Matching Items (7)
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- All Subjects: Cocaine
- Creators: Neisewander, Janet
- Member of: Barrett, The Honors College Thesis/Creative Project Collection
- Resource Type: Text
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
MicroRNAs are small, non-coding transcripts that control gene expression by preventing mRNA from translating into proteins. They have been implicated to play a role in many drug addictions. We previously found that miR-495 targets several addiction-related genes (ARGs) and is highly expressed in the nucleus accumbens (NAc). We also found miR-495 is downregulated in the NAc following acute cocaine administration, and cocaine motivation measured by breakpoint on a progressive ratio schedule of cocaine reinforcement is decreased when miR-495 is overexpressed. In this study, we manipulated the endogenous levels of miR-495 by using a viral vector. Using an animal model, rats were first trained for self-administration on a fixed ratio (FR) schedule of reinforcement. After they were infused with a lentivirus to overexpress (LV-miR-495) or decrease (LV-Sponge) miR-495, in the NAc shell. The rats were then tested for extinction and reinstatement of cocaine-seeking behavior, which are measures of motivation for cocaine. We measured the relative levels of miR-495 in the NAc shell using qRT-PCR. Our results show that overexpression of miR-495 decreased cocaine-seeking behavior during extinction and cocaine reinstatement, as we hypothesized. Surprisingly, miR-495 LV-sponge also decreased cocaine-seeking behavior in extinction, not as we hypothesized. However, we found that LV-Sponge failed to significantly decrease levels of miR-495 as intended. In conclusion, understanding why LV-Sponge decreased, rather than increased, miR-495 will need further study, however, the results with LV-miR-495 extend previous findings that miR-495 plays a vital role in the molecular mechanism that influences motivation to seek cocaine.
ContributorsChaudhury, Trisha (Author) / Neisewander, Janet (Thesis director) / Newbern, Jason (Committee member) / Powell, Gregory (Committee member) / Department of Psychology (Contributor) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
Description
Nicotine use is an outstanding public health problem with associated social and economic consequences. Nicotine is an active alkaloid compound in tobacco and is recognized as a psychoactive drug. Preclinically, nicotine addiction and relapse can be modeled using a self-administration-reinstatement paradigm. Here, we used a nicotine self-administration and contingent cue-induced reinstatement model to examine rapid, transient synaptic plasticity (t-SP) induced by nicotine cue-triggered motivation. Although preliminary, treatment with the NMDA GluN2B subunit antagonist, ifenprodil, reduced reinstated nicotine seeking, and increased the percentage of spines with smaller head diameters. Thus, future studies are needed to fully parse out the role of NAcore GluN2B receptors in cued nicotine seeking and t-SP.
ContributorsMccallum, Joseph John (Author) / Gipson-Reichardt, Cassandra (Thesis director) / Neisewander, Janet (Committee member) / Olive, Michael Foster (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
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 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
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
The epidemic of drug addiction continues to grow at an alarming rate and cocaine-related overdoses have increased by more than 33% over the last decade. Cocaine targets the mesolimbic reward system in the brain to produce the “high” felt when taking cocaine. There is currently no single cure for psychostimulant abuse, but researchers continue to find viable therapeutic options. Dopamine receptors have been a recent target for researchers. We tested a novel D3R-antagonist, SWR-5, with 905-fold D3/D2 selectivity, on addiction using a rat self- administration model and hypothesized that it would reduce motivation for cocaine. SWR-5 significantly reduced cocaine intake on a high-effort PR schedule at a dose of 10 mg/kg but did not affect sucrose intake. Also, SWR-5 did not affect either spontaneous or cocaine-induced locomotion. From our results, we concluded that SWR-5 affects motivation for cocaine, not sucrose, and does not produce adverse locomotor effects. Further research would include taking a behavioral economics approach to determine the cost/benefit ratio of taking the drug, as well as performing cue reinstatement tests to solidify whether SWR-5 plays a role in cocaine-seeking behavior.
ContributorsMokbel, Ayleen Marie Halim (Co-author) / Neisewander, Janet (Thesis director) / Sanabria, Federico (Committee member) / Vannan, Annika (Committee member) / School of International Letters and Cultures (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05