Profiling the Effects of Repetitive Morphine Administration on Motor Behavior in Rats
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ABSTRACT:
SUBMITTER: Paul A
PROVIDER: S-EPMC8308092 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:RATIONALE: Disturbances in impulse control are key features of substance abuse disorders, and conversely, many drugs of abuse are known to elicit impulsive behavior both clinically and preclinically. To date, little is known with respect to the involvement of the opioid system in impulsive behavior, although recent findings have demonstrated its involvement in delay discounting processes. The aim of the present study was to further investigate the role of the opioid system in varieties of impulsivity. MATERIALS AND METHODS: To this end, groups of rats were trained in the five-choice serial reaction time task (5-CSRTT) and stop-signal task (SST), operant paradigms that provide measures of inhibitory control and response inhibition, respectively. In addition, another group of rats was trained in the delayed reward paradigm, which measures the sensitivity towards delay of gratification and as such assesses impulsive choice. RESULTS AND DISCUSSION: Results demonstrated that morphine, a selective micro-opioid receptor agonist, primarily impaired inhibitory control in the 5-CSRTT by increasing premature responding. In addition, in keeping with previous data, morphine decreased the preference for the large over small reward in the delayed reward paradigm. The effects of morphine on measures of impulsivity in both the 5-CSRTT and delayed reward paradigm were blocked by naloxone, a micro-opioid receptor antagonist. Naloxone by itself did not alter impulsive behavior, suggesting limited involvement of an endogenous opioid tone in impulsivity. Response inhibition measured in the SST was neither altered by morphine nor naloxone, although some baseline-dependent effects of morphine on response inhibition were observed. CONCLUSION: In conclusion, the present data demonstrate that acute challenges with morphine modulate distinct forms of impulsive behavior, thereby suggesting a role for the opioid system in impulsivity.
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Project description:Repetitive transcranial magnetic stimulation (rTMS) is a popular noninvasive technique for modulating motor cortical plasticity and has therapeutic potential for the treatment of Parkinson's disease (PD). However, the therapeutic benefits and related mechanisms of rTMS in PD are still uncertain. Accordingly, preclinical animal research is helpful for enabling translational research to explore an effective therapeutic strategy and for better understanding the underlying mechanisms. Therefore, the current study was designed to identify the therapeutic effects of rTMS on hemiparkinsonian rats. A hemiparkinsonian rat model, induced by unilateral injection of 6-hydroxydopamine (6-OHDA), was applied to evaluate the therapeutic potential of rTMS in motor functions and neuroprotective effect of dopaminergic neurons. Following early and long-term rTMS intervention with an intermittent theta burst stimulation (iTBS) paradigm (starting 24 h post-6-OHDA lesion, 1 session/day, 7 days/week, for a total of 4 weeks) in awake hemiparkinsonian rats, the effects of rTMS on the performance in detailed functional behavioral tests, including video-based gait analysis, the bar test for akinesia, apomorphine-induced rotational analysis, and tests of the degeneration level of dopaminergic neurons, were identified. We found that four weeks of rTMS intervention significantly reduced the aggravation of PD-related symptoms post-6-OHDA lesion. Immunohistochemically, the results showed that tyrosine hydroxylase- (TH-) positive neurons in the substantia nigra pars compacta (SNpc) and fibers in the striatum were significantly preserved in the rTMS treatment group. These findings suggest that early and long-term rTMS with the iTBS paradigm exerts neuroprotective effects and mitigates motor impairments in a hemiparkinsonian rat model. These results further highlight the potential therapeutic effects of rTMS and confirm that long-term rTMS treatment might have clinical relevance and usefulness as an additional treatment approach in individuals with PD.
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Project description:Self-administration of addictive drugs is a widely used tool for studying behavioral, neurobiological, and genetic factors in addiction. However, how locomotor activity is affected during self-administration of addictive drugs has not been extensively studied. In our present study, we tested the locomotor activity levels during acquisition, extinction and reinstatement of morphine self-administration in rats. We found that compared with saline self-administration (SA), rats that trained with morphine SA had higher locomotor activity. Rats that successfully acquired SA also showed higher locomotor activity than rats that failed in acquiring SA. Moreover, locomotor activity was correlated with the number of drug infusions but not with the number of inactive pokes. We also tested the locomotor activity in the extinction and the morphine-primed reinstatement session. Interestingly, we found that in the first extinction session, although the number of active pokes did not change, the locomotor activity was significantly lower than in the last acquisition session, and this decrease can be maintained for at least six days. Finally, morphine priming enhanced the locomotor activity during the reinstatement test, regardless of if the active pokes were significantly increased or not. Our results clearly suggest that locomotor activity, which may reflect the pharmacological effects of morphine, is different from drug seeking behavior and is a distinctive index in drug self-administration.
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Project description:The present studies sought to determine whether prenatal cocaine administration (15 mg/kg b.i.d. between gestational ages 1-20) had enduring effects on emotional behavior of rats. Rats prenatally treated with cocaine interacted less with other rats in the social interaction test of anxiety at both 30 and 120 days of age. However, there were no differences in the elevated plus maze test of anxiety. Rats prenatally treated with cocaine were significantly more immobile in the forced-swim test at 60 and 120 days of age. In addition, animals exposed to prenatal cocaine were more sensitive to the enhancing effect of phencyclidine (2.0 mg/kg) on startle responses to an acoustic stimulus. The cocaine-treated animals tested at 50 to 60 days of age showed higher levels of prepulse inhibition, in comparison to the saline group, after vehicle pretreatment, but not after phencyclidine. Although there were gender differences in the expression of some of these behavioral tasks, there were no gender differences in the effects of cocaine. These findings indicate that when emotional behavior is altered by prenatal cocaine administration, the effects are enduring.
| S-EPMC3121143 | biostudies-other
Project description:Neuroadaptations in the ventral striatum (VS) and ventral midbrain (VMB) following chronic opioid administration are thought to contribute to the pathogenesis and persistence of opiate addiction. In order to identify candidate genes involved in these neuroadaptations, we utilized a behavior-genetics strategy designed to associate contingent intravenous drug self-administration with specific patterns of gene expression in inbred mice differentially predisposed to the rewarding effects of morphine. In a Yoked-control paradigm, C57BL/6J mice showed clear morphine-reinforced behavior, whereas DBA/2J mice did not. Moreover, the Yoked-control paradigm revealed the powerful consequences of self-administration versus passive administration at the level of gene expression. Morphine self-administration in the C57BL/6J mice uniquely up- or down-regulated 237 genes in the VS and 131 genes in the VMB. Interestingly, only a handful of the C57BL/6J self-administration genes (<3%) exhibited a similar expression pattern in the DBA/2J mice. Hence, specific sets of genes could be confidently assigned to regional effects of morphine in a contingent- and genotype-dependent manner. Bioinformatics analysis revealed that neuroplasticity, axonal guidance and micro-RNAs (miRNAs) were among the key themes associated with drug self-administration. Noteworthy were the primary miRNA genes H19 and micro-RNA containing gene (Mirg), processed, respectively, to mature miRNAs miR-675 and miR-154, because they are prime candidates to mediate network-like changes in responses to chronic drug administration. These miRNAs have postulated roles in dopaminergic neuron differentiation and mu-opioid receptor regulation. The strategic approach designed to focus on reinforcement-associated genes provides new insight into the role of neuroplasticity pathways and miRNAs in drug addiction.
| S-EPMC3477247 | biostudies-literature
Project description:IntroductionDuring voluntary muscle contraction, the amplitude of the somatosensory evoked potential (SEP) is reduced by inhibiting sensory information from a peripheral nerve supplying the contracted muscle. This phenomenon is called "gating." We reported that participants with good motor skills indicated strong suppression of somatosensory information. The present study investigated the effects of motor performance improvement following repetitive practice on the SEP amplitude.MethodsThe ball rotation task (BR task) was practiced by 15 healthy participants repetitively. SEPs were recorded before (pre) and after (post) repetitive practice.ResultsThe BR task performance was significantly improved and the required muscle activation to perform the task was significantly reduced after the repetitive practice. The degree of gating was not significant between pre and post- for the SEP amplitude. A significant correlation was found between changes in SEP amplitude from pre to post and performance improvement.DiscussionAfter repetitive practice, the degree of gating did not change, but the performance of the BR task improved, and the muscle activity required for the BR task decreased. These results suggest that repetitive practice does not change the degree of gating but changes the mechanism of gating. Furthermore, they indicate that suppression of the somatosensory area may play a role in improving task performance.
| S-EPMC10090363 | biostudies-literature
Project description:Repetitive behaviors are diagnostic for autism spectrum disorder (ASD) and commonly observed in other neurodevelopmental disorders. Currently, there are no effective pharmacological treatments for repetitive behavior in these clinical conditions. This is due to the lack of information about the specific neural circuitry that mediates the development and expression of repetitive behavior. Our previous work in mouse models has linked repetitive behavior to decreased activation of the subthalamic nucleus, a brain region in the indirect and hyperdirect pathways in the basal ganglia circuitry. The present experiments were designed to further test our hypothesis that pharmacological activation of the indirect pathway would reduce repetitive behavior. We used a combination of adenosine A1 and A2A receptor agonists that have been shown to alter the firing frequency of dorsal striatal neurons within the indirect pathway of the basal ganglia. This drug combination markedly and selectively reduced repetitive behavior in both male and female C58 mice over a six-hour period, an effect that required both A1 and A2A agonists as neither alone reduced repetitive behavior. The adenosine A1 and A2A receptor agonist combination also significantly increased the number of Fos transcripts and Fos positive cells in dorsal striatum. Fos induction was found in both direct and indirect pathway neurons suggesting that the drug combination restored the balance of activation across these complementary basal ganglia pathways. The adenosine A1 and A2A receptor agonist combination also maintained its effectiveness in reducing repetitive behavior over a 7-day period. These findings point to novel potential therapeutic targets for development of drug therapies for repetitive behavior in clinical disorders.
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Project description:Environmental factors profoundly affect the addictive potential of drugs of abuse and may also modulate the neuro-anatomical/neuro-chemical impacts of uncontrolled drug use and relapse propensity. This study examined the impact of environmental enrichment on heroin self-administration, addiction-related behaviors, and molecular processes proposed to underlie these behaviors. Male Sprague-Dawley rats in standard and enriched housing conditions intravenously self-administered similar amounts of heroin over 14 days. However, environmental enrichment attenuated progressive ratio, extinction, and reinstatement session responding after 14 days of enforced abstinence. Molecular mechanisms, namely DNA methylation and gene expression, are proposed to underlie abstinence-persistent behaviors. A global reduction in methylation is reported to coincide with addiction, but no differences in total genomic methylation or repeat element methylation were observed in CpG or non-CpG (CH) contexts across the mesolimbic circuitry as assessed by multiple methods including whole genome bisulfite sequencing. Immediate early gene expression associated with drug seeking, taking, and abstinence also were examined. EGR1 and EGR2 were suppressed in mesolimbic regions with heroin-taking and environmental enrichment. Site-specific methylation analysis of EGR1 and EGR2 promoter regions using bisulfite amplicon sequencing (BSAS) revealed hypo-methylation in the EGR2 promoter region and EGR1 intragenic CpG sites with heroin-taking and environmental enrichment that was associated with decreased mRNA expression. Taken together, these findings illuminate the impact of drug taking and environment on the epigenome in a locus and gene-specific manner and highlight the need for positive, alternative rewards in the treatment and prevention of drug addiction.
| S-EPMC6067959 | biostudies-literature
Project description:Individual differences indicate stronger phenotypes than model animals especially in behavioral studies, and some animals show unexpected behaviors in control and animal model groups. High-throughput analysis including cDNA microarray analysis are more affected by individual differences, because more samples are needed to reduce the difference in multiple factor analysis than single factor analysis such as real-time PCR. We measured the depressive-like behavior of over 100 normal rats in the forced swimming test and selected the rats for control and depression group from them to minimize the individual difference using data of force swimming test. Here, we provided the detail of methods and quality control parameters for the cDNA microarray data. This dataset can reflect the increase of depressive-like behavior. The dataset is deposited in the gene expression omnibus (GEO), series GSE63377.
| S-EPMC4583661 | biostudies-literature
Project description:Background:Opiate addiction is a major health problem in many countries. A crucial component of the medical treatment is the management of highly aversive opiate withdrawal signs, which may otherwise lead to resumption of drug taking. In a medication-assisted treatment (MAT), methadone and buprenorphine have been implemented as substitution drugs. Despite MAT effectiveness, there are still limitations and side effects of using methadone and buprenorphine. Thus, other alternative therapies with less side effects, overdosing, and co-morbidities are desired. One of the potential pharmacotherapies may involve kratom's major indole alkaloid, mitragynine, since kratom (Mitragyna speciosa Korth.) preparations have been reported to alleviate opiate withdrawal signs in self-treatment in Malaysian opiate addicts. Methods:Based on the morphine withdrawal model, rats were morphine treated with increasing doses from 10 to 50 mg/kg twice daily over a period of 6 days. The treatment was discontinued on day 7 in order to induce a spontaneous morphine abstinence. The withdrawal signs were measured daily after 24 h of the last morphine administration over a period of 28 abstinence days. In rats that developed withdrawal signs, a drug replacement treatment was given using mitragynine, methadone, or buprenorphine and the global withdrawal score was evaluated. Results:The morphine withdrawal model induced profound withdrawal signs for 16 days. Mitragynine (5-30 mg/kg; i.p.) was able to attenuate acute withdrawal signs in morphine dependent rats. On the other hand, smaller doses of methadone (0.5-2 mg/kg; i.p.) and buprenorphine (0.4-1.6 mg/kg; i.p.) were necessary to mitigate these effects. Conclusions:These data suggest that mitragynine may be a potential drug candidate for opiate withdrawal treatment.
| S-EPMC7221179 | biostudies-literature