Electronic Theses and Dissertations

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Browsing Electronic Theses and Dissertations by Subject "5-HT2A receptor"

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    Individual sensitivity to novelty and (+)-3,4-methylenedioxymethamphetamine: Roles for serotonin and GABA neurotransmission
    (2005-01-27) Julie Danielle Ross; Kathryn A. Cunningham; Thomas A. Kent; Terry E. Robinson; Mary L. Thomas; Cheryl S. Watson
    Drug addiction continues to be a problem in our society, and better understanding of the neuroanatomical and neurochemical alterations that delineate the switch between causal drug use and compulsive drug addiction is needed. Characterizing what makes one individual more vulnerable to the development of compulsive drug-taking behaviors may hold the key to this complex phenomenon. Because individual differences in humans exist to the subjective effects of 3,4-methylenedioxymethamphetamine (MDMA) and these differences are rooted, in part, in individual sensitivity to the drug effects, we utilized two animal models of increased sensitivity in the current studies. First, in a sensitization animal model we examined the mechanisms of increased sensitivity to (+)-MDMA and found a critical role for serotonin (5-HT) neurotransmission, in particular the 5-HT2A receptor (5-HT2AR) in the nucleus accumbens (NAc) and prefrontal cortex (PFC). We then carried this finding into a model of individual difference in which animals are separated based on their differential locomotor response to a novel environment into high responder rats (HR) and low responder rats (LR). In addition to an increased sensitivity to (+)-MDMA, we uncovered basal differences in the 5-HT system between HR and LR rats, an increased level of expression of the 5-HT2AR in the NAc of HR rats in particular. Additionally, we examined the brain structures activated secondary to novelty in HR vs. LR rats and the phenotype-specific behavioral changes after repeated exposure to the environment. Our findings revealed a strong influence of GABA neurotransmission that may underlie the differences between HR vs. LR behavioral phenotypes. These findings lend support to the idea that the neural systems underlying drug-induced and stress-induced behaviors overlap and may help to understand how individual sensitivity to both (+)-MDMA and novelty may confer an increased vulnerability to the development of compulsive drug-taking behavior.
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    Profiling the Serotonin2 Receptor System Functional Capacity: Towards Identification of a Cocaine Use Disorder Biosignature
    (2020-05-01T05:00:00.000Z) Land, Michelle Ann
    Vulnerability to developing a cocaine use disorder (CUD) starts with a background of genetics and environment and results in changes in neuroplasticity that leads to a greater drive to take cocaine. The intricate interplay between these variables differs for each individual, presenting a barrier to understanding the origin of the disorder as well as the development of treatments. Characterization of a CUD biosignature through the use of defining biological markers will greatly improve our ability to predict patient response, disease risk, accurate CUD diagnosis and potentially even identify novel targets for medications development, all the while moving CUD treatment towards an age of precision medicine. The cycling progressive nature of CUD stymies efforts to stay abstinent with vulnerability to abuse and relapse during abstinence often precipitated by impulsive behavior. The loss of impulse control has been particularly noted in cocaine-dependent subjects who also express high reactivity to cocaine-associated cues (“cue reactivity”) suggesting that impulsivity and cue reactivity are interlocked contributors to relapse, a cardinal facet of addiction. Serotonin (5-HT) neurotransmission through the 5-HT2C receptor (5-HT2CR) and 5-HT2A receptor (5-HT2AR) within the central nervous system is a critical driver of the cognitive and/or behavioral dimensions underlying impulsivity and cue reactivity. Characterization of how these receptors are regulated or altered by genetic and epigenetic means will lead to the identification of a 5-HT2R-mediate biosignature for CUD. To bridge this gap in knowledge, we first investigated the functional effects of a single nucleotide polymorphism (SNP) of the 5-HT2CR that converts a cysteine (Cys) to a serine (Ser) at amino acid codon 23 in the N-terminal extracellular domain (Cys23Ser; rs6318). We established that the Cys23Ser SNP dramatically reduces efficacy of 5-HT at the 5-HT2CR with a decrease in potency as a result of reduced plasma membrane expression from altered localization through the secretory and recycling pathway. We also demonstrate in vivo, that overexpressing the human Ser23 5-HT2CR in the medial prefrontal cortex, a key region implicated in relapse-like behaviors, of rodents exhibit dampened cocaine-seeking behavior accompanied by greater plasma membrane expression of the 5-HT2CR versus rodents expressing the Cys23 5-HT2CR. Finally, we characterized methylation patterns of the HTR2A, 5-HT2AR human gene, promoter that correlated with relapse-related behavior in cocaine-dependent participants. Taken together, we have identified genetic and epigenetic makers of the 5-HT2R system with great potential to define a high-risk relapse biosignature of CUD.
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    Strategies to Identify Therapeutic Opportunities in the Treatment of Addictive Disorders
    Price, Amanda Elizabeth
    Addictive disorders are a collection of maladaptive behaviors characterized by the uncontrolled use of a rewarding substance. These include substance use disorders, binge eating disorder, certain subtypes of obesity, gambling disorder, and internet gaming disorder. Each of these disorders share similar behavioral characteristics that may be motivated by common neural substrates and molecular mechanisms. This dissertation aims to elucidate some of the drivers of addictive behaviors and proposes four strategies to identify therapeutic opportunities in the treatment of addictive disorders, with a special emphasis on binge eating disorder. The current work demonstrates an association between high fat food binge intake and cue reactivity, both of which are modulated by insula activity. Further, the clinically-approved serotonin (5-HT) 5-HT2A receptor (5-HT2AR) antagonist/inverse agonist pimavanserin and 5-HT2CR agonist lorcaserin used alone or in combination demonstrate efficacy in suppressing measures of binge eating. Pharmacological studies further show that activation of the 5-HT2CR may suppress binge eating by decreasing the reinforcing and motivational properties of high fat food. Finally, a possible role for a 5-HT2AR:5-HT2CR protein interaction in the protection against addictive behaviors is proposed. This dissertation concludes by discussing possible routes of implementation of the present findings into clinical practice. The strategies discussed – neuronal modulation, behavioral-guided therapy, drug repurposing, and combined therapeutic approaches – offer great possibilities in the development of new therapeutic approaches in the treatment of addictive disorders.