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- All Subjects: Addiction
- All Subjects: Brain
- Creators: Neisewander, Janet
Description
Intermittent social defeat stress induces cross-sensitization to psychostimulants and escalation of drug self-administration. These behaviors could result from the stress-induced neuroadaptation in the mesocorticolimbic dopamine circuit. Brain-derived neurotrophic factor (BDNF) in the ventral tegmental area (VTA) is persistently elevated after social defeat stress, and may contribute to the stress-induced neuroadaptation in the mesocorticolimbic dopamine circuit. BDNF modulates synaptic plasticity, and facilitates stress- and drug-induced neuroadaptations in the mesocorticolimbic system. The present research examined the role of mesolimbic BDNF signaling in social defeat stress-induced cross-sensitization to psychostimulants and the escalation of cocaine self-administration in rats. We measured drug taking behavior with the acquisition, progressive ratio, and binge paradigms during self-administration. With BDNF overexpression in the ventral tegmental area (VTA), single social defeat stress-induced cross-sensitization to amphetamine (AMPH) was significantly potentiated. VTA-BDNF overexpression also facilitates acquisition of cocaine self-administration, and a positive correlation between the level of VTA BDNF and drug intake during 12 hour binge was observed. We also found significant increase of DeltaFosB expression in the nucleus accumbens (NAc), the projection area of the VTA, in rats received intra-VTA BDNF overexpression. We therefore examined whether BDNF signaling in the NAc is important for social defeat stress-induced cross-sensitization by knockdown of the receptor of BDNF (neurotrophin tyrosine kinase receptor type 2, TrkB) there. NAc TrkB knockdown prevented social defeat stress-induced cross-sensitization to psychostimulant. Also social defeat stress-induced increase of DeltaFosB in the NAc was prevented by TrkB knockdown. Several other factors up-regulated by stress, such as the GluA1 subunit of Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and BDNF in the VTA were also prevented. We conclude that BDNF signaling in the VTA increases social defeat stress-induced vulnerability to psychostimulants, manifested as potentiated cross-sensitization/sensitization to AMPH and escalation of cocaine self-administration. Also BDNF signaling in the NAc is necessary for the stress-induced neuroadaptation and behavioral sensitization to psychostimulants. Therefore, TrkB in the NAc could be a therapeutic target to prevent stress-induced vulnerability to drugs of abuse in the future. DeltaFosB in the NAc shell could be a neural substrate underlying persistent cross-sensitization and augmented cocaine self-administration induced by social defeat stress.
ContributorsWang, Junshi (Author) / Hammer, Ronald (Thesis advisor) / Feuerstein, Burt (Committee member) / Nikulina, Ella (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2013
Description
Food is an essential driver of animal behavior. For social organisms, the acquisition of food guides interactions with the environment and with group-mates. Studies have focused on how social individuals find and choose food sources, and share both food and information with group-mates. However, it is often not clear how experiences throughout an individual's life influence such interactions. The core question of this thesis is how individuals’ experience contributes to within-caste behavioral variation in a social group. I investigate the effects of individual history, including physical injury and food-related experience, on individuals' social food sharing behavior, responses to food-related stimuli, and the associated neural biogenic amine signaling pathways. I use the eusocial honey bee (Apis mellifera) system, one in which individuals exhibit a high degree of plasticity in responses to environmental stimuli and there is a richness of communicatory pathways for food-related information. Foraging exposes honey bees to aversive experiences such as predation, con-specific competition, and environmental toxins. I show that foraging experience changes individuals' response thresholds to sucrose, a main component of adults’ diets, depending on whether foraging conditions are benign or aversive. Bodily injury is demonstrated to reduce individuals' appetitive responses to new, potentially food-predictive odors. Aversive conditions also impact an individual's social food sharing behavior; mouth-to-mouse trophallaxis with particular groupmates is modulated by aversive foraging conditions both for foragers who directly experienced these conditions and non-foragers who were influenced via social contact with foragers. Although the mechanisms underlying these behavioral changes have yet to be resolved, my results implicate biogenic amine signaling pathways as a potential component. Serotonin and octopamine concentrations are shown to undergo long-term change due to distinct foraging experiences. My work serves to highlight the malleability of a social individual's food-related behavior, suggesting that environmental conditions shape how individuals respond to food and share information with group-mates. This thesis contributes to a deeper understanding of inter-individual variation in animal behavior.
ContributorsFinkelstein, Abigail (Author) / Amdam, Gro V (Thesis advisor) / Conrad, Cheryl (Committee member) / Smith, Brian (Committee member) / Neisewander, Janet (Committee member) / Bimonte-Nelson, Heather A. (Committee member) / Arizona State University (Publisher)
Created2017
Description
Approximately 2.8 million Americans seek medical care for traumatic brain injury (TBI) each year. Of this population, the majority are sufferers of diffuse TBI, or concussion. It is unknown how many more individuals decline to seek medical care following mild TBI. This likely sizeable population of un- or self-treated individuals combined with a lack of definitive biomarkers or objective post-injury diagnostics creates a unique need for practical therapies among diffuse TBI sufferers. Practical therapies stand to decrease the burden of TBI among those who would otherwise not seek treatment or do not meet clinical diagnostic criteria upon examination. For this unique treatment niche, practical therapies for TBI are defined as having one or more of the following qualities: common availability, easy administration, excellent safety profile, and cost-effectiveness. This dissertation identifies and critically examines the efficacy of four classes of practical treatments in improving rodent outcome from experimental diffuse traumatic brain injury.
Over-the-counter (OTC) analgesics, omega-3 fatty acids, specialized pro-resolving mediators (SPMs), and remote ischemic conditioning (RIC) were administered before or following midline fluid percussion injury. Behavioral, histological, and molecular analyses were used to assess treatment effects on functional outcome and secondary injury progression. Acute administration of common OTC analgesics had little effect on post-injury outcome in mice. Dietary supplementation with omega-3 fatty acid docosahexaenoic acid (DHA) prior to or following diffuse TBI significantly reduced injury-induced sensory sensitivity and markers of neuroinflammation with no effect on spatial learning. Intraperitoneal administration of omega-3 fatty acid-derived SPM resolvin E1 significantly increased post-injury sleep and suppressed microglial activation. Aspirin-triggered (AT) resolvin D1 administration improved both motor and cognitive outcome following diffuse TBI. RIC treatment in mice demonstrated little effect on functional outcome from diffuse TBI. Untargeted proteomic analysis of plasma samples from RIC-treated mice was used to identify candidate molecular correlates of RIC. Identification of these candidates represents a vital first step in elucidating the neuroprotective mechanisms underlying RIC. The overall findings suggest that omega-3 fatty acid supplementation, SPM administration, and RIC may serve as effective practical therapies to reduce the somatic, cognitive, and neurological burden of diffuse TBI felt by millions of Americans.
Over-the-counter (OTC) analgesics, omega-3 fatty acids, specialized pro-resolving mediators (SPMs), and remote ischemic conditioning (RIC) were administered before or following midline fluid percussion injury. Behavioral, histological, and molecular analyses were used to assess treatment effects on functional outcome and secondary injury progression. Acute administration of common OTC analgesics had little effect on post-injury outcome in mice. Dietary supplementation with omega-3 fatty acid docosahexaenoic acid (DHA) prior to or following diffuse TBI significantly reduced injury-induced sensory sensitivity and markers of neuroinflammation with no effect on spatial learning. Intraperitoneal administration of omega-3 fatty acid-derived SPM resolvin E1 significantly increased post-injury sleep and suppressed microglial activation. Aspirin-triggered (AT) resolvin D1 administration improved both motor and cognitive outcome following diffuse TBI. RIC treatment in mice demonstrated little effect on functional outcome from diffuse TBI. Untargeted proteomic analysis of plasma samples from RIC-treated mice was used to identify candidate molecular correlates of RIC. Identification of these candidates represents a vital first step in elucidating the neuroprotective mechanisms underlying RIC. The overall findings suggest that omega-3 fatty acid supplementation, SPM administration, and RIC may serve as effective practical therapies to reduce the somatic, cognitive, and neurological burden of diffuse TBI felt by millions of Americans.
ContributorsHarrison, Jordan L (Author) / Lifshitz, Jonathan (Thesis advisor) / Neisewander, Janet (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Willyerd, Frederick A (Committee member) / Pirrotte, Patrick (Committee member) / Arizona State University (Publisher)
Created2017
Description
Drug addiction is a pervasive problem in society, as it produces major increases in health care costs, crime, and loss of productivity. With over 3 million long-term users in America alone, cocaine is one of the most identifiable and addictive drugs. Cocaine produces major neurological changes in the central nervous system, including widespread changes in gene expression. MicroRNAs are small, non-coding transcripts that regulate gene expression post-transcriptionally by preventing translation into function protein. Given that one miRNA can target several genes simultaneously, they have the potential to attenuate drug-induced changes in gene expression. We previously found that the microRNA miR-495 regulates several addiction-related genes (ARGs) and is highly expressed in the nucleus accumbens (NAc), an important brain region involved in reward and motivation. Furthermore, acute cocaine decreases miR-495 expression and increases ARG expression in the NAc. Therefore, the aim of this thesis was to determine the effect of miR-495 overexpression in the NAc on cocaine self-administration behavior. Male Sprague Dawley rats were trained to lever press for cocaine and were then infused with a lentivirus into the NAc that either overexpressed green fluorescent protein (GFP, control) or miR-495+GFP. We then tested the rats on several doses of cocaine on both a fixed ratio (5) and progressive ratio (PR) schedule of reinforcement. We performed a follow-up experiment that included the same viral manipulation and testing, but the reinforcer was switched to food pellets. We found that NAc miR-495 overexpression reduces cocaine self-administration on a PR, but not an FR5, schedule of reinforcement. We found no effects of miR-495 overexpression on food reinforcement. These data suggest that NAc miR-495 regulates genes involved in motivation for cocaine, but not general motivation based on the data with food reinforcement. Future studies will seek to determine the specific target genes responsible for our behavioral effects.
ContributorsGalles, Nick (Author) / Neisewander, Janet (Thesis director) / Bastle, Ryan (Committee member) / Foster, M. (Committee member) / Barrett, The Honors College (Contributor)
Created2016-05
Description
Cocaine is a highly addictive psychostimulant that is widely used around the world. It is far more cost effective to curb this problem through treatment than by any other method as medicinal drug treatment is 15 times more effective than law enforcement at reducing the societal costs of cocaine use as determine by RAND corp. In a previous paper from our lab, it was found that via virally mediated introduction of additional 5-HT1B receptors into the nucleus accumbens there was a leftward shift in the cocaine intake dose-response curve in animals that were self-administering cocaine by pressing a lever. These findings suggest that 5-HT1B receptor action enhances the reinforcing effects of cocaine. However, when animals were given a 21-day period of prolonged abstinence and then tested for cocaine intake, it was determined that 5-HT1B receptor action had the opposite effect of decreasing cocaine intake presumably due to a decrease in the reinforcing effects of cocaine: [16]. The experiment in the current paper was devised to further test this finding via pharmacological means using the 5-HT1B agonist CP 94253 to increase stimulation of 5-HT1B receptors. Animals were trained to self-administer by pressing a lever on fixed ratio schedules of cocaine reinforcement given at 0.75 mg/kg and 0.075 mg/kg doses of cocaine. These doses allowed us to examine changes in self-administration on both the ascending and descending limbs of the inverted u-shaped cocaine dose-effect curve. Our results indicated that in animals given CP 94253 exhibited a decrease in responding on both the ascending and descending limbs of the dose response curve demonstrating a downward shift after prolonged abstinence. These exciting results suggest that the agonist decreases cocaine intake, and therefore, the agonist may be a useful treatment for cocaine dependence.
ContributorsYanamandra, Krishna Teja (Author) / Neisewander, Janet (Thesis director) / Goldstein, Elliott (Committee member) / Pentkowski, Nathan (Committee member) / Barrett, The Honors College (Contributor)
Created2013-05
Description
Substance abuse disorders affect 15.3 million people worldwide. The field has primarily focused on dopaminergic drugs as treatments for substance use disorders. However, recent work has demonstrated the potential of serotonergic compounds to treat substance abuse. Specifically, the serotonin 1B receptor (5-HT1BR), a Gi-coupled receptor located throughout the mesocorticolimbic dopamine system, has been implicated in the incentive motivational and rewarding effects of cocaine. Our research suggests that the stimulation of 5-HT1BRs produces different effects at various time points in the addiction cycle. During maintenance of chronic cocaine administration, 5-HT1BR stimulation has a facilitative effect on the reinforcing properties of cocaine. However 5-HT1BR stimulation exhibits inhibitory effects on reinforcement during prolonged abstinence from cocaine. The aim of this study was to examine the possibility of a switch in the functional role of 5-HT1BRs in the locomotor effects of cocaine at different time points of chronic cocaine administration in mice. We found that the 5-HT1BR agonist CP 94,253 increased locomotor activity in mice tested one day after the last chronic cocaine administration session regardless of whether the chronic treatment was cocaine or saline and regardless of challenge injection (i.e., cocaine or saline). Yet after abstinence, CP 94,253 induced a decrease in locomotor activity in mice challenged with saline and attenuated cocaine-induced locomotion relative to cocaine challenge after vehicle pretreatment. These findings suggest that a switch in the functional role of 5-HT1BR is observed at different stages of the addiction cycle and further suggest that clinical applications of drugs acting on 5-HT1BR should consider these effects.
ContributorsBrunwasser, Samuel Joshua (Author) / Neisewander, Janet (Thesis director) / Pentkowski, Nathan (Committee member) / Der-Ghazarian, Taleen (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / Department of Psychology (Contributor)
Created2014-05
Description
The serotonin (5-hydroxytryptamine, 5-HT) system is implicated in the study of drug addiction. Of the 14 known serotonin receptor subtypes, the 5-HT7R is the most recently discovered and, therefore, one of the least rigorously studied. However, the 5-HT7R has been shown to play a role in multiple psychiatric conditions, including depression, anxiety, and alcoholism. This is not surprising, as the 5-HT7R is expressed in brain regions associated with emotion and reward, such as the amygdala, dorsal raphe nucleus, and striatum. MC-RG19 is a novel 5-HT7R antagonist which has >114-fold selectivity for the 5-HT7 over other serotonin receptors. This compound was developed by our collaborators at the Temple University School of Pharmacy. Due to this specificity, and the implications of the 5-HT7 in behavior, we hypothesized that MC-RG19 would have an effect on addiction-related behaviors. We investigated the effects of MC-RG19 on spontaneous locomotion, cue-induced reinstatement, and cocaine/sucrose multiple schedule self-administration. We observed a dose-dependent decrease in spontaneous locomotor activity with significance at a MC-RG19 dose of 10 mg/kg. A dose of 5.6 mg/kg, which did not significantly decrease locomotion, significantly reduces cocaine-seeking behavior (active lever pressing) in response to the reintroduction of drug-paired cues after a period of extinction. No dose (3, 5.6, or 10 mg/kg) produced a significant effect on a multiple schedule of self-administration with alternating availability of sucrose and cocaine as the reinforcer. These results indicate that MC-RG19 has an effect on the incentive \u2014 motivational properties of reward-paired cues.
ContributorsCarlson, Andrew Kenneth (Author) / Neisewander, Janet (Thesis director) / Gipson-Reichardt, Cassandra (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Abstract White matter thickness correlates with various mental illness. Commissure white matter tracts are responsible for interconnecting the same cortical area in both hemispheres. Injury to the brain can result in thinning and shrinkage even collapsing and detachment of the white matter tracts' myelin sheaths. Injury can affect cognitive function and time points are essential for therapeutic intervention. Research is beginning to identify gradual long-term neurodegenerative effects. With the advancement of brain imaging technology, we know that Wallerian degeneration has a significant negative impact on the white matter tracts throughout the brain (Johnson, Stewart, & Smith, 2013). If major tracts become injured like, the corpus callosum, then it can affect interhemispheric communication. Once myelin is damaged the axon becomes vulnerable, and the mechanisms of nerve recovery are not well known. Myelin sheath recovery has been studied in hopes to proliferate the oligodendrocytes that make up for the atrophied myelin. Neurotoxic chemicals released at activation of macrophages which hinders the brains ability to proliferate myelin protein needed for myelin differentiation adequately. In the central nervous system myelin has mechanisms to recover. Neurogenesis is a naturally occurring recovery mechanism seen after brain injury. Understanding the time points in which brain recovery occurs is important for treatment of diffuse injuries that cannot be identified through some imaging techniques. To better understand critical timepoints of natural recovery after brain injury can allow further investigation for early intervention to promote adequate recovery.
ContributorsLiptow, Kristen Ashley (Author) / Neisewander, Janet (Thesis director) / Law, L. Matthew (Committee member) / School of Social and Behavioral Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-12
Description
Abstract Cocaine is highly addictive because it exacerbates the action responsible for creating the feeling of "reward," which is controlled by the neurotransmitter dopamine. Dopamine receptors can be divided into five subtypes: D1, D2, D3, D4, and D5. The localization of D3 receptors is restricted to the mesolimbic pathway, which is often called the "reward pathway." This pathway is associated with emotions, motivation, and behavior. There is evidence that these receptors are upregulated in response to the repeated use of psychostimulants, such as cocaine, making these receptors a potential target for pharmaceutical therapeutics for drug addiction. In the present study, two compounds selective for D3 receptors, MC-250041 and LS-3-134, were examined for their effects on spontaneous and cocaine-primed locomotor activity. The present study also aimed to examine the effects of MC-250041 and LS-3-134 on the number of lever presses and infusions under a progressive ratio (PR) schedule when subjects are trained to self-administer cocaine within an operant conditioning chamber. Based on the present research on D3 receptor compounds and D3Rs, I hypothesized that pretreatment with MC-250041 or LS-3-134 decreases cocaine self-administration under a progressive ratio (PR) schedule of cocaine reinforcement at doses that would have no effect on locomotor activity. The results showed no significant effects on spontaneous or cocaine-primed locomotor activity following an injection of MC-250041 (1, 3, 5.6 mg/kg IP). Similarly, there was no change in the amount of lever presses or drug infusions within an operant conditioning chamber at any of the examined doses of MC-250041 (3, 5.6, 10 mg/kg IP) during self-administration. LS-3-134 decreased cocaine-primed locomotor activity, as well as lever presses and infusions during self-administration at the 5.6 mg/kg dose; however, there was no effect on spontaneous locomotor activity at any of the examined doses (1, 3.2, 5.6 mg/kg IP). In conclusion, the results of the study suggest that LS-3-134 effectively reduced motivation for cocaine at the 5.6 mg/kg dose; whereas, MC-250041 was unsuccessful at warranting any significant effect on motivation for cocaine at any of the examined doses.
ContributorsMendoza, Rachel Ann (Author) / Neisewander, Janet (Thesis director) / Olive, Foster (Committee member) / Powell, Greg (Committee member) / School of Social Transformation (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
Description
Serotonin 1B receptors (5-HT1BRs) are a novel target for developing pharmacological therapies to reduce psychostimulant craving. 5-HT1BRs are expressed in the mesolimbic pathway projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), which is involved in reward and motivation. 5-HT1BR agonists modulate both cocaine- and methamphetamine-seeking behaviors in rat models of psychostimulant craving. In this dissertation, I tested the central hypothesis that 5-HT1BRs regulate cocaine and methamphetamine stimulant and rewarding effects in mice. I injected mice daily with cocaine for 20 days and then tested them 20 days after their last injection. The results showed that the 5-HT1BR agonist CP94253 attenuated sensitization of cocaine-induced locomotion and cocaine-seeking behavior, measured as a decrease in the ability of a cocaine priming injection to reinstate extinguished cocaine-conditioned place preference (CPP). Subsequent experiments showed that CP94253 given prior to conditioning sessions had no effect on acquisition of methamphetamine-CPP, a measure of drug reward; however, CP94253 given prior to testing attenuated expression of methamphetamine-CPP, a measure of drug seeking. To examine brain regions and cell types involved in CP94253 attenuation of methamphetamine-seeking, I examined changes in the immediate early gene product, Fos, which is a marker of brain activity involving gene transcription changes. Mice expressing methamphetamine-CPP showed elevated Fos expression in the VTA and basolateral amygdala (BlA), and reduced Fos in the central nucleus of the amygdala (CeA). In mice showing CP94253-induced attenuation of methamphetamine-CPP expression, Fos was increased in the VTA, NAc shell and core, and the dorsal medial caudate-putamen. CP94253 also reversed the methamphetamine-conditioned decrease in Fos expression in the CeA and the increase in the BlA. In drug-naïve, non-conditioned control mice, CP94253 only increased Fos in the CeA, suggesting that the increases observed in methamphetamine-conditioned mice were due to conditioning rather than an unconditioned effect of CP94253 on Fos expression. In conclusion, 5-HT1BR stimulation attenuates both cocaine and methamphetamine seeking in mice, and that the latter effect may involve normalizing activity in the amygdala and increasing activity in the mesolimbic pathway. These findings further support the potential efficacy of 5-HT1BR agonists as pharmacological interventions for psychostimulant craving in humans.
ContributorsDer-Ghazarian, Taleen (Author) / Neisewander, Janet (Thesis advisor) / Olive, Foster (Committee member) / Newbern, Jason (Committee member) / Wu, Jie (Committee member) / Arizona State University (Publisher)
Created2018