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Elucidating the effects of estrous cycle on social stress-induced amphetamine sensitization in female rats

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Consequences of drug abuse and addiction affect both men and women, but women tend to rapidly progress through drug addiction phases, have higher drug dependency, and have higher relapse rates. Ovarian hormones fluctuate with female reproductive cycles and are thought

Consequences of drug abuse and addiction affect both men and women, but women tend to rapidly progress through drug addiction phases, have higher drug dependency, and have higher relapse rates. Ovarian hormones fluctuate with female reproductive cycles and are thought to cause increased sensitivity to psychostimulants. Additionally, intermittent social defeat stress induces social avoidance, weight loss, and long-lasting cross-sensitization to psychostimulants, which is associated with increased FosB/ΔFosB expression in the nucleus accumbens (NAc) shell. In this study, we examined the estrous cycle in female rats on social defeat stress-induced amphetamine cross-sensitization through FosB/ΔFosB expression in the NAc shell. Every third day for ten days, we induced social defeat stress in rats through short confrontations with a lactating female resident rat and her pups. In parallel, a group of rats were handled for control. Vaginal swabs were taken daily to assess estrous stage. Ten days after the last stress exposure, rats were administered a low dose of amphetamine (0.5 mg/kg, i.p.), which induced cross-sensitization in stressed rats, evidenced by enhanced locomotor activity. Approximately 3-10 days after amphetamine challenge, brain tissue was collected for immunohistochemistry analyses. Stressed female rats had lower body weight gain, higher social avoidance, and increased FosB/ΔFosB expression in the NAc shell. Differences in FosB/ΔFosB expression in the NAc shell was also observed in handled animals in different estrous stages. Furthermore, rats in proestrous/estrous stages displayed enhanced social defeat stress-induced amphetamine cross-sensitization in comparison to rats in metestrous/diestrous stages. Elucidating the effects of the female reproductive cycle on drug use may provide a novel approach to treatments or therapies in preventing women’s stress-induced vulnerability to substance abuse.

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2019-05

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Effects of miR-495 in Cocaine Addiction: Viral Mediated Overexpression and Inhibition of miR-495 Affects Cocaine-Seeking Behavior

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MicroRNAs are small, non-coding transcripts that control gene expression by preventing mRNA from translating into proteins. They have been implicated to play a role in many drug addictions. We previously found that miR-495 targets several addiction-related genes (ARGs) and is

MicroRNAs are small, non-coding transcripts that control gene expression by preventing mRNA from translating into proteins. They have been implicated to play a role in many drug addictions. We previously found that miR-495 targets several addiction-related genes (ARGs) and is highly expressed in the nucleus accumbens (NAc). We also found miR-495 is downregulated in the NAc following acute cocaine administration, and cocaine motivation measured by breakpoint on a progressive ratio schedule of cocaine reinforcement is decreased when miR-495 is overexpressed. In this study, we manipulated the endogenous levels of miR-495 by using a viral vector. Using an animal model, rats were first trained for self-administration on a fixed ratio (FR) schedule of reinforcement. After they were infused with a lentivirus to overexpress (LV-miR-495) or decrease (LV-Sponge) miR-495, in the NAc shell. The rats were then tested for extinction and reinstatement of cocaine-seeking behavior, which are measures of motivation for cocaine. We measured the relative levels of miR-495 in the NAc shell using qRT-PCR. Our results show that overexpression of miR-495 decreased cocaine-seeking behavior during extinction and cocaine reinstatement, as we hypothesized. Surprisingly, miR-495 LV-sponge also decreased cocaine-seeking behavior in extinction, not as we hypothesized. However, we found that LV-Sponge failed to significantly decrease levels of miR-495 as intended. In conclusion, understanding why LV-Sponge decreased, rather than increased, miR-495 will need further study, however, the results with LV-miR-495 extend previous findings that miR-495 plays a vital role in the molecular mechanism that influences motivation to seek cocaine.

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2017-05

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Nicotine Self-Administration and the Social Context

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Research suggests that the more positive the first drug experience, the more likely addiction will develop. Since smoking is initiated in a social setting, it is surprising how little is known about social context effects on acquisition of nicotine self-administration.

Research suggests that the more positive the first drug experience, the more likely addiction will develop. Since smoking is initiated in a social setting, it is surprising how little is known about social context effects on acquisition of nicotine self-administration. We investigated this issue in rats during late adolescence using conjoined self-administration chambers that had a removable shared wall. Rats were assigned to training conditions with either a solid black plexiglass or wire mesh partition in place throughout 22 subsequent 2-hour daily training sessions. Initially, 58 day-old (late-adolescent) male and female rats received 2, 30-min habituation sessions/day over 2 consecutive days, with only an inactive lever present. Sessions began with presentation of a retractable lever and thereafter each response on that lever resulted in simultaneous delivery of saline or 1 of 2 doses of nicotine (0.015 or 0.030 mg/kg, IV) and lever retraction for a 20-second time out. The findings indicate that the social context inhibits nicotine self-administration in female rats during the development of addiction, but has little effect on the initial stages of drug acquisition. Furthermore, the data suggest that in male rats the social context enhances responding independent of nicotine, but has few effects on nicotine self-administration during the development of addiction. The findings have important implications for substance use disorders.

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2015-05

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MicroRNA regulation of addiction-related gene expression and motivation for cocaine in rats

Description

MicroRNAs are small, non-coding transcripts that post-transcriptionally regulate expression of multiple genes. Recently microRNAs have been linked to the etiology of neuropsychiatric disorders, including drug addiction. Following genome-wide sequence analyses, microRNA-495 (miR-495) was found to target several genes within the

MicroRNAs are small, non-coding transcripts that post-transcriptionally regulate expression of multiple genes. Recently microRNAs have been linked to the etiology of neuropsychiatric disorders, including drug addiction. Following genome-wide sequence analyses, microRNA-495 (miR-495) was found to target several genes within the Knowledgebase of Addiction-Related Genes (KARG) database and to be highly expressed in the nucleus accumbens (NAc), a pivotal brain region involved in reward and motivation. The central hypothesis of this dissertation is that NAc miR-495 regulates drug abuse-related behavior by targeting several addiction-related genes (ARGs). I tested this hypothesis in two ways: 1) by examining the effects of viral-mediated miR-495 overexpression or inhibition in the NAc of rats on cocaine abuse-related behaviors and gene expression, and 2) by examining changes in NAc miR-495 and ARG expression as a result of brief (i.e., 1 day) or prolonged (i.e., 22 days) cocaine self-administration. I found that behavioral measures known to be sensitive to motivation for cocaine were attenuated by NAc miR-495 overexpression, including resistance to extinction of cocaine conditioned place preference (CPP), cocaine self-administration on a high effort progressive ratio schedule of reinforcement, and cocaine-seeking behavior during both extinction and cocaine-primed reinstatement. These effects appeared specific to cocaine, as there was no effect of NAc miR-495 overexpression on a progressive ratio schedule of food reinforcement. In contrast, behavioral measures known to be sensitive to cocaine reward were not altered, including expression of cocaine CPP and cocaine self-administration under a low effort FR5 schedule of reinforcement. Importantly, the effects were accompanied by decreases in NAc ARG expression, consistent with my hypothesis. In further support, I found that NAc miR-495 levels were reduced and ARG levels were increased in rats following prolonged, but not brief, cocaine self-administration experience. Surprisingly, inhibition of NAc miR-495 expression also decreased both cocaine-seeking behavior during extinction and NAc ARG expression, which may reflect compensatory changes or unexplained complexities in miR-495 regulatory effects. Collectively, the findings suggest that NAc miR-495 regulates ARG expression involved in motivation for cocaine. Therefore, using microRNAs as tools to target several ARGs simultaneously may be useful for future development of addiction therapeutics.

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Date Created
2016

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The role of nucleus accumbens NMDA receptors on rapid, transient synaptic plasticity induced by cued nicotine reinstatement

Description

Nicotine use is an outstanding public health problem with associated social and economic consequences. Nicotine is an active alkaloid compound in tobacco and is recognized as a psychoactive drug. Preclinically, nicotine addiction and relapse can be modeled using a self-administration-reinstatement

Nicotine use is an outstanding public health problem with associated social and economic consequences. Nicotine is an active alkaloid compound in tobacco and is recognized as a psychoactive drug. Preclinically, nicotine addiction and relapse can be modeled using a self-administration-reinstatement paradigm. Here, we used a nicotine self-administration and contingent cue-induced reinstatement model to examine rapid, transient synaptic plasticity (t-SP) induced by nicotine cue-triggered motivation. Although preliminary, treatment with the NMDA GluN2B subunit antagonist, ifenprodil, reduced reinstated nicotine seeking, and increased the percentage of spines with smaller head diameters. Thus, future studies are needed to fully parse out the role of NAcore GluN2B receptors in cued nicotine seeking and t-SP.

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2017-05