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Sex Differences in the Addiction-Like Properties of Ketamine.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Sex Differences in the Addiction-Like Properties of Ketamine./
Author:	Wright, Katherine Nicole.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2017,
Description:	121 p.
Notes:	Source: Dissertations Abstracts International, Volume: 79-09, Section: B.
Contained By:	Dissertations Abstracts International79-09B.
Subject:	Biology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10690347
ISBN:	9780355618877

Sex Differences in the Addiction-Like Properties of Ketamine.
Wright, Katherine Nicole.

Sex Differences in the Addiction-Like Properties of Ketamine. - Ann Arbor : ProQuest Dissertations & Theses, 2017 - 121 p.

Source: Dissertations Abstracts International, Volume: 79-09, Section: B.

Thesis (Ph.D.)--The Florida State University, 2017.

.

Depression is a devastating disease that is the leading cause of disability worldwide. One reason for its massive disease burden is that classical antidepressants require several weeks of administration to take effect, and they are only effective in roughly half of patients. Ketamine, previously known as primarily a veterinary anesthetic, rapidly alleviates treatment-resistant depressive symptoms at sub-anesthetic doses. Indeed, a single intravenous (i.v.) infusion of ketamine elicits an antidepressant effect within 2 hours and can last up to 2 weeks. Furthermore, this therapeutic effect of ketamine can be prolonged with repeated intermittent treatments. However, there are still many unanswered questions regarding ketamine's safety, especially with respects to the long-term effects of prolonged, repeated exposure. Since ketamine is also a popular club drug with addictive properties, it is critical to characterize the safety and abuse liability of this drug. We sought to determine if intermittent self-administration of ketamine in rats can trigger drug-seeking behavior, at a dose that is close to the therapeutic human dose, and if the stage of the four-day estrous cycle can influence this behavior, as antidepressant-like effects of ketamine in females depends on estrous cycle stage. To that end, rats were trained to self-administer ketamine in an operant chamber once every fourth day for males, while females' self- administration sessions coincided with either diestrus 1, or proestrus. Ketamine intake in diestrus-trained females rapidly declined, while proestrus-trained females and males were stable across the acquisition phase of the experiment. After extinction training, proestrus-trained females and males displayed reinstated ketamine-seeking behavior when re-exposed to discrete cues that were previously paired to ketamine availability. Interestingly, a ketamine priming injection in the absence of cues did not reinstate ketamine-seeking behavior as is consistently seen with a priming injection of cocaine, a drug with very high abuse potential. Together, this indicates not only that ketamine-paired cues are more salient precipitators of relapse than the pharmacological effects of ketamine on its own, but also that the stage of estrous cycle associated with high levels of gonadal hormones supports female's ketamine intake and subsequent ketamine relapse. To address comorbid depression and ketamine addiction, we assessed ketamine addictive- like behaviors in males and females previously exposed to unpredictable chronic mild stress (CMS), a procedure shown to induce a depressive-like phenotype in rodents. They were treated with four intermittent therapeutic i.v. ketamine infusions, designed to mimic infusion protocols used in clinics. They were then given access to self-administer 0.5 mg/kg/infusion ketamine and tested for their motivation to obtain ketamine using progressive ratio schedule (PR) and persistence of incubated ketamine craving after a period of forced abstinence, which is a major factor in the precipitation of relapse. CMS decreased sucrose intake in both sexes, but ketamine had no effect on anhedonia like-behaviors. Ketamine treatment reduced anxiety-induced neophagia, measured by the novelty-suppressed feeding test, suggesting that i.v. ketamine's antidepressant-like effects may be symptom- and species-specific. While prior ketamine exposure and CMS had no effect on subsequent ketamine addiction-like behavior in males, females that underwent CMS displayed more addiction-like behavior than non-stressed females, suggesting that chronic stress can increase the risk for ketamine abuse in females. Additionally, ketamine pre-exposed females displayed lower ketamine intake, with no alterations in motivated responding or craving. Finally, dendritic spine density and morphology was assessed in the nucleus accumbens (NAc), the central processor for rewarding stimuli that is affected by both depression and addiction. Females with prior ketamine exposure regardless of stress condition had an increase in spine density that was primarily driven by the formation of immature thin spines; there were no changes in males. Together this suggests that although ketamine pre-treatment may alter NAc plasticity in a sex-dependent manner, it does not potentiate ketamine addiction-like behavior. Taken together, this work demonstrates that although ketamine and drug-paired cues have strong reinforcing effects, prior exposure to therapeutic ketamine infusions do not increase the risk of abuse. Estrous cycle stage and prior exposure to chronic stress influences the reinforcing properties of ketamine in females, suggesting an influence of ovarian hormones. The fact that ketamine-seeking behavior was dependent on the drug-paired cues rather than the acute pharmacological effects of ketamine, and that prior therapeutic ketamine did not increase the subsequent development of addiction-like behavior, suggests that there may be little overlap in ketamine's antidepressant effects and addictive effects. It is possible that ketamine, if administered under the appropriate conditions, may have limited abuse potential, but research is necessary to determine if these sex-specific effects in rats translate to humans. (Abstract shortened by ProQuest.).

ISBN: 9780355618877Subjects--Topical Terms:

522710
Biology.
Subjects--Index Terms:

Addiction

Sex Differences in the Addiction-Like Properties of Ketamine.
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We sought to determine if intermittent self-administration of ketamine in rats can trigger drug-seeking behavior, at a dose that is close to the therapeutic human dose, and if the stage of the four-day estrous cycle can influence this behavior, as antidepressant-like effects of ketamine in females depends on estrous cycle stage. To that end, rats were trained to self-administer ketamine in an operant chamber once every fourth day for males, while females' self- administration sessions coincided with either diestrus 1, or proestrus. Ketamine intake in diestrus-trained females rapidly declined, while proestrus-trained females and males were stable across the acquisition phase of the experiment. After extinction training, proestrus-trained females and males displayed reinstated ketamine-seeking behavior when re-exposed to discrete cues that were previously paired to ketamine availability. Interestingly, a ketamine priming injection in the absence of cues did not reinstate ketamine-seeking behavior as is consistently seen with a priming injection of cocaine, a drug with very high abuse potential. Together, this indicates not only that ketamine-paired cues are more salient precipitators of relapse than the pharmacological effects of ketamine on its own, but also that the stage of estrous cycle associated with high levels of gonadal hormones supports female's ketamine intake and subsequent ketamine relapse. To address comorbid depression and ketamine addiction, we assessed ketamine addictive- like behaviors in males and females previously exposed to unpredictable chronic mild stress (CMS), a procedure shown to induce a depressive-like phenotype in rodents. They were treated with four intermittent therapeutic i.v. ketamine infusions, designed to mimic infusion protocols used in clinics. They were then given access to self-administer 0.5 mg/kg/infusion ketamine and tested for their motivation to obtain ketamine using progressive ratio schedule (PR) and persistence of incubated ketamine craving after a period of forced abstinence, which is a major factor in the precipitation of relapse. CMS decreased sucrose intake in both sexes, but ketamine had no effect on anhedonia like-behaviors. Ketamine treatment reduced anxiety-induced neophagia, measured by the novelty-suppressed feeding test, suggesting that i.v. ketamine's antidepressant-like effects may be symptom- and species-specific. While prior ketamine exposure and CMS had no effect on subsequent ketamine addiction-like behavior in males, females that underwent CMS displayed more addiction-like behavior than non-stressed females, suggesting that chronic stress can increase the risk for ketamine abuse in females. Additionally, ketamine pre-exposed females displayed lower ketamine intake, with no alterations in motivated responding or craving. Finally, dendritic spine density and morphology was assessed in the nucleus accumbens (NAc), the central processor for rewarding stimuli that is affected by both depression and addiction. Females with prior ketamine exposure regardless of stress condition had an increase in spine density that was primarily driven by the formation of immature thin spines; there were no changes in males. Together this suggests that although ketamine pre-treatment may alter NAc plasticity in a sex-dependent manner, it does not potentiate ketamine addiction-like behavior. Taken together, this work demonstrates that although ketamine and drug-paired cues have strong reinforcing effects, prior exposure to therapeutic ketamine infusions do not increase the risk of abuse. Estrous cycle stage and prior exposure to chronic stress influences the reinforcing properties of ketamine in females, suggesting an influence of ovarian hormones. The fact that ketamine-seeking behavior was dependent on the drug-paired cues rather than the acute pharmacological effects of ketamine, and that prior therapeutic ketamine did not increase the subsequent development of addiction-like behavior, suggests that there may be little overlap in ketamine's antidepressant effects and addictive effects. It is possible that ketamine, if administered under the appropriate conditions, may have limited abuse potential, but research is necessary to determine if these sex-specific effects in rats translate to humans. (Abstract shortened by ProQuest.).
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