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

Description

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

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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Date Created
  • 2017-05

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The Combined Effects of Methamphetamine and Alcohol on Brain Reward Function as Assessed Using Intracranial Self-Stimulation

Description

Polysubstance abuse is far more common than single substance abuse. One of the most widely abused, yet greatly understudied combination of drugs is the simultaneous use of methamphetamine (meth) and

Polysubstance abuse is far more common than single substance abuse. One of the most widely abused, yet greatly understudied combination of drugs is the simultaneous use of methamphetamine (meth) and alcohol. Because little research has been conducted on the co-abuse of meth and alcohol, it is important to study the behavioral and neural mechanisms underlying the use of both to combat addiction and come closer to finding an effective treatment of this form of drug abuse. This study uses a rodent model to attempt to identify the mechanisms underlying this co-abuse through the stimulation of the medial forebrain bundle (MFB) and thus the activation of the mesocorticolimbic pathway, the brain's pleasure circuit. First, self-stimulation thresholds (the lowest electrical current the rats are willing to respond for) were determined using a process called Discrete Trials Training. This threshold was later used as a baseline measure to reference when the rats were administered the drugs of abuse: meth and alcohol, both alone and in combination. Our overall results did not show any significant effects of combining alcohol and meth relative to the effects of either drug alone, although subject attrition may have resulted in sample sizes that were statistically underpowered. The results of this and future studies will help provide a clearer understanding of the neural mechanisms underlying the polyabuse of meth and alcohol and can potentially lead to more successfully combating and treating this addiction.

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Date Created
  • 2016-12

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The Sackler Family and Their Role in the Opioid Crisis

Description

Purdue Pharma was started by Arthur, Mortimer, and Raymond Sackler in the 1950s. Its most successful product was OxyContin. Purdue failed to perform the required trials and used misleading marketing

Purdue Pharma was started by Arthur, Mortimer, and Raymond Sackler in the 1950s. Its most successful product was OxyContin. Purdue failed to perform the required trials and used misleading marketing practices to promote the drug. The Sackler family encouraged these false advertising campaigns in an attempt to drive up sales. These deceitful tactics caught up with the company and Purdue Pharma’s affiliate pled guilty to deliberately misbranding the drug in 2006. Purdue Pharma currently faces thousands of lawsuits, with Sackler family members personally named, for misleading marketing practices. States uncovering evidence of the Sackers attempting to hide their fortune via wire transfers and offshore accounts and institutions removing the family name from their doors threaten both the Purdue Pharma and the Sackler family’s money and influence.
The opioid crisis was inflamed by multiple sources, from which Purdue Pharma and other pharmaceutical companies benefited. The first is the Revolving Door, where government workers go to work for the companies they were once in charge of regulating. Existing loopholes allow former officials to immediately become lobbyists and perform consulting work. The Food and Drug Administration has close ties with lobbyists and pharmaceutical companies, which casts doubt and suspicion on its policies. Tightening and expanding current Revolving Door regulations would begin to stem this problem. Extending the cooling-off period to a minimum of five years would prevent former government workers from immediately influencing government policies. Furthermore, the laws need to be modified to include more specific language to eliminate loopholes. Banning former government employees from any counseling services or lobbying any government branch, agency, or office will make it much more difficult to circumvent the rules.
The second are “pill mills,” whereby physicians, clinics, or pharmacies prescribe prescription drugs inappropriately. There exists a web of regulation and reporting laws from federal and state governments, but pill mills still established themselves. Florida enacted laws that created stricter requirements for dispensing drugs, medical examinations, and follow-ups before and after prescribing opioids for chronic pain. These laws had positive results in stopping pill mills. Similar laws should be enacted nationally. Existing laws focusing on the pharmaceutical manufacturers, distributors, and pharmacies should be expanded to improve reporting between those agencies and the DEA and the DEA and other government agencies.
The last one is the American drug addiction rehab system. It is fraught with stigma, lax insurance information, inconsistent treatments, and poorly utilized information. The system often fails to provide care for those who need it. Increasing the scope of treatments would boost its effectiveness. States need to require insurance companies to cover mental health treatment to the same extent and degree as physical health issues and use a uniform, standardized tool to decide the necessary level of care addiction patients need. Public report cards for treatment centers would improve their long-term level of care and ease patients in finding a treatment center that fits them.
Addressing these problems has already begun at the both federal and state level. As these causes are identified and attacked, it will become easier to pass the laws needed to repair the system that allowed the opioid crisis to occur.

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Created

Date Created
  • 2020-05

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The Chase for a Legal High: Discovering What Arizonans Know About Designer Drugs

Description

This creative project explores the trend of designer/synthetic drug use in Arizona and nationwide. The project serves as "gap research" - bringing to light the problem of limited use statistics

This creative project explores the trend of designer/synthetic drug use in Arizona and nationwide. The project serves as "gap research" - bringing to light the problem of limited use statistics and constantly-changing drug chemical compounds. The project was thoroughly researched using media reports, psychology/drug addiction experts, community education organizers and available healthcare statistics. The results provided not definitive answer other than that more work needs to be done in the area of synthetic drug use. Parents and youth must educate themselves on the dangers of using these "legal" drugs.

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Created

Date Created
  • 2014-05

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Nicotine Self-Administration and the Social Context

Description

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

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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Date Created
  • 2015-05

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

Description

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.

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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Created

Date Created
  • 2019-05

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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,

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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Created

Date Created
  • 2016

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Mesolimbic GluA1 AMPA Receptor Signaling in Dopaminergic Neurons Plays a Critical Role in the Induction of Cross-Sensitization to Psychostimulants in Response to Social Stress

Description

Intermittent social defeat stress induces psychostimulant cross-sensitization, as well as long-lasting social avoidance behavior. Previous data reveal heightened expression of AMPA receptor (AMPAR) GluA1 subunits in rat ventral tegmental area

Intermittent social defeat stress induces psychostimulant cross-sensitization, as well as long-lasting social avoidance behavior. Previous data reveal heightened expression of AMPA receptor (AMPAR) GluA1 subunits in rat ventral tegmental area (VTA), which occurs concurrently with social stress-induced amphetamine (AMPH) cross-sensitization. These studies described herein examined whether VTA GluA1 AMPARs are important for the behavioral consequences of social stress and investigated the role of the infralimbic (IL) to VTA pathway in the induction of these responses. Functional inactivation of GluA1 in VTA DA neurons prevented stress-induced AMPH sensitization without affecting social avoidance behavior, while GluA1 overexpression in VTA DA neurons mimicked the effects of stress on AMPH sensitization. Female rats were more sensitive to the effects of stress on AMPH administration than males, specifically during proestrus/estrus, which is characterized by higher circulating estradiol. Fluorescent immunohistochemistry revealed that females expressed higher GluA1 in VTA DA neurons as a result of intermittent social defeat stress, independent of estrus stage; by contrast, females during proestrus/estrus displayed higher tyrosine kinase receptor type 2 (TrkB) expression, which is the receptor for brain derived neurotrophic factor (BDNF), in VTA DA neurons, independent of stress exposure. Functional inactivation of GluA1 in VTA DA neurons prevented stress-induced AMPH sensitization and overexpression mimicked the effects of stress on AMPH sensitization. This suggests that BDNF-TrkB signaling may work concomitantly with GluA1 signaling in the VTA to drive sex-dependent differences in stress-induced locomotor sensitization effects. Optogenetic inhibition of the IL-VTA pathway in male rats prevented stress-induced AMPH sensitization compared to control animals. In addition, fluorescent immunohistochemistry displayed less Fos labeling in the nucleus accumbens (NAc) of rats with IL-VTA light inhibition compared to control animals. This suggests that the IL-VTA pathway plays a critical role in the induction of stress-induced sensitivity to AMPH, and blocking this pathway prevents mesolimbic DA signaling to the NAc. We conclude that IL glutamate projections onto GluA1-homomeric AMPA receptors in VTA DA neurons play a critical role in driving the stress-induced sensitization response in males and females. Therefore, GluA1 VTA DA neurons could potentially be a therapeutic target to prevent stress-induced drug susceptibility in the future.

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Created

Date Created
  • 2020

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Novel cues reinstate cocaine-seeking behavior and induce Fos Protein as effectively as conditioned cues

Description

The capability of cocaine-associated stimuli in eliciting craving in human addicts, even after extended periods of abstinence, is modeled in animals using cue reinstatement of extinguished cocaine-seeking behavior. This study

The capability of cocaine-associated stimuli in eliciting craving in human addicts, even after extended periods of abstinence, is modeled in animals using cue reinstatement of extinguished cocaine-seeking behavior. This study aimed to examine brain activation in response to cocaine cues in this model apart from activation produced by test novelty using a novel cue control. Rats trained to self-administer cocaine paired with either an oscillating light or tone cue underwent daily extinction training and were then tested for reinstatement of extinguished cocaine-seeking behavior elicited by response-contingent presentations of either their assigned cocaine-paired cue or the alternate, novel cue. Additional controls received saline infusions and cue presentations yoked to a cocaine-trained rat. Brains were harvested for Fos immunohistochemistry immediately after the 90-min reinstatement test. Surprisingly, conditioned and novel cues both reinstated responding to a similar degree; however magnitude of reinstatement did vary by cue modality with the greatest reinstatement to the light cues. In most brain regions, Fos expression was enhanced in rats with a history of cocaine training regardless of cue type with the exception of the Cg1 region of the anterior cingulate cortex, which was sensitive to test cue modality. Also Fos expression within the dorsomedial caudate-putamen was correlated with responding in the novel, but not conditioned, cue groups. In subsequent experiments, we observed a similar pattern of reinstatement in rats trained and tested for sucrose-seeking behavior, whereas rats trained and tested with the cues only reinstated to a novel light and tone, but not a familiar cue. The results suggest that novel cues reinstate responding to a similar extent as conditioned cues regardless of whether animals have a history of operant-delivered drug or a natural reinforcer. Furthermore, similar brain circuits as those involved in cocaine-seeking behavior are activated by novel cues, suggesting converging processes exist to drive conditioned and novel reinforcement seeking.

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Created

Date Created
  • 2012