preference (CPP) induced by paced mating behavior. Ovariectomized female rats of the Wistar strain were used. The administration of amphetamine (1 mg/kg) induced a clear CPP that was completely blocked by the DA antagonists flupentixol (0.25 mg/kg) or raclopride (0.125 mg/kg). These doses had no effect on motor coordination. Female rats that mated in a pacing chamber developed a clear CPP. Neither flupentixol nor raclopride blocked the reward state induced by paced mating behavior. These results indicate that DA is not involved in the reward state induced by paced mating behavior in female rats.     

A morphine-paired environment alters c-Fos expression in the forebrain of rats displaying conditioned place preference or aversion

The question of whether a common mechanism mediates both aversive and rewarding drug-paired cues is still unclear. In this study, we used a place preference conditioning paradigm to train rats to associate 1 chamber with morphine and the other chamber with saline. On the test day, rats were divided into those displaying conditioned place preferences (CPP) versus conditioned place aversion (CPA). After the test, all rats were killed and c-Fos immunocytochemistry was performed. For the control group, rats were treated with the same procedure except that the injections of morphine or saline had no association with the chambers. Compared with the control group, the CPP and CPA groups showed a significant increase of c-Fos expression in the dorsomedial striatum, central medial nucleus of the thalamus, and the basolateral amygdala. However, we saw no difference between CPP and CPA rats in any brain region examined. These results suggest that a morphine-paired environment can elicit neural activity in brain regions that are involved in emotional learning. Morphine-conditioned place preference and aversion may share a common neural circuitry elicited by a morphine-paired environment.