Matching Items (30)
Description
Cocaine use remains a prevalent problem, yet there are no effective pharmacological treatments against cocaine use disorders. Cocaine is known to affect serotonin neurotransmission in the brain. Previous data has shown the modulatory role of CP 94,253, a serotonin 1B receptor (5-HT1BR) agonist on cocaine self-administration at different periods of the use-abstinence-relapse cycle. CP 94,253 facilitates cocaine self-administration in rats during the use maintenance phase, where rats are receiving daily intake of cocaine, yet attenuates it after a period of abstinence, when drug delivery is discontinued and rats are placed in home cages. Here we study the therapeutic potential of 5-HT1BR agonist pre-treatment on cocaine self-administration during these different time periods. Male and free-cycling female rats were trained to lever-press for cocaine (0.75 mg/kg i.v.) or sucrose pellets, until they met stable performance for total number of infusions on a fixed ratio 5 schedule of reinforcement. Rats were then tested with either the FDA-approved but less selective 5-HT1BR agonist zolmitriptan (3, 5.6, and 10 mg/kg s.c.; in descending order) prior to a period of abstinence or the more selective 5-HT1BR agonist CP 94,253 (5.6 mg/kg s.c.) after a period of prolonged abstinence and relapse (i.e. resumption of daily cocaine self-administration after a period of abstinence). Each session ran for 2 hours during which the training dose was available for the 1st hour and a low dose of cocaine (0.075 mg/kg i.v.) for the 2nd hour. Zolmitriptan was found to attenuate cocaine self-administration measures at a dose of 3 and 5.6 mg/kg when testing at the low dose of cocaine and at all three doses (3, 5.6, and 10 mg/kg) when testing at the training dose of cocaine. Zolmitriptan at the doses effective at attenuating cocaine intake did not alter sucrose self-administration. CP 94,253 (5.6 mg/kg s.c.) was found to have significant attenuative effects on self-administration measures both after a period of prolonged abstinence and after a period of relapse. Overall, these experiments showed that zolmitriptan decreased cocaine reinforcement without altering sucrose reinforcement as well as that CP 94,253 attenuates cocaine intake even after a period of relapse. These findings support the therapeutic potential of 5-HT1BR agonists as pharmacological treatments for cocaine use disorders.
ContributorsLe, Tien (Author) / Neisewander, Janet (Thesis director) / Newbern, Jason (Committee member) / Garcia, Raul (Committee member) / Chemical Engineering Program (Contributor, Contributor) / School of International Letters and Cultures (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
With opioid use disorder (OUD) being an epidemic, it is important to investigate the mechanisms as to why this is so. This study established a self-administration paradigm to model and investigate the mechanisms of polysubstance, sequential use in conjunction with the analysis of withdrawal symptomatology driven by opioid withdrawal. The independent variables were dichotomized into the control group (food/cocaine) and the experimental group (oxycodone/cocaine). We hypothesized that more cocaine would be self-administered on the first day of oxycodone withdrawal. In addition, we hypothesized that somatic signs of withdrawal would increase at 16 hours post-oxycodone self-administration. Finally, we hypothesized that cocaine intake during oxycodone withdrawal would potentiate subsequent oxycodone self-administration. Our findings revealed that animals readily discriminated between the active (food or oxycodone) and inactive levers - but will however require more animals to achieve the appropriate power. Further, the average cocaine infusions across phases exhibited significance between the oxycodone/cocaine and food/cocaine group, with the average cocaine infusions being lower in food than in oxycodone-experienced animals. This implies that the exacerbation of the sequential co-use pattern in this case yields an increase in cocaine infusions that may be driven by oxycodone withdrawal. Further, to characterize withdrawal from oxycodone self-administration, somatic signs were examined at either 0 or 16 hrs following completion of oxycodone self-administration. The oxycodone/cocaine group exhibited significantly lower body temperature at 16 hrs of oxycodone withdrawal compared to 0 hrs. No differences in somatic signs of withdrawal in the food/cocaine group was found between the two timepoints. Oxycodone withdrawal was not found to potentiate any subsequent self-administration of oxycodone. Future research is needed to uncover neurobiological underpinnings of motivated polysubstance use in order to discover novel pharmacotherapeutic treatments to decrease co-use of drugs of abuse. Overall, this study is of importance as it is the first to establish a working preclinical model of a clinically-relevant pattern of polysubstance use. By doing so, it enables an exceptional opportunity to examine co-use in a highly-controlled setting.
ContributorsUlangkaya, Hanaa Corsino (Author) / Gipson-Reichardt, Cassandra (Thesis director) / Olive, M. Foster (Committee member) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
Alzheimer’s disease (AD) is a progressive cognitive and behavior disorder that is characterized by the deposition of extracellular Aβ plaques, intracellular neurofibrillary tangles, and neuroinflammation. Aβ is generated by cleavage of the amyloid precursor protein (APP) by β-secretase (BACE1) and, subsequently, y- secretase. In recent years, there has been an increasing interest in studying and understanding inflammation as a therapeutic target for AD. Inflammation manifests in the brain in the form of activated microglia and astrocytes. These cells are able to release high levels of inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α). TNF-α is a major cytokine, which is involved in early inflammatory events and plays a role in the progression of AD pathology. There are currently no treatments that target chronic neuroinflammation. However, previous work in our laboratory with transgenic mice modeling AD suggested that the anti-cancer drug lenalidomide could lower neuroinflammation and slow AD progression, though the cellular and molecular mechanisms are yet to be elucidated. Here we hypothesized that lenalidomide can modulate TNF-α production in microglia and decrease amyloidogenesis. Using immortal cell lines mimicking several brain cell types, we discovered that lenalidomide is likely to decrease inflammation by modulating microglia cells rather than neurons or astrocytes. In addition, the drug may prevent the overexpression of BACE1 upon inflammation, thus blocking the overproduction of Aβ. If confirmed, these results could lead to a better understanding of how inflammation regulates Aβ synthesis and provide novel cellular and molecular therapeutic targets to control the progression AD.
ContributorsGujju, Manasa (Author) / DeCourt, Boris (Thesis director) / Olive, M. Foster (Committee member) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Nicotine addiction remains a prevalent public health issue, and the FDA has released a statement outlining the systematic reduction of nicotine to non-zero levels in the coming years. Current research has not yet established the effects of abrupt nicotine dose reduction on vulnerability to relapse, nor has abrupt nicotine dose reduction been evaluated in terms of behavioral economic characteristics of demand and elasticity been evaluated for reduced doses of nicotine. Using a rat model, we first evaluated the comparability of between- and within-session protocols for establishing characteristics of demand and elasticity for nicotine to shorten experimental timelines for this study and future studies. We then tested environmental enrichment and sex as factors of elasticity of demand for nicotine. Using a rat model of relapse to cues, we also examined the effects of nicotine dose-reduction on vulnerability to relapse. We found differences in maximum consumption and demand between the between- and within-session protocols, as well as sex differences in elasticity of demand on the within-session protocol where male demand was more elastic than female demand. Additionally, we found that enrichment significantly increased elasticity of demand for nicotine for both males and females. Finally, preliminary analyses revealed that nicotine dose reduction yields more inelastic demand and higher maximum consumption, and these outcomes predict increased time to extinction of the association between nicotine and contingent cues, and increased rates of relapse. These studies highlight the usefulness and validity of within-session protocols, and also illustrate the necessity for rigorous testing of forced dose reduction on nicotine vulnerability.
ContributorsCabrera-Brown, Gabriella Paula (Author) / Gipson-Reichardt, Cassandra (Thesis director) / Olive, M. Foster (Committee member) / Davis, Mary (Committee member) / Sanford School of Social and Family Dynamics (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12
Description
Cases of heroin use and overdose are on the rise in the United States which has created what some call a public health crisis. Previous studies have investigated the beneficial effect of social interaction recovering addicts, and in animal models of addiction, social interaction can prevent or reverse the conditioned rewarding effects of cocaine. This study sought to determine if social interaction would prevent or diminish a conditioned preference for a heroin-paired context. Following establishment of baseline place preference, adult male Sprague-Dawley rats underwent once daily conditioning with either saline, heroin (1 mg/kg), or the animal's cage-mate for a total of 8 conditioning sessions. Assessment of post-conditioning place preference revealed that both the heroin injections and the presence of the cage-mate produced a place preference . In contrast to the findings of previous studies using cocaine as the conditioning drug, it was determined that rats preferred the heroin-paired context over that paired with the cage-mate.. These findings suggest that the protective effects of social interaction found in prior studies using cocaine as the conditioning drug may not extend to opiates, perhaps a result of stronger contextual conditioning and/or rewarding effects of this class of abused drugs.
ContributorsMarble, Krista Lillian (Author) / Olive, M. Foster (Thesis director) / Tomek, Seven (Committee member) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12
Description
The RAS/MAPK (RAS/Mitogen Activated Protein Kinase) pathway is a highly conserved, canonical signaling cascade that is highly involved in cellular growth and proliferation as well as cell migration. As such, it plays an important role in development, specifically in development of the nervous system. Activation of ERK is indispensable for the differentiation of Embryonic Stem Cells (ESC) into neuronal precursors (Li z et al, 2006). ERK signaling has also shown to mediate Schwann cell myelination of the peripheral nervous system (PNS) as well as oligodendrocyte proliferation (Newbern et al, 2011). The class of developmental disorders that result in the dysregulation of RAS signaling are known as RASopathies. The molecular and cell-specific consequences of these various pathway mutations remain to be elucidated. While there is evidence for altered DNA transcription in RASopathies, there is little work examining the effects of the RASopathy-linked mutations on protein translation and post-translational modifications in vivo. RASopathies have phenotypic and molecular similarities to other disorders such as Fragile X Syndrome (FXS) and Tuberous Sclerosis (TSC) that show evidence of aberrant protein synthesis and affect related pathways. There are also well-defined downstream RAS pathway elements involved in translation. Additionally, aberrant corticospinal axon outgrowth has been observed in disease models of RASopathies (Xing et al, 2016). For these reasons, this present study examines a subset of proteins involved in translation and translational regulation in the context of RASopathy disease states. Results indicate that in both of the tested RASopathy model systems, there is altered mTOR expression. Additionally the loss of function model showed a decrease in rps6 activation. This data supports a role for the selective dysregulation of translational control elements in RASopathy models. This data also indicates that the primary candidate mechanism for control of altered translation in these modes is through the altered expression of mTOR.
ContributorsHilbert, Alexander Robert (Author) / Newbern, Jason (Thesis director) / Olive, M. Foster (Committee member) / Bjorklund, Reed (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
Description
Previously we found that the serotonin 1B receptor (5-HT1BR) agonist CP 94,253 (CP) enhances the reinforcing properties of cocaine when given to male rats self-administering the drug daily, however, CP had the opposite effect following a 21-day period of abstinence. Methamphetamine, like cocaine, has similar mechanisms of action on the monoamine neurotransmitter systems. Therefore, we predicted that CP would have effects on the reinforcing properties of methamphetamine similar to cocaine. Additionally, we examined effects of the FDA-approved 5-HT1B/DR agonist, zolmitriptan, on psychostimulant self-administration. We first tested the effects of CP on methamphetamine self-administration utilizing a fixed ratio or progressive ratio schedule of reinforcement and found that regardless of whether or not rats experienced abstinence, CP decreased methamphetamine intake. We next verified that the effects of CP were mediated by 5-HT1BRs by demonstrating they were reversed when paired with a 5-HT1BR antagonist. We then tested the effects of zolmitriptan on methamphetamine responding and found the same results as found with CP. Finally, we tested whether the effects of zolmitriptan generalize to female rats. Both male and female rats were given access to various doses of cocaine after treatment with zolmitriptan. We also ruled out 5-HT1BR ligands has having an effect on locomotion, to rule out motor impairment as the reason behind the decreases in drug intake. Unlike our previous findings with CP effects on cocaine self-administration, zolmitriptan attenuated cocaine intake both before and after abstinence in both male and female rats. The pre-abstinence effects of zolmitriptan in attenuating intake of different psychostimulants suggest its potential as a pharmacological treatment for psychostimulant use disorders.
ContributorsCotter, Austin Richard (Author) / Neisewander, Janet (Thesis director) / Newbern, Jason (Committee member) / Garcia, Raul (Committee member) / School of International Letters and Cultures (Contributor) / School of Life Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Evidence from the 20th century demonstrated that early life stress (ELS) produces long lasting neuroendocrine and behavioral effects related to an increased vulnerability towards psychiatric illnesses such as major depressive disorder, post-traumatic stress disorder, schizophrenia, and substance use disorder. Substance use disorders (SUDs) are complex neurological and behavioral psychiatric illnesses. The development, maintenance, and relapse of SUDs involve multiple brain systems and are affected by many variables, including socio-economic and genetic factors. Pre-clinical studies demonstrate that ELS affects many of the same systems, such as the reward circuitry and executive function involved with addiction-like behaviors. Previous research has focused on cocaine, ethanol, opiates, and amphetamine, while few studies have investigated ELS and methamphetamine (METH) vulnerability. METH is a highly addictive psychostimulant that when abused, has deleterious effects on the user and society. However, a critical unanswered question remains; how do early life experiences modulate both neural systems and behavior in adulthood? The emerging field of neuroepigenetics provides a potential answer to this question. Methyl CpG binding protein 2 (MeCP2), an epigenetic tag, has emerged as one possible mediator between initial drug use and the transition to addiction. Additionally, there are various neural systems that undergo long lasting epigenetics changes after ELS, such as the response of the hypothalamo-pituitary-adrenal (HPA) axis to stressors. Despite this, little attention has been given to the interactions between ELS, epigenetics, and addiction vulnerability. The studies described herein investigated the effects of ELS on METH self-administration (SA) in adult male rats. Next, we investigated the effects of ELS and METH SA on MeCP2 expression in the nucleus accumbens and dorsal striatum. Additionally, we investigated the effects of virally-mediated knockdown of MeCP2 expression in the nucleus accumbens core on METH SA, motivation to obtain METH under conditions of increasing behavioral demand, and reinstatement of METH-seeking in rats with and without a history of ELS. The results of these studies provide insights into potential epigenetic mechanisms by which ELS can produce an increased vulnerability to addiction in adulthood. Moreover, these studies shed light on possible novel molecular targets for treating addiction in individuals with a history of ELS.
ContributorsLewis, Candace (Author) / Olive, M. Foster (Thesis advisor) / Hammer, Ronald (Committee member) / Neisewander, Janet (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2015
Description
Serotonin 1B receptor (5-HT1BR) agonists enhance cocaine intake in rats during daily self-administration (SA) sessions, yet decrease cocaine intake after prolonged abstinence. The goal of my dissertation was to examine if 5-HT1BRs are suitable targets for treatment development to attenuate psychostimulant intake. I first investigated if 5-HT1BR agonist effects that had been observed with cocaine generalize across psychostimulants, i.e., methamphetamine. Rats trained to self-administer methamphetamine received either CP 94,253 or the clinically-available but less selective 5-HT1D/1BR agonist, zolmitriptan, prior to tests for effects on SA both before and after a 21-day abstinence period. I found that CP 94,253 and zolmitriptan decreased the reinforcing and incentive motivational effects of methamphetamine, regardless of abstinence, unlike the pre-abstinence increase in cocaine SA observed previously with 5-HT1BR agonists. The attenuating effects of CP 94,253 on methamphetamine were antagonized in a 5-HT1BR-mediated manner. Subsequently, I investigated the efficacy and mechanism involved in effects of zolmitriptan on cocaine SA in male and female rats. Rats trained to self-administer cocaine received zolmitriptan prior to tests for effects on SA before a 21-day abstinence period. I found that zolmitriptan decreased cocaine intake in both sexes regardless of abstinence and without altering sucrose intake. I further demonstrated that the zolmitriptan effects on cocaine SA were mediated by both 5-HT1BRs and 5-HT1DRs. Finally, I examined if the abstinence-induced decrease in cocaine intake observed with the selective 5-HT1BR agonist, CP 94,253, persists during relapse after abstinence or reverts to enhancing cocaine intake, similar to effects observed without an abstinence period. Rats trained to self-administer cocaine resumed daily cocaine SA sessions after the forced abstinence period to investigate the effects of CP 94,253 on cocaine relapse. I found that CP 94,253 attenuated cocaine intake in relapse tests, suggesting that the abstinence-dependent attenuation of CP 94,253 on cocaine SA remains even after resumption of daily cocaine intake. The findings suggest that 5-HT1BR agonists like CP 94,253 and zolmitriptan have clinical potential as treatments for psychostimulant use disorders.
ContributorsGarcia, Raul (Author) / Neisewander, Janet L (Thesis advisor) / Olive, Michael Foster (Committee member) / Sanabria, Federico (Committee member) / Newbern, Jason M (Committee member) / Arizona State University (Publisher)
Created2020
Description
Use of psychostimulants, such as cocaine, is associated with an increased risk of human immunodeficiency virus (HIV) infection. Dopaminergic signaling within the nucleus accumbens (NAc) is critically implicated in both disease states, mediating the addictive and reinforcing effects of cocaine and perpetuating HIV replication throughout the central nervous system (CNS). Cocaine and HIV induce neurobehavioral deficits separately; however, little is known regarding how they interact to dysregulate neuroimmune function or how this impacts relapse vulnerability. We have previously shown that inhibition of dopamine D3 receptor (D3R) signaling using MC-25-41, a novel and highly selective D3R partial agonist, attenuates cocaine-seeking behavior. Here, we sought to characterize changes in neuroimmune function in a rat model of combined HIV and cocaine use disorders across abstinence and examined the therapeutic efficacy of MC-25-41 in the presence of this comorbidity. Male rats were systemically treated with the HIV protein gp120 after establishing a history of cocaine self-administration and then, following 21 days of abstinence, were administered a systemic injection of MC-25-41 (10 mg/kg) prior to cue reactivity testing. Glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1) immunoreactivity were analyzed after 5 or 21 days of cocaine abstinence as an index of glial cell levels. We demonstrate that inhibition of D3R signaling significantly attenuates cue-induced cocaine seeking among control rats but not gp120-exposed rats. Moreover, we show that NAc core GFAP and Iba1 expression is impaired by 5 days of abstinence, which persists into protracted abstinence and cue reactivity testing. However, we also demonstrate that neither gp120 nor D3R inhibition significantly altered NAc core GFAP or Iba1 expression. Altogether, these results reveal significant changes in glial cell function across cocaine abstinence and unique behavioral interactions with gp120 may inhibit the effectiveness of medication regimens, which highlights the need to consider these comorbidities when treating HIV infection.
ContributorsPhillips, Megan (Author) / Neisewander, Janet (Thesis director) / Olive, M. Foster (Committee member) / Namba, Mark (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2021-12