GluR2-3Y Inhibits the Acquisition and Reinstatement of Morphine-Induced Conditioned Place Preference in Rats.
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ABSTRACT:
SUBMITTER: Lin XJ
PROVIDER: S-EPMC5563740 | biostudies-other | 2016 Apr
REPOSITORIES: biostudies-other
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Project description:It is well established that glutamate and its receptors, particularly the N-methyl-D-aspartate receptor (NMDAR), play a significant role in addiction and that the inhibition of glutamatergic hyperfunction reduces addictive behaviors in experimental animals. Specifically, NMDAR antagonists such as MK-801, and an inducer of the expression of glutamate transporter subtype-1 (GLT-1) (ceftriaxone) are known to inhibit addictive behavior. The purpose of this study was to determine whether the combined action of a low dose of MK-801 and a low dose of ceftriaxone provides better inhibition of the acquisition, extinction, and reinstatement of morphine-induced conditioned place preference (CPP) than either compound alone.A morphine-paired CPP experiment was used to study the effects of low doses of MK-801, ceftriaxone and a combination of both on reward-related memory (acquisition, extinction, and reinstatement of morphine preference) in rats.A low dose of neither MK-801 (0.05 mg/kg, i.p.) nor ceftriaxone (25 mg/kg, i.p.) alone effectively impaired CPP behaviors. However, when applied in combination, they reduced the acquisition of morphine-induced CPP and completely prevented morphine reinstatement. Their combination also notably impaired the extinction of morphine-induced CPP.The combined action of a low dose of an NMDAR antagonist (MK-801) and GLT-1 activation by ceftriaxone effectively changed different phases of CPP behavior.
| S-EPMC5561921 | biostudies-other
Project description:Gut microbiota has been found to establish a bidirectional relationship with the central nervous system. Variations of the gut microbiota has been implicated in various mental disorders, including opioid use disorders. Morphine exposure has been repeatedly found to disrupt the gut microbiota, but association between the gut microbiota and the sensitivity to morphine reward remains unknown. In this study the conditioned place preference (CPP) paradigm was used for morphine-treated rats and saline-treated rats. After the CPP procedure, the morphine-treated rats were divided equally into the low and high CPP (L- and H-CPP) groups according to the CPP scores. We adopted 16S rRNA sequencing for the fecal bacterial communities at baseline and post-conditioning. By comparing the morphine-treated group with saline-treated group, we found alterations of microbial composition in the morphine-treated group, but no significant differences in alpha diversity. The L-CPP group and H-CPP group differed in microbial composition both before and after morphine treatment. The relative abundance of certain taxa was correlated to the CPP scores, such as Alloprevotella and Romboutsia. This study provides direct evidence that morphine exposure alters the composition of the gut microbiota in rats and that microbial alterations are correlated to the sensitivity to morphine reward. These findings may help develop novel therapeutic and preventive strategies for opioid use disorder.
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Project description:Objective:To explore the optimal time points for deep brain stimulation (DBS) on the treatment of morphine addiction and its possible mechanisms by investigating how high-frequency stimulation (HFS) in bilateral nucleus accumbens (NAc) at different time points influences the addictive behaviors of rats with drug addiction. Methods:The rats were randomly divided into extinction stimulation group (n?=?20) and postextinction stimulation group (n?=?20). Ten rats in the extinction stimulation group were treated using 120?Hz HFS during extinction stage while another 10 rats with pseudostimulation were served as control group. The CPP scores were evaluated at the second day after intervention, with total 9 sections accomplished. The CPP scores were evaluated at the second day of the intervention. In the postextinction stimulation group, 120?Hz HFS was intervened during the postextinction stage in 10 experimental rats and pseudostimulation was performed in 10 control rats. Stimulation was performed for 7 days continuously, and a small dose of morphine was administrated to induce relapse after the postextinction period. Results:During the extinction phase, CPP scores after HFS were significantly higher. During the postextinction phase, relapse CPP scores after HFS were dramatically lower. Conclusion:HFS of bilateral NAc inhibits the extinction of addictive behavior during the extinction phase, and HFS during the postextinction period suppresses relapse of drug seeking behavior.
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Project description:Acupuncture has been used for treating drug addiction since the 1970s, but little is known about the mechanisms by which acupuncture affects drug cue-induced relapse. The transcription factor delta-FosB (ΔFosB) plays a critical role in behavior and pathology after chronic use of cocaine. ΔFosB regulates glutamate receptor signaling and dendritic spine morphology in animal models. This experimental study compared the effects of electroacupuncture (EA) at acupoints LI4 and LI11 with those of another potentially beneficial intervention, gabapentin (GBP), alone or in combination, on reinstatement of cocaine-induced conditioned place preference (CPP) and levels of ΔFosB and glutamate receptor subunit 2 (GluR2) expression in the nucleus accumbens (NAc). EA at LI4 and LI11 significantly prevented cue-induced cocaine CPP reinstatement, whereas needle insertion without electrical stimulation at these acupoints had no such effect. EA also significantly attenuated cocaine-induced increases in ΔFosB and GluR2 expression in the NAc. Unexpectedly, these effects were reversed when GBP was combined with EA. Treatment with EA at LI4 and LI11 prevented cocaine-induced increases in dendritic spine density in the NAc core and shell. Our results suggest that EA at LI4 and LI11 may prevent cocaine relapse by modulating ΔFosB and GluR2 expression, as well as dendritic spine density.
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Project description:Patients suffering from opioid use disorder often relapse during periods of abstinence, which is posited to be caused by negative affective states that drive motivated behaviors. Here, we explored whether conditioning mice with morphine in a conditioned place preference (CPP) training paradigm evoked anxiety-like behavior during morphine abstinence. To do this, mice were conditioned with morphine (10 mg/kg, i.p.) for 5 days. Twenty-four hours following conditioning, anxiety levels were tested by measuring time in the open arms of the elevated plus-maze. The next day, mice were placed in the three-compartment chamber to measure morphine-induced CPP. Our results show that following morphine conditioning, mice spent significantly less time in the open arm of the elevated plus-maze and expressed robust morphine CPP on CPP test day. Furthermore, we found that an acute treatment with (R,S)-ketamine (10 mg/kg, i.p.), a medication demonstrating promise for preventing anxiety-related phenotypes, 30 min before testing on post-conditioning day 1, increased time spent in the open arm of the elevated plus-maze in saline- and morphine-conditioned mice. Additionally, we found that the second injection of ketamine 30 min before CPP tests on post-conditioning day 2 prevented morphine-induced CPP, which lasted for up to 28 days post-conditioning. Furthermore, we found that conditioning mice with 10% (w/v) sucrose using an oral self-administration procedure did not evoke anxiety-like behavior, but elicited robust CPP, which was attenuated by ketamine treatment 30 min before CPP tests. Overall, our results suggest that the ketamine-induced block of morphine CPP may not be attributed solely to alleviating negative affective states, but potentially through impaired memory of morphine-context associations.
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Project description:BackgroundNumerous reports indicate that MDMA users consume other psychoactive drugs, among which cannabis is one of the most common. The aim of the present study was to evaluate, using the conditioned place preference, the effect of the cannabinoid agonist WIN 55,212-2 on the rewarding effects of MDMA in mice.MethodsIn the first experiment adolescent mice were initially conditioned with 1.25, 2.5 or 5 mg/kg of MDMA or 0.1 or 0.5 mg/kg of WIN and subsequently with both drugs. Reinstatement of the extinguished preference by priming doses was performed in the groups that showed CPP. In the second experiment, animals were conditioned with 2.5 or 5 mg/kg of MDMA and, after extinction, reinstatement of the preference was induced by 0.5 or 0.1 mg/kg of WIN.ResultsA low dose of WIN 55212-2 (0.1 mg/kg) increased the rewarding effects of low doses of MDMA (1.25 mg/kg), although a decrease in the preference induced by MDMA (5 and 2.5 mg/kg) was observed when the dose of WIN 55212-2 was raised (0.5 mg/kg). The CB1 antagonist SR 141716 also increased the rewarding effects of the lowest MDMA dose and did not block the effects of WIN. Animals treated with the highest WIN dose plus a non-neurotoxic dose of MDMA exhibited decreases of striatal DA and serotonin in the cortex. On the other hand, WIN 55212-2-induced CPP was reinstated by priming injections of MDMA, although WIN did not reinstate the MDMA-induced CPP.ConclusionsThese results confirm that the cannabinoid system plays a role in the rewarding effects of MDMA and highlights the risks that sporadic drug use can pose in terms of relapse to dependence. Finally, the potential neuroprotective action of cannabinoids is not supported by our data; on the contrary, they are evidence of the potential neurotoxic effect of said drugs when administered with MDMA.
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Project description:Methamphetamine abuse is a major public health crisis. Because accumulating evidence supports the hypothesis that the gut microbiota plays an important role in central nervous system (CNS) function, and research on the roles of the microbiome in CNS disorders holds conceivable promise for developing novel therapeutic avenues for treating CNS disorders, we sought to determine whether administration of methamphetamine leads to alterations in the intestinal microbiota. In this study, the gut microbiota profiles of rats with methamphetamine-induced conditioned place preference (CPP) were analyzed through 16S rRNA gene sequencing. The fecal microbial diversity was slightly higher in the METH CPP group. The propionate-producing genus Phascolarctobacterium was attenuated in the METH CPP group, and the family Ruminococcaceae was elevated in the METH CPP group. Short chain fatty acid analysis revealed that the concentrations of propionate were decreased in the fecal matter of METH-administered rats. These findings provide direct evidence that administration of METH causes gut dysbiosis, enable a better understanding of the function of gut microbiota in the process of drug abuse, and provide a new paradigm for addiction treatment.
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Project description:Relapse to smoking occurs at higher rates in women compared with men, especially when triggered by stress. Studies suggest that sex-specific interactions between nicotine reward and stress contribute to these sex differences. Accordingly, novel treatment options targeting stress pathways, such as guanfacine, an α2-adrenergic receptor agonist, may provide sex-sensitive therapeutic effects. Preclinical studies are critical for elucidating neurobiological mechanisms of stress-induced relapse and potential therapies, but rodent models of nicotine addiction are often hindered by large behavioral variability. In this study, we used nicotine conditioned place preference to investigate stress-induced reinstatement of nicotine preference in male and female mice, and the effects of guanfacine on this behavior. Our results showed that overall, nicotine induced significant place preference acquisition and swim stress-induced reinstatement in both male and female mice, but with different nicotine dose-response patterns. In addition, we explored the variability in nicotine-dependent behaviors with median split analyses and found that initial chamber preference in each sex differentially accounted for variability in stress-induced reinstatement. In groups that showed significant stress-induced reinstatement, pretreatment with guanfacine attenuated this behavior. Finally, we evaluated neuronal activation by Arc immunoreactivity in the infralimbic cortex, prelimbic cortex, anterior insula, basolateral amygdala, lateral central amygdala and nucleus accumbens core and shell. Guanfacine induced sex-dependent changes in Arc immunoreactivity in the infralimbic cortex and anterior insula. This study demonstrates sex-dependent relationships between initial chamber preference and stress-induced reinstatement of nicotine conditioned place preference, and the effects of guanfacine on both behavior and neurobiological mechanisms.
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Project description:The α2a-adrenergic receptor (α2a-AR) agonist guanfacine has been investigated as a potential treatment for substance use disorders. While decreasing stress-induced reinstatement of cocaine seeking in animal models and stress-induced craving in human studies, guanfacine has not been reported to decrease relapse rates. Although guanfacine engages α2a-AR autoreceptors, it also activates excitatory Gi-coupled heteroreceptors in the bed nucleus of the stria terminalis (BNST), a key brain region in driving stress-induced relapse. Thus, BNST α2a-AR heteroreceptor signaling might decrease the beneficial efficacy of guanfacine. We aimed to determine the role of α2a-AR heteroreceptors and BNST Gi-GPCR signaling in stress-induced reinstatement of cocaine conditioned place preference (CPP) and the effects of low dose guanfacine on BNST activity and stress-induced reinstatement. We used a genetic deletion strategy and the cocaine CPP procedure to first define the contributions of α2a-AR heteroreceptors to stress-induced reinstatement. Next, we mimicked BNST Gi-coupled α2a-AR heteroreceptor signaling using a Gi-coupled designer receptor exclusively activated by designer drug (Gi-DREADD) approach. Finally, we evaluated the effects of low-dose guanfacine on BNST cFOS immunoreactivity and stress-induced reinstatement. We show that α2a-AR heteroreceptor deletion disrupts stress-induced reinstatement and that BNST Gi-DREADD activation is sufficient to induce reinstatement. Importantly, we found that low-dose guanfacine does not increase BNST activity, but prevents stress-induced reinstatement. Our findings demonstrate a role for α2a-AR heteroreceptors and BNST Gi-GPCR signaling in stress-induced reinstatement of cocaine CPP and provide insight into the impact of dose on the efficacy of guanfacine as a treatment for stress-induced relapse of cocaine use.
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Project description:BackgroundMicroRNA (miRNA) emerges as important player in drug abuse. Yet, their expression profile in neurological disorder of cocaine abuse has not been well characterized. Here, we explored the changes of miRNA expression in rat hippocampus following repeated cocaine exposure and subsequent abstinence from cocaine treatment.ResultsConditioned place preference (CPP) procedure was used to assess the acquisition and extinction of cocaine-seeking behavior in rats. MiRNA microarray was performed to examine miRNAs levels in rat hippocampus. Quantitative RT-PCR was conducted to further confirm results in microarray study. Finally, bioinformatic predictions were made to suggest potential target genes of cocaine-responsive miRNA in this study. MiRNA array found that 34 miRNA levels were changed in rat hippocampus while acquiring cocaine CPP and 42 miRNAs levels were altered after the cocaine-induced CPP were extinguished, as compared to normal controls. The findings from qRT-PCR study support results from microarray analysis.ConclusionsThe current study demonstrated dynamic changes in miRNA expression in rat hippocampus during the acquisition and extinction of cocaine-induced CPP. Some miRNAs which have been previously reported to be involved in brain disorders and drug abuse, including miR-133b, miR-134, miR-181c, miR-191, miR-22, miR-26b, miR-382, miR-409-3p and miR-504, were found to be changed in their expression following repeated cocaine exposure and subsequent abstinence from cocaine treatment. These findings may extend our understanding of the regulatory network underlying cocaine abuse and may provide new targets for the future treatment of drug abuse.
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