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1.
Agnieszka Gieryk Barbara Ziolkowska Wojciech Solecki Jakub Kubik Ryszard Przewlocki 《Psychopharmacology》2010,208(2):291-300
Rationale
Vulnerability to drug abuse disorders is determined not only by environmental but also by genetic factors. A body of evidence suggests that endogenous opioid peptide systems may influence rewarding effects of addictive substances, and thus, their individual expression levels may contribute to drug abuse liability.Objectives
The aim of our study was to assess whether basal genotype-dependent brain expression of opioid propeptides genes can influence sensitivity to morphine reward.Methods
Experiments were performed on inbred mouse strains C57BL/6J, DBA/2J, and SWR/J, which differ markedly in responses to morphine administration: DBA/2J and SWR/J show low and C57BL/6J high sensitivity to opioid reward. Proenkephalin (PENK) and prodynorphin (PDYN) gene expression was measured by in situ hybridization in brain regions implicated in addiction. The influence of the κ opioid receptor antagonist nor-binaltorphimine (nor-BNI), which attenuates effects of endogenous PDYN-derived peptides, on rewarding actions of morphine was studied using the conditioned place preference (CPP) paradigm.Results
DBA/2J and SWR/J mice showed higher levels of PDYN and lower levels of PENK messenger RNA in the nucleus accumbens than the C57BL/6J strain. Pretreatment with nor-BNI enhanced morphine-induced CPP in the opioid-insensitive DBA/2J and SWR/J strains.Conclusions
Our results demonstrate that inter-strain differences in PENK and PDYN genes expression in the nucleus accumbens parallel sensitivity of the selected mouse strains to rewarding effects of morphine. They suggest that high expression of PDYN may protect against drug abuse by limiting drug-produced reward, which may be due to dynorphin-mediated modulation of dopamine release in the nucleus accumbens. 相似文献2.
Rationale
Dysregulated reward processing is a hallmark feature of drug addiction; however, scant research has evaluated restructuring reward processing in the context of addiction treatment.Objectives
We examined effects of Mindfulness-Oriented Recovery Enhancement (MORE) on reward responsiveness (RR) and opioid cue-reactivity in a sample of chronic pain patients with opioid use problems. We previously reported that MORE decreased pain, opioid misuse, and craving relative to a social support control group (SG). Here, we examined whether these outcomes were linked to changes in RR in a subset of participants.Methods
Participants were chronic pain patients (71 % women, age 46.6?±?13.9) who received MORE (n?=?20) or SG (n?=?29). RR was measured before and after 8 weeks of treatment via heart rate (HR) and heart rate variability (HRV) responses during a dot probe task that included opioid-related, pain-related, and natural reward stimuli, as well as craving ratings.Results
The MORE group, who reported decreased opioid misuse and opioid craving during treatment, evidenced less subjective opioid cue-reactivity, greater HR decelerations, and greater increases in HRV to all cues after treatment compared to the SG; HR and HRV effects were most pronounced for natural reward cues. Within the MORE group, HR deceleration to natural reward cues was correlated with increased subjective arousal to the cues, whereas HR deceleration to opioid cues was correlated with decreased subjective arousal. Effects of MORE on craving were mediated by enhanced RR.Conclusions
Results suggest that during treatment with MORE, cardiac-autonomic responsiveness to non-drug reward increases, while reactivity to opioid reward decreases. Studies are needed to discern whether changes in RR were a result or a determinant of reductions in opioid misuse and craving. RR may play a role in addiction treatment. 相似文献3.
Lene S. Schmidt Anthony D. Miller Deranda B. Lester Cecilie Bay-Richter Christina Schülein Henriette Frikke-Schmidt Jürgen Wess Charles D. Blaha David P. D. Woldbye Anders Fink-Jensen Gitta Wortwein 《Psychopharmacology》2010,207(4):547-558
Introduction
Muscarinic M5 receptors are the only muscarinic receptor subtype expressed by dopamine-containing neurons of the ventral tegmental area. These cells play an important role for the reinforcing properties of psychostimulants and M5 receptors modulate their activity. Previous studies showed that M5 receptor knockout (M 5 ?/? ) mice are less sensitive to the reinforcing properties of addictive drugs.Materials and methods
Here, we investigate the role of M5 receptors in the effects of amphetamine and cocaine on locomotor activity, locomotor sensitization, and dopamine release using M 5 ?/? mice backcrossed to the C57BL/6NTac strain.Statistical analyses
Sensitization of the locomotor response is considered a model for chronic adaptations to repeated substance exposure, which might be related to drug craving and relapse. The effects of amphetamine on locomotor activity and locomotor sensitization were enhanced in M 5 ?/? mice, while the effects of cocaine were similar in M 5 ?/? and wild-type mice.Results
Consistent with the behavioral results, amphetamine-, but not cocaine, -elicited dopamine release in nucleus accumbens was enhanced in M 5 ?/? mice.Discussion
The different effects of amphetamine and cocaine in M 5 ?/? mice may be due to the divergent pharmacological profile of the two drugs, where amphetamine, but not cocaine, is able to release intracellular stores of dopamine. In conclusion, we show here for the first time that amphetamine-induced hyperactivity and dopamine release as well as amphetamine sensitization are enhanced in mice lacking the M5 receptor. These results support the concept that the M5 receptor modulates effects of addictive drugs. 相似文献4.
Bilbao A Cippitelli A Martín AB Granado N Ortiz O Bezard E Chen JF Navarro M Rodríguez de Fonseca F Moratalla R 《Psychopharmacology》2006,185(2):160-168
Rationale
Caffeine and other methylxanthines induce behavioral activation and anxiety responses in mice via antagonist action at A2A adenosine receptors. When combined with the opioid antagonist naloxone, methylxanthines produce a characteristic quasi-morphine withdrawal syndrome (QMWS) in opiate-naive animals.Objectives
The aim of this study was to establish the role of A2A receptors in the quasi-morphine withdrawal syndrome induced by co-administration of caffeine and naloxone and in the behavioral effects of caffeine.Methods
We have used A2A receptor knockout (A2AR?/?) mice in comparison with their wild-type and heterozygous littermates to measure locomotor activity in the open field and withdrawal symptoms induced by caffeine and naloxone. Naïve wild-type and knockout mice were also examined for enkephalin and dynorphin mRNA expression by in situ hybridization and for μ-opiate receptor by ligand binding autoradiography to check for possible opiate receptor changes induced by A2A receptor inactivation.Results
Caffeine increases locomotion and anxiety in wild-type animals, but it has no psychomotor effects in A2AR?/? mice. Co-administration of caffeine (20 mg/kg) and naloxone (2 mg/kg) resulted in a severe quasi-morphine withdrawal syndrome in wild-type mice that was almost completely abolished in A2AR?/? mice. Heterozygous animals exhibited a 40% reduction in withdrawal symptoms, suggesting that there is no genetic/developmental compensation for the inactivation of one of the A2AR alleles. A2AR?/? and wild-type mice have similar levels of striatal μ-opioid receptors, thus the effect is not due to altered opioid receptor expression.Conclusions
Our results demonstrate that A2A receptors are required for the induction of quasi-morphine withdrawal syndrome by co-administration of caffeine and naloxone and implicate striatal A2A receptors and μ-opiate receptors in tonic inhibition of motor activity in the striatum. 相似文献5.
Saara Nuutinen Kaj Karlstedt Teemu Aitta-aho Esa R. Korpi Pertti Panula 《Psychopharmacology》2010,208(1):75-86
Rationale
Neuronal histamine has a prominent role in sleep–wake control and body homeostasis, but a number of studies suggest that histamine has also a role in higher brain functions including drug reward.Objective
The present experiments characterized the involvement of histamine and its H3 receptor in ethanol-related behaviors in mice.Materials and methods
Male histidine decarboxylase knockout (HDC KO) and control mice were used to study the role of histamine in ethanol-induced stimulation of locomotor activity, impairment of motor coordination, and conditioned place preference (CPP). Male C57BL/6Sca mice were used to study the effects of H3 receptor antagonist in the effects of ethanol on locomotor activity.Results
The HDC KO mice displayed a weaker stimulatory response to acute ethanol than the wild-type (WT) mice. No differences between genotypes were found after ethanol administration on accelerating rotarod. The HDC KO mice showed stronger ethanol-induced CPP than the WT mice. Binding of the GABAA receptor ligand [3H]Ro15-4513 was not markedly changed in HDC KO mouse brain and thus could not explain altered responses in KO mice. Ethanol increased the activity of C57BL/6Sca mice, and H3 receptor antagonist ciproxifan inhibited this stimulation. In CPP paradigm ciproxifan, an H3 receptor inverse agonist potentiated ethanol reward.Conclusions
Histaminergic neurotransmission seems to be necessary for the stimulatory effect of ethanol to occur, whereas lack of histamine leads to changes that enhance the conditioned reward by ethanol. Our findings also suggest a role for histamine H3 receptor in modulation of the ethanol stimulation and reward. 相似文献6.
Xavier De Jaeger Stephanie F. Bishop Tasha Ahmad Danika Lyons Garye Ami Ng Steven R. Laviolette 《Psychopharmacology》2013,225(3):687-695
Rationale
The medial prefrontal cortex (mPFC) is a key neural region involved in opiate-related reward memory processing. AMPA receptor transmission in the mPFC modulates opiate-related reward memory processing, and chronic opiate exposure is associated with alterations in intra-mPFC AMPA receptor function.Objective
The objectives of this study were to examine how pharmacological blockade of AMPA receptor transmission in the prelimbic (PLC) division of the mPFC may modulate opiate reward memory acquisition and whether opiate exposure state may modulate the functional role of intra-PLC AMPA receptor transmission during opiate reward learning.Methods
Using an unbiased conditioned place preference (CPP) procedure in rats, we performed discrete, bilateral intra-PLC microinfusions of the AMPA receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione, prior to behavioral morphine CPP conditioning, using sub-reward threshold conditioning doses of either systemic (0.05 mg/kg; i.p.) or intra-ventral tegmental area (VTA) morphine (250 ng/0.5 μl).Results
We show that, in both opiate-naïve and opiate-dependent states, intra-PLC blockade of AMPA receptor transmission, but not the infralimbic cortex, increases the behavioral reward magnitude of systemic or intra-VTA morphine. This effect is dependent on dopamine (DA)ergic signaling because pre-administration of cis-(Z)-flupenthixol-dihydrochloride (α-flu), a broad-spectrum dopamine receptor antagonist, blocked the morphine-reward potentiating effects of AMPA receptor blockade.Conclusions
These findings suggest a critical role for intra-PLC AMPA receptor transmission in the processing of opiate reward signaling. Furthermore, blockade of AMPA transmission specifically within the PLC is capable of switching opiate reward processing to a DA-dependent reward system, independently of previous opiate exposure history. 相似文献7.
8.
Rationale
Opioid-dependent humans are reported to show accelerated delay discounting of opioid rewards when compared to monetary rewards. It has been suggested that this may reflect a difference in discounting of consumable and non-consumable goods not specific to dependent individuals. Here, we evaluate the discounting of similar morphine and non-morphine oral rewards in dependent and non-dependent ratsMethods
We first tested the analgesic and rewarding effects of our morphine solution. In a second experiment, we assigned rats randomly to either dependent or non-dependent groups that, 30 min after daily testing, received 30 mg/kg subcutaneous dose of morphine, or saline, respectively. Delay discounting of drug-free reward was examined prior to initiation of the dosing regimen. We tested discounting of the morphine reward in half the rats and retested the discounting of the drug-free reward in the other half. All tests were run 22.5 h after the daily maintenance dose.Results
Rats preferred the morphine cocktail to the drug-free solution and consumed enough to induce significant analgesia. The control quinine solution did not produce these effects. Dependent rats discounted morphine rewards more rapidly than before dependence and when compared to discounting drug-free rewards. In non-dependent rats both reward types were discounted similarly.Conclusions
These results show that morphine dependence increases impulsiveness specifically towards a drug reward while morphine experience without dependence does not. 相似文献9.
Ewa Galaj Ivonne Cruz Jordan Schachar Matthew Koziolek Robert Ranaldi 《Psychopharmacology》2013,229(1):125-132
Rationale
Heroin users report reward deficits as well as reward enhancements (to drug stimuli). To better understand the causal relation between chronic heroin and alterations in natural reward processing, we used experimental techniques in animal models.Methods
Separate groups of rats were trained in several food reward paradigms: conditioned place preference (CPP), food-reinforced lever pressing under a progressive ratio schedule of reinforcement, free feeding, and lever pressing with conditioned reinforcement. After training, the rats were subjected to 10 daily heroin (2 mg/kg) or saline vehicle injections and tested at 3, 15, and 30 days post-treatment.Results
Repeated heroin treatment abolished the CPP and significantly reduced break points for food reward at 3, 15, and 30 days post-treatment. Repeated heroin did not affect free feeding. Finally, repeated heroin significantly enhanced responding for a food-based conditioned reinforcer.Conclusions
Repeated heroin decreases the attractiveness of food-associated cues and reduces motivation to work for natural reward. However, it appears to enhance natural conditioned reward processes that involve the acquisition of novel responding. Thus, repeated heroin appears to produce differential effects on natural reward processing depending on the nature of the reward-directed behavior. 相似文献10.
Samuel R. Chamberlain Karin Mogg Brendan P. Bradley Annelize Koch Chris M. Dodds Wenli X. Tao Kay Maltby Bhopinder Sarai Antonella Napolitano Duncan B. Richards Edward T. Bullmore Pradeep J. Nathan 《Psychopharmacology》2012,224(4):501-509
Rationale
Translational research implicates the mu opioid neurochemical system in hedonic processing, but its role in dissociable high-level cognitive functions is not well understood. Binge-eating represents a useful model of ??behavioural addiction?? for exploring this issue.Objective
The aim of this study was to objectively assess the cognitive effects of a mu opioid receptor antagonist in obese individuals with binge-eating symptoms.Methods
Adults with moderate to severe binge-eating and body mass index ??30?kg/m2 received 4?weeks of treatment with a mu opioid receptor antagonist (GSK1521498) 2 or 5?mg per day, or placebo, in a double-blind randomised parallel design. Neuropsychological assessment was undertaken at baseline and endpoint to quantify processing bias for food stimuli (visual dot probe with 500- and 2,000-ms stimulus presentations and food Stroop tasks) and other distinct cognitive functions (N-back working memory, sustained attention, and power of attention tasks).Results
GSK1521498 5?mg/day significantly reduced attentional bias for food cues on the visual dot probe task versus placebo (p?=?0.042), with no effects detected on other cognitive tasks (all p?>?0.10). The effect on attentional bias was limited to the longer stimulus duration condition in the higher dose cohort alone.Conclusions
These findings support a central role for mu opioid receptors in aspects of attentional processing of food cues but militate against the notion of major modulatory influences of mu opioid receptors in working memory and sustained attention. The findings have implications for novel therapeutic directions and suggest that the role of different opioid receptors in cognition merits further research. 相似文献11.
Rationale
Fendiline is a GABAB receptor-positive allosteric modulator and L-type Ca2+ channel blocker that is safe for human use. Based on these pharmacological properties, fendiline may be useful to disrupt associative memories that can drive relapse to drug use in drug-addicted individualsObjective
The current study evaluated the potential of fendiline to inhibit the maintenance and expression of learned associations between methamphetamine (meth) and an environmental context using conditioned place preference (CPP) in rats, to model for the associative learning that occurs during drug abuse by humansMethods
Following meth conditioning (1 mg/kg), fendiline (5 mg/kg) was administered at various post-conditioning times to ascertain if there was a temporal window during which fendiline would be effective.Results
Two once-daily injections of fendiline did not influence the maintenance of CPP regardless of the post-conditioning treatment time while 10 once-daily fendiline treatments inhibited CPP maintenance (p?<?0.05). Fendiline administered immediately prior to the CPP test inhibited expression of meth-induced CPP in rats with a fendiline treatment history of 10 once-daily injections (p?<?0.05) or those that received two injections that corresponded to the last 2 days of the 10-day treatment (p?<?0.05). Fendiline did not produce preference or aversion on its own, nor did it alter motivated motor behavior.Conclusion
Maintenance and expression of meth CPP is mitigated by repeated fendiline treatments when administered during the days that precede CPP testing. Reduction in the significance of meth-associated cues can reduce relapse; therefore, fendiline may be of value for addiction therapy in abstinent, meth-addicted humans. 相似文献12.
Role of GABAA receptors in dorsal raphe nucleus in stress-induced reinstatement of morphine-conditioned place preference in rats 总被引:1,自引:0,他引:1
Rationale
The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Our data indicate that stress inhibits the dorsal raphe nucleus (DRN)-5-HT system via stimulation of GABA synaptic activity by the stress neurohormone corticotropin-releasing factor and, more recently, that morphine history sensitizes DRN-5-HT neurons to GABAergic inhibitory effects of stress.Objectives
We tested the hypothesis that DRN GABAA receptors contribute to stress-induced reinstatement of morphine-conditioned place preference (CPP).Methods
First, we tested if activation of GABAA receptors in the DRN would reinstate morphine CPP. Second, we tested if blockade of GABAA receptors in the DRN would attenuate swim stress-induced reinstatement of morphine CPP. CPP was induced by morphine (5 mg/kg) in a 4-day conditioning phase followed by a conditioning test. Upon acquiring conditioning criteria, subjects underwent 4 days of extinction training followed by an extinction test. Upon acquiring extinction criteria, animals underwent a reinstatement test. For the first experiment, the GABAA receptor agonist muscimol (50 ng) or vehicle was injected into the DRN prior to the reinstatement test. For the second experiment, the GABAA receptor antagonist bicuculline (75 ng) or vehicle was injected into the DRN prior to a forced swim stress, and then, animals were tested for reinstatement of CPP.Results
Intraraphe injection of muscimol reinstated morphine CPP, while intraraphe injection of bicuculline attenuated swim stress-induced reinstatement.Conclusions
These data provide evidence that GABAA receptor-mediated inhibition of the serotonergic DRN contributes to stress-induced reinstatement of morphine CPP. 相似文献13.
Vicky Katsidoni Polyxeni Alexiou Marilena Fotiadou Maria Pelecanou Marina Sagnou George Panagis 《Psychopharmacology》2014,231(23):4467-4478
Rationale
Recent animal studies reported that curcumin, the active constituent of Curcuma longa, has several central actions and may attenuate morphine tolerance.Objectives
In the present study, we utilized the intracranial self-stimulation (ICSS) paradigm to examine the effects of the commercially available curcuminoid mixture and each one of its components, individually, on brain stimulation reward and on the reward-facilitating effect of morphine.Methods
Male Sprague-Dawley rats were implanted with an electrode into the medial forebrain bundle and trained to respond for electrical stimulation using a rate-frequency paradigm. In the first study, rats were injected with graded doses either of the curcuminoid mixture, or curcumin I, or II, or III. In the second study, we examined whether a low dose of the curcuminoid mixture or each individual curcumin analogue composing it could counteract the reward-facilitating effect of morphine.Results
At low doses, both the curcuminoid mixture and curcumin I did not affect brain stimulation reward, whereas, higher doses increased ICSS thresholds. Curcumin II and curcumin III did not affect brain stimulation reward at any doses. Subthreshold doses of the curcuminoid mixture and curcumin I inhibited the reward-facilitating effect of morphine.Conclusion
Both the curcuminoid mixture and curcumin I lack hedonic properties and moderate the reward-facilitating effect of morphine. Our data suggest that curcumin interferes with brain reward mechanisms responsible for the expression of the acute reinforcing properties of opioids and provide evidence that curcumin may be a promising adjuvant for attenuating morphine’s rewarding effects in patients who are under long-term opioid therapy. 相似文献14.
Rationale
Serotonergic (5-hydroxytryptamine, 5-HT) and opioidergic mechanisms are intimately involved in appetite regulation.Objectives
In view of recent evidence of positive anorectic interactions between opioid and various non-opioid substrates, our aim was to assess the behavioural specificity of anorectic responses to the opioid receptor antagonist naltrexone, the 5-HT2C/1B receptor agonist mCPP and their combination.Methods
Behavioural profiling techniques, including the behavioural satiety sequence (BSS), were used to examine acute drug effects in non-deprived male rats tested with palatable mash. Experiment 1 characterised the dose–response profile of mCPP (0.1–3.0 mg/kg), while experiment 2 assessed the effects of combined treatment with a sub-anorectic dose of mCPP (0.1 mg/kg) and one of two low doses of naltrexone (0.1 and 1.0 mg/kg).Results
Experiment 1 confirmed the dose-dependent anorectic efficacy of mCPP, with robust effects on intake and feeding-related measures observed at 3.0 mg/kg. However, that dose was also associated with other behavioural alterations including increased grooming, reductions in locomotion and sniffing, and disruption of the BSS. In experiment 2, naltrexone dose-dependently reduced food intake and time spent feeding, effects accompanied by a behaviourally selective acceleration in the BSS. However, the addition of 0.1 mg/kg mCPP did not significantly alter the behavioural changes observed in response to either dose of naltrexone given alone.Conclusions
In contrast to recently reported positive anorectic interactions involving low-dose combinations of opioid receptor antagonists or mCPP with cannabinoid CB1 receptor antagonists, present results would not appear to provide any support for potentially clinically relevant anorectic interactions between opioid and 5-HT2C/1B receptor mechanisms. 相似文献15.
Rationale
Drug addiction represents a pathological usurpation of neural processes involved in learning and memory. Retrieval of drug-related memories can result in drug craving and relapse. Recently, the insula was identified as part of the neuronal circuit responsible for the processing of drug memory; however, its precise role remains unclear.Objective
To investigate the involvement of insular muscarinic acetylcholine receptors (mAChRs) in the processing of drug memory.Method
The morphine-induced conditioned place preference (CPP) was used to assess drug memory. All rats were first trained with morphine to establish the CPP. Sub-groups of these rats were used for contextual cue-induced CPP reinstatement. Other sub-groups of rats underwent extinction of the CPP, and 5 m/kg morphine was used for priming-induced CPP reinstatement. Microinjection of mAChR antagonists or agonists into the insula was performed prior to the CPP tests in order to evaluate their effect on CPP expression.Results
Insular microinjections of the nonselective mAChR antagonist, scopolamine, and the M1 antagonist, pirenzepine, significantly inhibited CPP expression in both contextual cue- and priming-induced CPP reinstatement; the M1 agonist, MCN-A-343, and the M4 antagonist, tropicamide, enhanced CPP expression. The M4 agonist, LY2033298, inhibited CPP expression. The M2 antagonist, methoctramine, and M3 antagonist, 4-DAMP, had no effect on CPP expression.Conclusion
Our results demonstrate that insular mAChRs play a role in the processing of drug memory. M1 and M4 mAChRs work paradoxically; M1 activation and M4 inhibition attenuate the expression of drug memory, while M1 inhibition and M4 activation augment the expression of drug memory. 相似文献16.
Rationale
Several studies implicate stress as a risk factor for the development and maintenance of drug addictive behaviors and drug relapse. Kappa opioid receptor (KOR) antagonists have been shown to attenuate behavioral responses to stress and stress-induced reinstatement of cocaine and ethanol seeking and preference.Objectives
In the current study, we determined whether the selective KOR antagonist, norbinaltorphimine (nor-BNI), would block stress-induced reinstatement of nicotine preference.Methods
Adult Institute of Cancer Research mice were conditioned with 0.5 mg/kg nicotine, injected subcutaneously (s.c.) for 3 days and tested in the nicotine-conditioned place preference (CPP) model. After 3 days extinction, nor-BNI (10 mg/kg, s.c.) was administered 16 h prior to a priming dose of nicotine (0.1 mg/kg, s.c.), and mice were tested in the CPP model for nicotine-induced reinstatement of CPP. A separate group of mice was subjected to a 2-day modified forced swim test (FST) paradigm to induce stress after 3 days extinction from CPP. Mice were given vehicle or nor-BNI (10 mg/kg, s.c.) 16 h prior to each FST session.Results
Nor-BNI pretreatment significantly attenuated stress-induced reinstatement of nicotine-CPP, but had no effect on nicotine-primed reinstatement.Conclusions
Blockade of KORs by selective antagonists attenuates stress-induced reinstatement of nicotine-CPP. Overall, the kappa opioid system may serve as a therapeutic target for suppressing multiple signaling processes which contribute to maintenance of smoking, smoking relapse, and drug abuse in general. 相似文献17.
Cristiane Ribeiro De Carvalho Fabrício Alano Pamplona Jéssica Silveira Cruz Reinaldo Naoto Takahashi 《Psychopharmacology》2014,231(7):1417-1425
Rationale
Drug addicts constantly relapse to drug seeking after recall of memories linked to the drug experience. It is believed that a successful application of therapies that block memory reconsolidation may end the continuous cycle of drug relapse.Objectives
The purpose of this study is to investigate whether modulation of the endocannabinoid system would impact the reconsolidation of opioid-related hedonic memories in rats previously paired to morphine context.Methods
Male Wistar rats were trained to acquire a morphine-conditioned place preference (CPP). One week later, morphine-CPP memory was reactivated by a brief exposure to a drug-paired context. Immediately after the memory reactivation session, independent groups of morphine-trained rats received a single subcutaneous injection of different doses of cannabinoid CB1 receptor antagonist rimonabant, CB2-selective antagonist AM630, potent CB1/CB2 agonist WIN 55,212-2, inhibitor of enzyme fatty acid amide hydrolase URB597, or vehicle. Morphine-CPP was retested 1 and 2 weeks after reactivation.Results
Blockade of CB1 (but not CB2) cannabinoid receptors impaired CPP reconsolidation of morphine-CPP at both tests 1 and 2 weeks post-reactivation, whereas direct activation of cannabinoid receptors did not produce significant effects on morphine-induced CPP. However, boosting endocannabinoid signaling by inhibition of anandamide metabolism promoted a transient CB1-dependent enhancement of the CPP. 相似文献18.
Purpose
This study investigated the role of an ABC transporter, Mrp3/Abcc3 in intestinal folate absorption.Methods
Plasma concentrations of folic acid and leucovorin, given orally, were determined in wild-type and Mrp3 ?/? mice. Mucosal-to-serosal transport was determined in the everted intestinal sacs. The plasma concentrations of endogenous 5-methyltetrahydrofolic acid, homocysteine and vitamin B12, and mRNA levels of hepatic and intestinal folate metabolizing enzymes were compared between wild-type and Mrp3 ?/? mice.Results
C max and area-under plasma concentration–time curve of folic acid were 3.0- and 2.3-fold lower in Mrp3 ?/? mice compared with wild-type mice, whereas the total body clearance was unchanged. Absorption of leucovorin was significantly delayed in Mrp3 ?/? mice. Mucosal-to-serosal transport of folic acid and leucovorin was significantly decreased in the duodenum of Mrp3 ?/? mice, where their PS serosal was decreased to 6.3 and 22% of that in wild-type mice, respectively. PS serosal of 5-methyltetrahydrofolic acid was moderately decreased in Mrp3 ?/? mice. There was no obvious abnormality in folate homeostasis in Mrp3 ?/? mice.Conclusions
Mrp3 accounts for the serosal efflux of folic acid and leucovorin, while it makes a moderate contribution to the serosal efflux of 5-methyltetrahydrofolic acid in mice. Mrp3 dysfunction does not disrupt folate homeostasis in mouse. 相似文献19.
Cassano T Gaetani S Macheda T Laconca L Romano A Morgese MG Cimmino CS Chiarotti F Bambico FR Gobbi G Cuomo V Piomelli D 《Psychopharmacology》2011,214(2):465-476
Rationale
By enhancing brain anandamide tone, inhibitors of fatty acid amide hydrolase (FAAH) induce anxiolytic-like effects in rodents and enhance brain serotonergic transmission. Mice lacking the faah gene (FAAH?/?) show higher anandamide levels. However, their emotional phenotype is still debated and their brain serotonergic tone remained unexplored.Objectives and methods
In this study, we tested FAAH?/? mice in the social interaction and the open field tests performed under different lighting conditions (dim and bright) since variations of the experimental context were proposed to explain opposite findings. Moreover, by microdialysis performed under dim light, we analyzed their serotonergic transmission in frontal cortex (FC) and ventral hippocampus (vHIPP).Results
In both light conditions, FAAH?/? mice showed reduced emotionality, compared to wt controls, as suggested by the increased rearing and reduced thigmotaxis displayed in the open field and by the longer time spent in social interaction. Basal serotonergic tone was higher in the FC of mutant mice as compared to control mice, while no difference was observed in the vHIPP. K+-induced depolarization produced similar increases of serotonin in both areas of both genotypes. An acute treatment with the CB1 antagonist rimonabant completely abolished the emotional phenotype of FAAH?/? mice and prevented the K+-stimulated release of serotonin in their FC and vHIPP, without producing any effect in wt mice.Conclusions
Our results support the role of FAAH in the regulation of emotional reactivity and suggest that anandamide-mediated hyperactivation of CB1 is responsible for the emotional phenotype of FAAH?/? mice and for their enhanced serotonergic tone. 相似文献20.
Yukio Kato Yoshiyuki Kubo Daisuke Iwata Sayaka Kato Tomohisa Sudo Tomoko Sugiura Takashi Kagaya Tomohiko Wakayama Akiyoshi Hirayama Masahiro Sugimoto Kazushi Sugihara Shuichi Kaneko Tomoyoshi Soga Masahide Asano Masaru Tomita Toshiyuki Matsui Morimasa Wada Akira Tsuji 《Pharmaceutical research》2010,27(5):832-840