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- Open Access.
- Addiction is a chronic brain disease characterized by multiple relapses. Despite evidence in humans that sleep disturbances and circadian disruption are associated with both the development of addiction and relapse to drug use, this relationship has received relatively little attention in the field. As such, the goal of this dissertation is to examine how sleep and circadian disruption arise as an aspect of heroin addiction and how these disturbances might further contribute to the addiction process. Chapter 2 used electroencephalography and electromyography to record sleep in rats throughout an entire cycle of addiction, including acquisition of heroin intake, abstinence, and an animal model of relapse. Rats, known to be nocturnal, were given access to heroin or saline during the light phase of their light/dark cycle. Results showed that sleep patterns were severely disrupted, such that heroin self-administering rats were in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep more during the dark (active) phase than during the light (inactive) phase. This reversed pattern was sustained for REM sleep for nearly a week of abstinence. The persistence of this effect suggests that self-administering heroin during the light phase causes a circadian disruption in the timing of REM sleep in rats. In Chapter 3, this study was replicated, but the rats were given access to heroin or saline during the dark phase. Sleep patterns in these heroin self-administering rats were not affected during acquisition. During abstinence, REM sleep spiked during the first dark phase, but this occurred in both the heroin rats and the saline rats and likely reflected an effect of the procedure. These data indicate that self-administration has differential effects on sleep and circadian rhythms depending on the time of access. While we are now learning the effects of time of access on sleep-wake patterns, we know little about how it affects heroin self-administration. To address this question, rats were given access to heroin during either the light or the dark phase for 18 days, with one progressive ratio challenge, followed by an abstinence period with multiple extinction tests and a heroin-induced reinstatement test (Chapter 4). The results showed that, overall, Dark Access rats self-administered more heroin and exhibited more seeking during extinction than did Light Access rats, but they did not show more addiction-like behaviors (escalation of intake, motivation to take drug, incubation of heroin seeking, or reinstatement of heroin seeking following a heroin prime). Importantly, Dark Access rats decreased extinction seeking when tested during the light phase, whereas Light Access rats increased seeking when tested in the dark phase. These results indicate that the increased seeking in extinction was due to the time of testing (during the dark/active phase), rather than the time of training. Buprenorphine, a mu/kappa opioid receptor agonist, is commonly used in treatment for opioid use disorders, but it also has been shown to affect sleep. Chapter 5 investigated gender differences, with a particular interest in sleep disturbances, in human patients taking an abuse-deterrent formulation of buprenorphine/naloxone for opioid use disorder. The results showed that women consistently reported worse sleep quality than did men while on buprenorphine/naloxone. Interestingly, whereas about half of men reported that their sleep improved once they began medication-assisted treatment, only one third of women reported the same. In Chapter 6, medication-assisted treatment was revisited in the rodent model with buprenorphine. Specifically, I tested the hypothesis that chronic, daily injections of buprenorphine, given at dark onset during abstinence, would reduce heroin seeking and rescue the circadian disturbance in REM sleep timing caused by a history of heroin self-administration during the light phase. The results showed that saline-treated rats with a history of light phase heroin self-administration exhibited the same increase in REM sleep during the dark phase that was seen in Chapter 2 and a great deal of heroin seeking during extinction testing. Buprenorphine-treated rats, on the other hand, appropriately spent more time in REM sleep during the light phase than during the dark phase, exhibited decreased heroin seeking during extinction in rats with a history of high heroin taking, and exhibited decreased seeking following a heroin prime compared to the saline-treated rats. Overall, the data in this dissertation demonstrate that sleep and circadian disruption are a consequence of heroin self-administration and that correcting these disturbances may be beneficial for recovery from heroin addiction.
- Dissertation Note:
- Ph.D. Pennsylvania State University 2018.
- Technical Details:
- The full text of the dissertation is available as an Adobe Acrobat .pdf file ; Adobe Acrobat Reader required to view the file.
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