Elsevier

Brain Research Bulletin

Volume 123, May 2016, Pages 33-46
Brain Research Bulletin

Research report
Reversal of the sleep–wake cycle by heroin self-administration in rats

https://doi.org/10.1016/j.brainresbull.2015.09.008Get rights and content

Highlights

  • Heroin self-administration during the light cycle reverses the rat sleep–wake cycle.

  • Reversal does not depend on the amount of drug taken.

  • Wake and NREM sleep patterns recover immediately in abstinence.

  • REM sleep patterns remain reversed into early abstinence (3–6 days).

Abstract

The goal of this study was to examine how heroin self-administration, abstinence, and extinction/reinstatement affect circadian sleep–wake cycles and the associated sleep architecture. We used electroencephalography (EEG) and electromyography (EMG) to measure sleep patterns in male Sprague–Dawley rats over 16 trials of heroin self-administration (acquisition), 14 days of abstinence, and a single day of extinction and drug-induced reinstatement. Rats self-administering heroin showed evidence of reversed (diurnal) patterns of wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep throughout acquisition. During abstinence, their wake and NREM sleep patterns were immediately restored to the normal nocturnal distribution. REM patterns remained inverted for the first 3–6 days of abstinence in heroin self-administering rats. The single extinction/reinstatement test was without effect. These data suggest that heroin may have the ability to affect circadian distribution of sleep and wakefulness, either indirectly, where animals shift their sleep-wake cycle to allow for drug taking, or directly, through wake-promoting actions or actions at circadian oscillators in the brain.

Introduction

Addiction is a chronic disease, characterized by uncontrolled drug use and multiple relapses (Leshner, 1997). Heroin use in particular is on the rise in the United States, with the number of Americans who used heroin in the past year nearly doubling between 2007 and 2013 (Substance Abuse and Mental Health Services Administration, 2014). This disturbing trend parallels an increase in the prescription of opioid painkillers, which are abused by almost half of heroin addicts before switching to heroin—a less expensive and more accessible alternative (Cicero et al., 2012, Dart et al., 2015, Jones et al., 2015, Pollini et al., 2011). Heroin is a particularly insidious drug, as it is estimated that about half of current users are dependent on it (Substance Abuse and Mental Health Services Administration, 2012). In addition to increasing heroin use, the number of heroin overdose deaths has doubled among 28 states between 2010 and 2012 (Rudd et al., 2014). Overall, addiction has an estimated relapse rate of 40–60% in the first year following treatment (McLellan et al., 2000). Heroin relapse rates are much higher, with up to 80% of heroin addicts relapsing within one month of treatment (Smyth et al., 2010).

Disruption of sleep may put an addict at an even greater risk for relapse. In alcoholics, poor sleep quality is predictive of later relapse, a relationship hypothesized to exist across a number of different drugs, including alcohol, cocaine, amphetamines, nicotine, and opioids (Brower et al., 1998, Brower and Perron, 2010). In support, several studies have estimated that more than a third of heroin addicts report problems sleeping as a reason for relapse (Maulik et al., 2002, Raj et al., 2000). In addition, sleep disturbances plague as many as 35% of heroin addicts starting treatment, illustrating the importance of understanding heroin's impact on the sleep–wake cycle (Maremmani et al., 2007).

Despite evidence that drugs of abuse disrupt sleep, investigations into the effects of opioids on sleep are relatively few. The administration of morphine or heroin has been shown to cause an immediate decrease in rapid eye movement (REM) sleep in rats (Khazan et al., 1967) and in non-addicted humans in some cases (Lewis et al., 1970, Shaw et al., 2005), but not all (Dimsdale et al., 2007). In rats, a single injection of morphine also causes a reduction in slow wave sleep (Khazan et al., 1967). In this study, sleep recovered by the third day of increasing doses of morphine, but REM sleep took longer to recover and continued to be depressed with each increasing dose. By the fifth day of abstinence, all sleep parameters had recovered, but the authors did not examine any earlier abstinence data, so it is possible that sleep recovered earlier (Khazan et al., 1967). In humans, there is evidence of increased wakefulness, decreased NREM sleep, and decreased REM sleep in the first 5–7 days of heroin withdrawal (Howe et al., 1980a, Howe et al., 1980b, Howe et al., 1980c).

Even among studies examining drug effects on sleep, little attention has been given to the effects of drug taking and abstinence on circadian rhythm in addicts, despite evidence that drugs of abuse can entrain activity (Gillman et al., 2009, Honma et al., 1987, Kosobud et al., 1998, White et al., 2000). Recently, circadian effects of drugs has been gaining traction as a topic of interest (Hasler et al., 2012). Here, we sought to characterize the effects of heroin taking and abstinence on sleep patterns in rats. This investigation is the first, to our knowledge, to examine the effects of heroin self-administration on sleep across the entire addiction cycle, including acquisition of drug taking, abstinence, and a model of relapse. While Khazan et al. (1967) conducted a similar study using morphine, as described above, there are a number of key differences. First, the rats in Khazan et al. (1967) began with passive administration of increasing doses of morphine before they were switched to self-administration, whereas we used self-administration throughout our study. Second, due to the volume of data, Khazan et al. (1967) analyzed only select time periods. Here, we have analyzed all of the data collected, with a few gaps due to mechanical failure. Third, the earlier study provided morphine every hour to the rats, whereas our subjects were given access to drug during a discrete 6 h session within their light cycle in order to allow for examination of the impact of drug on the circadian cycle. While providing access to heroin during the inactive period may seem counterintuitive, it resembles the human experience. This schedule of availability leads to disruptions in the rats’ normal sleep patterns in order to take drug, a common occurrence in human addicts. Sleeping at significantly different times than controls has been reported in human addicts, and this effect has been suggested to be a consequence of their generally “nocturnal lifestyle[s]” (Oyefeso et al., 1997). Additionally, all of the experiments above that examined the effects of opioids on human sleep involved an injection of drug soon before the patients were allowed to sleep.

Here, fifteen male, Sprague–Dawley rats intravenously (i.v.) self-administered heroin (0.06 mg/infusion) or saline over the course of 16 trials to model acquisition of heroin taking. The animals were maintained in forced home cage abstinence for 14 days, followed by a drug-primed extinction/reinstatement test to model relapse. During the entire experiment, EEG and EMG signals were recorded continuously, 6 days per week, in each rat to allow for characterization of wakefulness, NREM sleep, and REM sleep.

Section snippets

Subjects

This study was performed in two separate replications (Replication 1: n = 2 saline, n = 4 heroin; Replication 2: n = 2 saline, n = 7 heroin). The subjects were 15 adult, male, drug-naïve Sprague–Dawley rats obtained from Charles River weighing between 155 and 377 g (mean = 290 ± 14) at the beginning of the experiment. They were housed individually in a temperature-controlled (21 °C) animal care facility with 12:12 h light–dark cycle (lights on at 7:00 am). The rats were maintained with free access to water

Missing data

Throughout the study, there were some blocks of missing sleep data due to mechanical failure. Sleep data during the 6 h self-administration sessions were missing for two of the saline animals and four of the heroin animals (two high drug takers, two low drug takers). The heroin animals were assumed to be awake for the entire 6 h, which was not significantly different from the available data from the other seven heroin animals (p > 0.05). For the saline animals, these data were supplemented using

Discussion

Across acquisition, high drug takers took more drug than saline rats. High drug takers also took more infusions than low drug takers by the end of acquisition. During the progressive ratio challenge, high drug takers took more infusions than low drug takers or saline rats, and low drug takers took more infusions than the saline animals. These data indicate that the high drug takers were more motivated to take heroin than were the low drug takers, and that both of these groups were willing to

Conclusion

In sum, individual differences were evident whereby some rats (high drug takers) self-administered more heroin than did others (low drug takers). The high drug takers also worked harder for the drug when challenged on a PR test than did the low drug takers, and they exhibited more seeking during both extinction and drug-induced reinstatement. Despite these differences in drug taking, all rats that self-administered heroin during the light cycle demonstrated a reversal of the sleep–wake cycle.

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgements

The authors thank the National Institute on Drug Abuse for generously providing heroin. Support was provided by a grant from the Pennsylvania Department of Health, Commonwealth Universal Research Enhancements SAP# 4100055576. We thank Caesar Imperio, Danielle Alexander, and Elizabeth Colechio for their technical assistance.

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