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Description
5-HT2A receptor (R) antagonists and 5-HT2CR agonists attenuate reinstatement of cocaine-seeking behavior (i.e., incentive motivation). 5-HT2Rs are distributed throughout the brain, primarily in regions involved in reward circuitry, including the prefrontal cortex (PFC), caudate putamen (CPu), and basolateral (BlA) and central (CeA) amygdala. Using animal models, we tested our hypotheses that 5-HT2ARs in the medial (m) PFC mediate the incentive motivational effects of cocaine and cocaine-paired cues; 5-HT2ARs and 5-HT2CRs interact to attenuate cocaine hyperlocomotion and functional neuronal activation (i.e, Fos protein); and 5-HT2CRs in the BlA mediate the incentive motivational effects of cocaine-paired cues and anxiety-like behavior, while 5-HT2CRs in the CeA mediate the incentive motivational effects of cocaine. In chapter 2, we infused M100907, a selective 5-HT2AR antagonist, directly into the mPFC and examined its effects on reinstatement of cocaine-seeking behavior. We found that M100907 in the mPFC dose- dependently attenuated cue-primed reinstatement, without affecting cocaine-primed reinstatement, cue-primed reinstatement of sucrose-seeking behavior, or locomotor activity. In chapter 3, we used subthreshold doses of M100907 and MK212, a 5-HT2CR agonist, to investigate whether these compounds interact to attenuate cocaine hyperlocomotion and Fos protein expression. Only the drug combination attenuated cocaine hyperlocomotion and cocaine-induced Fos expression in the CPu, but had no effect on spontaneous locomotion. Finally, in chapter 4 we investigated the effects of a 5- HT2CR agonist in the BlA and CeA on cocaine-seeking behavior and anxiety-like behavior. We found that CP809101, a selective 5-HT2CR agonist, infused into the BlA increased anxiety-like behavior on the elevated plus maze (EPM), but failed to alter cocaine-seeking behavior. CP809101 infused into the CeA attenuated cocaine-primed reinstatement and this effect was blocked by co-administration of a 5-HT2CR antagonist. Together, these results suggest that 5-HT2ARs in the mPFC are involved in cue-primed reinstatement, 5-HT2A and 5-HT2CRs may interact in the nigrostriatal pathway to attenuate cocaine hyperlocomotion and Fos expression, and 5-HT2CRs are involved in anxiety-like behavior in the BlA and cocaine-primed reinstatement in the CeA. Our findings add to the literature on the localization of 5-HT2AR antagonist and 5-HT2CR agonist effects, and suggest a potential treatment mechanism via concurrent 5-HT2AR antagonism and 5-HT2CR agonism.
ContributorsPockros, Lara Ann (Author) / Neisewander, Janet L (Thesis advisor) / Olive, Michael F (Committee member) / Conrad, Cheryl D. (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2013
Description
Cognitive function declines with normal age and disease states, such as Alzheimer's disease (AD). Loss of ovarian hormones at menopause has been shown to exacerbate age-related memory decline and may be related to the increased risk of AD in women versus men. Some studies show that hormone therapy (HT) can have beneficial effects on cognition in normal aging and AD, but increasing evidence suggests that the most commonly used HT formulation is not ideal. Work in this dissertation used the surgically menopausal rat to evaluate the cognitive effects and mechanisms of progestogens proscribed to women. I also translated these questions to the clinic, evaluating whether history of HT use impacts hippocampal and entorhinal cortex volumes assessed via imaging, and cognition, in menopausal women. Further, this dissertation investigates how sex impacts responsiveness to dietary interventions in a mouse model of AD. Results indicate that the most commonly used progestogen component of HT, medroxyprogesterone acetate (MPA), impairs cognition in the middle-aged and aged surgically menopausal rat. Further, MPA is the sole hormone component of the contraceptive Depo Provera, and my research indicates that MPA administered to young-adult rats leads to long lasting cognitive impairments, evident at middle age. Natural progesterone has been gaining increasing popularity as an alternate option to MPA for HT; however, my findings suggest that progesterone also impairs cognition in the middle-aged and aged surgically menopausal rat, and that the mechanism may be through increased GABAergic activation. This dissertation identified two less commonly used progestogens, norethindrone acetate and levonorgestrel, as potential HTs that could improve cognition in the surgically menopausal rat. Parameters guiding divergent effects on cognition were discovered. In women, prior HT use was associated with larger hippocampal and entorhinal cortex volumes, as well as a modest verbal memory enhancement. Finally, in a model of AD, sex impacts responsiveness to a dietary cognitive intervention, with benefits seen in male, but not female, transgenic mice. These findings have clinical implications, especially since women are at higher risk for AD diagnosis. Together, it is my hope that this information adds to the overarching goal of optimizing cognitive aging in women.
ContributorsBraden, Brittany Blair (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Neisewander, Janet L (Committee member) / Conrad, Cheryl D. (Committee member) / Baxter, Leslie C (Committee member) / Arizona State University (Publisher)
Created2012
Description
Smoking remains the leading cause of preventable death in the United States, and early initiation is associated with greater difficulty quitting. Among adolescent smokers, those with attention-deficit hyperactivity disorder (ADHD), characterized by difficulties associated with impulsivity, hyperactivity, and inattention, smoke at nearly twice the rate of their peers. Although cigarette smoking is highly addictive, nicotine is a relatively weak primary reinforcer, spurring research on other potential targets that may maintain smoking, including the potential benefits of nicotine on attention, inhibition, and reinforcer efficacy. The present study employs the most prevalent rodent model of ADHD, the spontaneously hypertensive rat (SHR) and its control comparison Wistar Kyoto (WKY) to examine the effects of acute and chronic subcutaneous nicotine injections on performance in three operant response inhibition paradigms. Functional activation in select regions of the prefrontal cortex and striatum was also explored. Acute (0.1, 0.3, 0.6 mg/kg) and chronic (0.3 mg/kg) nicotine increased impulsive responding regardless of strain, dose, or operant schedule. Dose-dependent decreases in latency to initiate the task were also observed. SHR receiving daily nicotine injections showed less activation in the nucleus accumbens shell compared to saline controls. Despite close similarities, one of the three operant tasks did not detect response inhibition deficits in SHR relative to WKY. A closer examination of these tasks may highlight critical components involved in the amelioration of response inhibition deficits.
ContributorsMazur, Gabriel Joseph (Author) / Sanabria, Federico (Thesis advisor) / Killeen, Peter R (Committee member) / Neisewander, Janet L (Committee member) / Wynne, Clive DL (Committee member) / Arizona State University (Publisher)
Created2014
Description
Nicotine is thought to underlie the reinforcing and dependence-producing effects of tobacco-containing products. Nicotine supports self-administration in rodents, although measures of its reinforcing effects are often confounded by procedures that are used to facilitate acquisition, such as food restriction, prior reinforcement training, or response-contingent co-delivery of a naturally reinforcing light. This study examined whether rats acquire nicotine self-administration in the absence of these facilitators. A new mathematical modeling procedure was used to define the criterion for acquisition and to determine dose-dependent differences in rate and asymptote levels of intake. Rats were trained across 20 daily 2-h sessions occurring 6 days/week in chambers equipped with active and inactive levers. Each active lever press resulted in nicotine reinforcement (0, 0.015, 0.03, 0.06 mg/kg, IV) and retraction of both levers for a 20-s time out, whereas inactive lever presses had no consequences. Acquisition was defined by the best fit of a logistic function (i.e., S-shaped) versus a constant function (i.e., flat line) for reinforcers obtained across sessions using a corrected Akaike information criterion (AICc) as a model selection tool. The results showed an inverted-U shaped function for dose in relation to the percentage of animals that acquired nicotine self-administration, with 46% acquiring at 0.015 mg/kg, 73% at 0.03 mg/kg, and 58% at 0.06 mg/kg. All saline rats failed to acquire as expected. For rats that acquired nicotine self-administration, multiple model comparisons demonstrated that the asymptote (highest number of reinforcers/session) and half learning point (h; session during which half the assymptote had been achieved) were justified as free parameters of the reinforcers/session function, indicating that these parameters vary with nicotine dose. Asymptote exhibited an inverted U-shaped function across doses and half learning point exhibited a negative relationship to dose (i.e., the higher the dose the fewer sessions to reach h). These findings suggest that some rats acquire nicotine self-administration without using procedures that confound measures of acquisition rate. Furthermore, the modeling approach provides a new way of defining acquisition of drug self-administration that takes advantage of using all data generated from individual subjects and is less arbitrary than some criteria that are currently used.
ContributorsCole, Natalie (Author) / Neisewander, Janet L (Thesis advisor) / Sanabria, Federico (Thesis advisor) / Bimonte-Nelson, Heather A. (Committee member) / Olive, Michael F (Committee member) / Arizona State University (Publisher)
Created2011
Description
Cognitive function is multidimensional and complex, and research indicates that it is impacted by age, lifetime experience, and ovarian hormone milieu. One particular domain of cognitive function that is susceptible to age-related decrements is spatial memory. Cognitive practice can affect spatial memory when aged in both males and females, and in females alone ovarian hormones have been found to alter spatial memory via modulating brain microstructure and function in many of the same brain areas affected by aging. The research in this dissertation has implications that promote an understanding of the effects of cognitive practice on aging memory, why males and females respond differently to cognitive practice, and the parameters and mechanisms underlying estrogen's effects on memory. This body of work suggests that cognitive practice can enhance memory when aged and that estrogen is a probable candidate facilitating the observed differences in the effects of cognitive practice depending on sex. This enhancement in cognitive practice effects via estrogen is supported by data demonstrating that estrogen enhances spatial memory and hippocampal synaptic plasticity. The estrogen-facilitated memory enhancements and alterations in hippocampal synaptic plasticity are at least partially facilitated via enhancements in cholinergic signaling from the basal forebrain. Finally, age, dose, and type of estrogen utilized are important factors to consider when evaluating estrogen's effects on memory and its underlying mechanisms, since age alters the responsiveness to estrogen treatment and the dose of estrogen needed, and small alterations in the molecular structure of estrogen can have a profound impact on estrogen's efficacy on memory. Collectively, this dissertation elucidates many parameters that dictate the outcome, and even the direction, of the effects that cognitive practice and estrogens have on cognition during aging. Indeed, many parameters including the ones described here are important considerations when designing future putative behavioral interventions, behavioral therapies, and hormone therapies. Ideally, the parameters described here will be used to help design the next generation of interventions, therapies, and nootropic agents that will allow individuals to maintain their cognitive capacity when aged, above and beyond what is currently possible, thus enacting lasting improvement in women's health and public health in general.
ContributorsTalboom, Joshua S (Author) / Bimonte-Nelson, Heather A. (Thesis advisor) / Conrad, Cheryl D. (Committee member) / Neisewander, Janet L (Committee member) / West, Stephen G. (Committee member) / Arizona State University (Publisher)
Created2011
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 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.
ContributorsBastle, Ryan (Author) / Neisewander, Janet L (Thesis advisor) / Sanabria, Federico (Committee member) / Olive, Michael F (Committee member) / Arizona State University (Publisher)
Created2012
Description
Social influences are important determinants of drug initiation in humans, particularly during adolescence and early adulthood. My dissertation tested three hypotheses: 1) conditioned and unconditioned nicotine and social rewards elicit unique patterns of neural signaling in the corticolimbic neurocircuitry when presented in combination versus individually; 2) play behavior is not necessary for expression of social reward; and 3) social context enhances nicotine self-administration. To test the first hypothesis, Fos protein was measured in response to social and nicotine reward stimuli given alone or in combination and in response to environmental cues associated with the rewards in a conditioned place preference (CPP) test. Social-conditioned environmental stimuli attenuated Fos expression in the nucleus accumbens core. A social partner elevated Fos expression in the caudate-putamen, medial and central amygdala, and both nucleus accumbens subregions. Nicotine decreased Fos expression in the cingulate cortex, caudate-putamen, and the nucleus accumbens core. Both stimuli combined elevated Fos expression in the basolateral amygdala and ventral tegmental area, suggesting possible overlap in processing both rewards in these regions. I tested the second hypothesis with an apparatus containing compartments separated by a wire mesh barrier that allowed limited physical contact with a rat or object. While 2 pairings with a partner rat (full physical contact) produced robust CPP, additional pairings were needed for CPP with a partner behind a barrier or physical contact with an object (i.e., tennis ball). The results demonstrate that physical contact with a partner rat is not necessary to establish social-reward CPP. I tested the third hypothesis with duplex operant conditioning chambers separated either by a solid or a wire mesh barrier to allow for social interaction during self-administration sessions. Nicotine (0.015 and 0.03 mg/kg, IV) and saline self-administration were assessed in male and female young-adult rats either in the social context or isolation. Initially, a social context facilitated nicotine intake at the low dose in male rats, but suppressed intake in later sessions more strongly in female rats, suggesting that social factors exert strong sex-dependent influences on self-administration. These novel findings highlight the importance of social influences on several nicotine-related behavioral paradigms and associated neurocircuitry.
ContributorsPeartree, Natalie (Author) / Neisewander, Janet L (Thesis advisor) / Conrad, Cheryl D. (Committee member) / Nikulina, Ella M (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2015
Description
Nicotine self-administration is associated with decreased expression of the glial glutamate transporter 1 (GLT-1) and the cystine-glutamate exchange protein xCT in the nucleus accumbens core (NAcore). N-acetylcysteine (NAC), which is an antioxidant, anti-inflammatory, and glutamatergic agent, restores these proteins associated with increased relapse vulnerability. However, the specific molecular mechanisms driving NAC inhibitory effects on cue-induced nicotine reinstatement are unknown. Thus, the present study assessed NAC’s effects on cue-induced nicotine reinstatement are dependent on NAcore GLT-1 expression. Here, rats were treated with NAC in combination with intra-NAcore vivo-morpholinos to examine the role of GLT-1 in NAC-mediated inhibition of cue-induced nicotine seeking. Subchronic NAC treatment attenuated cue-induced nicotine seeking in male rats and an antisense vivo-morpholino (AS) designed to selectively suppress GLT-1 expression in the NAcore blocked this effect. NAC treatment was also associated with an inhibition of pro-inflammatory tumor necrosis factor alpha (TNFα) expression in the NAcore. As well, GLT-1 AS markedly increased expression of CD40, a known marker of pro-inflammatory M1 activation of microglia and macrophages. To further examine whether NAC-induced decreases in nicotine seeking involve suppression of TNFα, we manipulated a downstream mediator of this pathway, nuclear factor kappa B (NF-kB). Considering the putative role of NF-κB in learning, memory, and synaptic plasticity, separate experiments were performed where rats were treated with herpes simplex virus (HSV) vectors designed to increase (HSV-IKKca) or decrease (HSV-IKKdn) NF-κB signaling through interactions with IκB Kinase (IKK). The goal was to examine the role of NF-κB signaling in mediating nicotine seeking behavior and if NF-κB signaling regulates GLT-1 expression. HSV-IKKdn alone and in combination with NAC inhibited cue-induced nicotine reinstatement, while HSV-IKKca blocked the attenuating effect of NAC on reinstatement. Interestingly, both HSV-IKKdn and HSV-IKKca, regardless of NAC treatment, inhibited GLT-1 expression. Taken together, these results suggest that while GLT-1 may be a conserved neurobiological substrate underlying relapse vulnerability across drugs of abuse, immunomodulatory mechanisms may regulate drug-induced alterations in glutamatergic plasticity that mediate cue-induced drug-seeking behavior through GLT-1-independent mechanisms.
ContributorsNamba, Mark Douglas (Author) / Gipson-Reichardt, Cassandra D (Thesis advisor) / Conrad, Cheryl D. (Committee member) / Neisewander, Janet L (Committee member) / Arizona State University (Publisher)
Created2019
Description
Cocaine use disorders (CUDs) and human immunodeficiency virus (HIV) are a common comorbidity, although it is largely unknown whether HIV interacts with cocaine abstinence to uniquely alter neuroimmune function and whether HIV may modulate the efficacy of medications intended to treat CUDs. My dissertation research demonstrates using preclinical rodent models of drug self-administration and craving that systemic exposure to the HIV protein gp120 produces a unique profile of neuroimmune changes within the nucleus accumbens core (NAc core) that is distinct from early cocaine abstinence alone. After a protracted period of abstinence, gp120 exposure abolished the effect of the dopamine D3 receptor (D3R) partial agonist MC-25-41, which successfully attenuated cue-induced cocaine seeking in non-exposed rats. Further probing the role of downstream, intracellular neuroimmune function on cue-induced cocaine seeking, I examined the role of the nuclear factor kappa B (NF-κB) signaling pathway within the NAc core on cue-induced cocaine seeking after a period of protracted abstinence across sex and reinforcer type. I demonstrated that knockdown of the p65 subunit of NF-κB results in a decrease in cue-induced cocaine seeking in males, but not in females. This effect was specific to cocaine, as p65 knockdown did not affect cue-induced sucrose seeking in either males or females. Moreover, I examined expression levels of the extracellular matrix enzyme MMP-9 within the NAc core, as it is regulated by NF-κB and is an important mediator of cue-induced cocaine seeking and associated synaptic plasticity. I demonstrated that males express higher levels of MMP-9 within the NAc compared to females, and that p65 knockdown decreases NAc core MMP-9 in males but not females among cocaine cue-exposed animals. Altogether, these results suggest that immunotherapeutic medications may be useful tools in the treatment of CUDs, particularly among males that are disproportionately impacted by HIV.
ContributorsNamba, Mark Douglas (Author) / Neisewander, Janet L (Thesis advisor) / Olive, M Foster (Thesis advisor) / Sanabria, Federico (Committee member) / Ferguson, Deveroux (Committee member) / Arizona State University (Publisher)
Created2022
Description
Substance use disorders (SUDs) are difficult to treat, in part because drug craving can be elicited by exposure to drug-associated environments and cues within the environment. Furthermore, this craving becomes more pronounced as abstinence progresses and it can take months to years for cue-elicited craving to finally wane. This important hallmark of addiction is modeled in rodents by exposing them to light/tone cues associated with the self-administration (SA) of cocaine. Cue exposure results in drug-seeking behavior, an animal analogue for drug craving. The overarching goal of this dissertation was to use the rodent SA model to explore the nucleus accumbens (NAc), a key brain region in the neural pathway of craving, and examine ribonucleic acid (RNA) expression that may underlie cocaine-seeking behavior. This includes messenger RNAs (mRNAs), which encode directly for proteins, and non-coding RNAs, which are important regulators of mRNA expression and cellular function. My first experiment aimed to identify non-coding microRNAs, which directly target and suppress mRNA expression, that are differentially expressed in animals with high or low cocaine-seeking behavior. In the second study, I compared RNA-sequencing (RNA-seq) datasets from rodent models of cocaine abstinence and developed a novel workflow to narrow candidate genes. In the final experiment, I utilized RNA-seq and reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) to identify and explore non-coding, circular RNAs that may influence gene regulatory networks and impact drug-seeking behavior. Overall, these studies promote our understanding of the neurogenetic mechanisms of craving and they suggest recommendations for improving the experimental design of future neurogenomic studies.
ContributorsVannan, Annika (Author) / Neisewander, Janet L (Thesis advisor) / Wilson, Melissa A (Thesis advisor) / Ferguson, Deveroux (Committee member) / Olive, Michael F (Committee member) / Perrone-Bizzozero, Nora I (Committee member) / Arizona State University (Publisher)
Created2022