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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
Globally, addiction to stimulants such as methamphetamine (METH) remains a significant public health problem. Despite decades of research, no approved anti-relapse medications for METH or any illicit stimulant exist, and current treatment approaches suffer from high relapse rates. Recently, synthetic cathinones have also emerged as popular abused stimulants, leading to numerous incidences of toxicity and death. However, contrary to traditional illicit stimulants, very little is known about their addiction potential. Given the high relapse rates and lack of approved medications for METH addiction, chapters 2 and 3 of this dissertation assessed three different glutamate receptor ligands as potential anti-relapse medications following METH intravenous self-administration (IVSA) in rats. In chapters 4 through 7, using both IVSA and intracranial self-stimulation (ICSS) procedures, experiments assessed abuse liability of the popular synthetic cathinones 3,4-Methylenedioxypyrovalerone (MDPV) , methylone, α-pyrrolidinovalerophenone (α-PVP) and 4-methylethylcathinone (4-MEC). Results from these seminal studies suggest that these drugs possess similar abuse potential to traditional illicit stimulants such as METH, cocaine, and 3,4-methylenedioxymethamphetamine (MDMA). Finally, studies outlined in chapter 8 assessed the potential neurotoxic or adverse cognitive effects of METH and MDPV following IVSA procedures for the purpose of identifying potential novel pharmacotherapeutic targets. However, results of these final studies did not reveal neurotoxic or adverse cognitive effects when using similar IVSA procedural parameters that were sufficient for establishing addiction potential, suggesting that these parameters do not allow for sufficient drug intake to produce similar neurotoxicity or cognitive deficits reported in humans. Thus, these models may be inadequate for fully modeling the adverse neural and psychological consequences of stimulant addiction. Together, these studies support the notion for continued research into the abuse liability and toxicity of METH and synthetic cathinones and suggest that refinements to traditional IVSA models are needed for both more effective assessment of potential cognitive and neural deficits induced by these drugs and screening of potentially clinically efficacious pharmacotherapeutics.
ContributorsWatterson, Lucas (Author) / Olive, Michael F (Thesis advisor) / Czyzyk, Traci (Committee member) / Neisewander, Janet (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2014
Description
ABSTRACT
Auditory hallucinations are a characteristic symptom of schizophrenia. Research has documented that the auditory cortex is metabolically activated when this process occurs, and that imbalances in the dopaminergic transmission in the striatum contribute to its physiopathology. Most animal models have focused the effort on pharmacological approaches like non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists to produce activation of the auditory cortex, or dopamine antagonists to alleviate it. I hypothesize that these perceptual phenomena can be explained by an imbalance activation of spiny projecting neurons in the striatal pathways, whereby supersensitive postsynaptic D2-like receptor, signaling in the posterior caudatoputamen generates activation of the auditory cortex. Therefore, I characterized the neuroanatomical component involved in the activation of the auditory cortex. I evaluated the participation of dopamine D2-like receptor using selective dopamine antagonist manipulations and identified the circuits related to the auditory cortex by retrograde trans-synaptic tracing using pseudorabies virus (PRV-152). My results show that dopamine infused in the posterior caudatoputamen dose dependently increases the transcription of the immediate early gene, zif268 in the auditory cortex, predominantly in layers III and IV, but also in cortical columns, suggesting enhanced functional auditory activity. This indicates the participation of the posterior striatum in the modulation of the secondary auditory cortex. I was able to demonstrate also that a coinfusion of a selective dopamine D2-like receptor antagonist, eticlopride and dopamine, attenuate the activation of the auditory cortex. Furthermore, using PRV-152 I delineate the distinctive circuit by axial mapping of the infected neurons. Thus, I found secondary projections from the posterior caudatoputamen that synapse in the thalamus before reaching the auditory cortex. These striatal projections correspond to the same brain region affected by dopamine during auditory cortical activation. My results further characterized a mechanism to generate intrinsic perception of sound that may be responsible for auditory hallucinations. I propose this paradigm may elucidate insight on the biological basis of psychotic behavior.
Auditory hallucinations are a characteristic symptom of schizophrenia. Research has documented that the auditory cortex is metabolically activated when this process occurs, and that imbalances in the dopaminergic transmission in the striatum contribute to its physiopathology. Most animal models have focused the effort on pharmacological approaches like non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists to produce activation of the auditory cortex, or dopamine antagonists to alleviate it. I hypothesize that these perceptual phenomena can be explained by an imbalance activation of spiny projecting neurons in the striatal pathways, whereby supersensitive postsynaptic D2-like receptor, signaling in the posterior caudatoputamen generates activation of the auditory cortex. Therefore, I characterized the neuroanatomical component involved in the activation of the auditory cortex. I evaluated the participation of dopamine D2-like receptor using selective dopamine antagonist manipulations and identified the circuits related to the auditory cortex by retrograde trans-synaptic tracing using pseudorabies virus (PRV-152). My results show that dopamine infused in the posterior caudatoputamen dose dependently increases the transcription of the immediate early gene, zif268 in the auditory cortex, predominantly in layers III and IV, but also in cortical columns, suggesting enhanced functional auditory activity. This indicates the participation of the posterior striatum in the modulation of the secondary auditory cortex. I was able to demonstrate also that a coinfusion of a selective dopamine D2-like receptor antagonist, eticlopride and dopamine, attenuate the activation of the auditory cortex. Furthermore, using PRV-152 I delineate the distinctive circuit by axial mapping of the infected neurons. Thus, I found secondary projections from the posterior caudatoputamen that synapse in the thalamus before reaching the auditory cortex. These striatal projections correspond to the same brain region affected by dopamine during auditory cortical activation. My results further characterized a mechanism to generate intrinsic perception of sound that may be responsible for auditory hallucinations. I propose this paradigm may elucidate insight on the biological basis of psychotic behavior.
ContributorsParga Becerra, Alejandro (Author) / Neisewander, Janet (Thesis advisor) / Hammer, Ronald (Thesis advisor) / Gallitano-Mendel, Amelia (Committee member) / McLoone, Jim (Committee member) / Vu, Jie (Committee member) / Arizona State University (Publisher)
Created2014
Description
Cocaine is a powerful psychomotor stimulant that can affect serotonin (5HT), dopamine, and norepinephrine systems in the brain. Previous studies with 5HT1B receptor agonist, CP94253, have shown dose-dependent decreases in cocaine-self administration in male rats during maintenance. However, these studies do not take into consideration sex differences between male rats and female rats. Female rats introduce a new complexity because they constantly undergo an estrous cycle that consists of four phases, metestrus, diestrus, proestrus, and estrus. It was hypothesized that cocaine infusions and active lever response rates would greatly decrease during proestrus and estrus in comparison to metestrus and diestrus due to hormonal level differences of LH, FSH, progesterone, and estradiol. In this study, female rats were trained to self-administer a training dose of 0.75 mg/kg/infusion on a fixed progressive ratio (FR5). Rats were then pretreated with CP94253 to test the effects of this 5HT1B agonist on female rat cocaine self-administration during the estrous cycle. Results showed there was no three-way interaction between cycle phase, pretreatment, and cocaine dose on infusions or active lever responses. However, pretreatment with CP94253 decreased cocaine intake and active lever responses at high cocaine doses, regardless of cycle phase. Lastly, there was a two-way interaction between pretreatment and cycle phase in which active lever responses decreased during diestrus and proestrus. These results imply that CP94253 enhances cocaine's effect regardless of cycle phase. Future work can work with ovariectomized (OVX) female rats to observe cocaine self-administration during controlled cycle phases.
ContributorsNguyen, Toan Thai Tran (Author) / Neisewander, Janet (Thesis director) / Gipson-Reichardt, Cassandra (Committee member) / Scott, Samantha (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
ContributorsChandler, N. Kayla (Author) / Neisewander, Janet (Thesis director) / Sanabria, Federico (Committee member) / Olive, M. Foster (Committee member) / Barrett, The Honors College (Contributor) / College of Liberal Arts and Sciences (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
Within the field of psychopharmacology, there has been difficultly with studying the functional effects of dopamine at the D2 receptor apart from other dopamine receptors due to the lack of drugs that are selective for the D2 receptor. The purpose of this study was to observe the motivational and locomotor effects of using three varying doses (1.0, 3.0, and 5.6 mg/kg) of a new, highly selective D2 antagonist, SV293. These doses were tested across five different conditions that explore the effects of controls, SV293 by itself, and in combination with cocaine. These tests are designed to separately assess the effects of the antagonist between drug-seeking behaviors and locomotor activity. The cue tests showed that SV293 reduced drug-seeking and increased response latency at the high dose, suggesting a decrease in motivational effects of cocaine-related cues. SV293 alone also reduced drug-seeking and increased response latency at the high dose, suggesting a decrease in motivation for cocaine. Cocaine in combination with SV293 did not produce any significant effects on drug-seeking behavior, suggesting that SV293 did not alter the motivational effects of cocaine itself. Spontaneous locomotor activity tests with SV293 alone showed no reduction in locomotor activity; however, the addition of cocaine showed a significant decrease in locomotor activity at the high dose of SV293. Overall, the 5.6 mg/kg dose of SV293 decreases drug-seeking behavior elicited by cocaine-related cues and environmental stimuli, as well as cocaine-induced locomotor activity. This selective D2 antagonism could ultimately help elucidate the mechanisms of other dopamine receptors with particular emphasis on their involvement with drug addiction. Key words: cocaine, SV293, D2, antagonists, dopamine
ContributorsLynn, Jeffrey Spencer (Author) / Neisewander, Janet (Thesis director) / Orchinik, Miles (Committee member) / Bastle, Ryan (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (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
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