R. Ross MacLean

Neurobiological mechanisms for the regulation of mammalian sleep–wake behavior: Reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence

At its most basic level, the function of mammalian sleep can be described as a restorative process of the brain and body; recently, however, progressive research has revealed a host of vital functions to which sleep is essential. Although many excellent reviews on sleep behavior have been published, none have incorporated contemporary studies examining the molecular mechanisms that govern the various stages of sleep. Utilizing a holistic approach, this review is focused on the basic mechanisms involved in the transition from wakefulness, initiation of sleep and the subsequent generation of slow-wave sleep and rapid eye movement (REM) sleep. Additionally, using recent molecular studies and experimental evidence that provides a direct link to sleep as a behavior, we have developed a new model, the cellular-molecular-network model, explaining the mechanisms responsible for regulating REM sleep. By analyzing the fundamental neurobiological mechanisms responsible for the generation and maintenance of sleep-wake behavior in mammals, we intend to provide a broader understanding of our present knowledge in the field of sleep research.

Weak ventral striatal responses to monetary outcomes predict an unwillingness to resist cigarette smoking

As a group, cigarette smokers exhibit blunted subjective, behavioral, and neurobiological responses to nondrug incentives and rewards, relative to nonsmokers. Findings from recent studies suggest, however, that there are large individual differences in the devaluation of nondrug rewards among smokers. Moreover, this variability appears to have significant clinical implications, since reduced sensitivity to nondrug rewards is associated with poorer smoking cessation outcomes. Currently, little is known about the neurobiological mechanisms that underlie these individual differences in the responsiveness to nondrug rewards. Here, we tested the hypothesis that individual variability in reward devaluation among smokers is linked to the functioning of the striatum. Specifically, functional magnetic resonance imaging was used to examine variability in the neural response to monetary outcomes in nicotine-deprived smokers anticipating an opportunity to smoke—circumstances found to heighten the devaluation of nondrug rewards by smokers in prior work. We also investigated whether individual differences in reward-related brain activity in those expecting to have access to cigarettes were associated with the degree to which the same individuals subsequently were willing to resist smoking in order to earn additional money. Our key finding was that deprived smokers who exhibited the weakest response to rewards (i.e., monetary gains) in the ventral striatum were least willing to refrain from smoking for monetary reinforcement. These results provide evidence that outcome-related signals in the ventral striatum serve as a marker for clinically meaningful individual differences in reward-motivated behavior among nicotine-deprived smokers.

Zolpidem reduces the blood oxygen level-dependent signal during visual system stimulation.

Zolpidem is a short-acting imidazopyridine hypnotic that binds at the benzodiazepine binding site on specific GABA(A) receptors to enhance fast inhibitory neurotransmission. The behavioral and receptor pharmacology of zolpidem has been studied extensively, but little is known about its neuronal substrates in vivo. In the present within-subject, double-blind, and placebo-controlled study, blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) at 3 Tesla was used to assess the effects of zolpidem within the brain. Healthy participants (n=12) were scanned 60 min after acute oral administration of zolpidem (0, 5, 10, or 20mg), and changes in BOLD signal were measured in the visual cortex during presentation of a flashing checkerboard. Heart rate and oxygen saturation were monitored continuously throughout the session. Zolpidem (10 and 20mg) reduced the robust visual system activation produced by presentation of this stimulus, but had no effects on physiological activity during the fMRI scan. Zolpidems modulation of the BOLD signal within the visual cortex is consistent with the abundant distribution of GABA(A) receptors localized in this region, as well as previous studies showing a relationship between increased GABA-mediated neuronal inhibition and a reduction in BOLD activation.

Modest abuse-related subjective effects of zolpidem in drug- naïve volunteers

Recent case reports suggest that the short-acting benzodiazepine-like hypnotic, zolpidem, may have abuse potential among individuals who have no personal history of abusing drugs or alcohol, particularly at doses higher than those recommended for treating insomnia. This study recruited drug-naive volunteers to assess the subjective effects of multiple doses of zolpidem (0, 5, 10, or 20 mg) administered in a within-subject double-blind design. Participants (n=11) answered computerized questionnaires (Addiction Research Center Inventory, visual analog scales, and a hypothetical Drug versus Money Choice) to address the hypothesis that a supratherapeutic dose (20 mg) would increase ratings of abuse-related subjective effects, while lower therapeutic doses (5 and 10 mg) would not. Although participants rated some effects as negative at 10 and 20 mg, the highest dose engendered predominantly positive abuse-like effects such as ‘High’, ‘Like’, and ‘Good Effects’. However, no dose of zolpidem was chosen over money (

Integrating Ecological Momentary Assessment and Functional Brain Imaging Methods: New Avenues for Studying and Treating Tobacco Dependence

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The relationship between anxiety and sleep-wake behavior after stressor exposure in the rat

10) when participants made hypothetical choices between them. Results suggest that although individuals without a drug abuse history are not inclined to choose zolpidem when presented with an alternative reinforcer such as money, it may possess moderate abuse potential that limits its clinical utility.

Kudzu Root Extract Does Not Perturb the Sleep/Wake Cycle of Moderate Drinkers

INTRODUCTION Ecological momentary assessment (EMA) and related methods typically entail repeatedly and intensively sampling behavior as it occurs over time and under naturalistic conditions. Although the methodological features of EMA make it a highly valuable research technique in its own right, EMA can also be a potent counterpart to other approaches. One methodological partnership with substantial yet largely untapped potential for the study of tobacco dependence is the pairing of EMA with functional brain imaging. METHODS The goal of this review is to outline the promise of this approach, with a focus on the combined use of EMA and functional magnetic resonance imaging (fMRI). Due to the unique and complementary strengths of each method, the merger of EMA and fMRI methods has the potential to advance the understanding of tobacco dependence in ways difficult or impossible to achieve through the use of either method in isolation. RESULTS In addition to describing a conceptual basis for combining EMA with fMRI, we provide a preliminary empirical illustration of this integrative approach using data from an ongoing study. CONCLUSIONS EMA and fMRI have independently yielded important findings regarding the nature and treatment of tobacco dependence. The integration of these powerful research methods, however, holds even greater potential for the field of tobacco research. Additionally, recent advances are paving the way for the synergistic use of fMRI and EMA-based methods to develop innovative approaches to tobacco cessation.

Effects of transcutaneous electric acupoint stimulation on drug use and responses to cue-induced craving: a pilot study

Disturbed sleep is a common subjective complaint among individuals diagnosed with anxiety disorders. In rodents, sleep is often recorded after exposure to various foot-shock paradigms designed to induce an anxiety state. Although differences in sleep-wake architecture are noted, the relationship to specific level of anxiety is often assumed or absent. Utilizing the elevated plus-maze (EPM) after exposure to escapable shock (ES), inescapable shock (IS) or fear conditioning (FC), resulting differences in sleep architecture were compared to an objective measure of anxiety. Male Wistar rats were implanted with EEG, EMG and hippocampal theta electrodes to record sleep-wake behavior. After recovery and recording of baseline sleep, rats were exposed to one of five manipulations: ES, IS, FC or control (CES or CIS; utilizing either chamber with no shock exposure). Shortly after experimental manipulation, the EPM was employed to quantify traditional and ethological measures of anxiety and polygraphic signs of sleep-wake behavior were recorded continuously for 6 h. Although no significance was observed in EPM measurements across groups, profound differences in sleep architecture were present. Individual correlation analysis revealed no differences in anxiety level and total percentage of time spent in sleep-wake states. These results indicate that differences in sleep architecture after foot-shock exposure may not be simply due to increased anxiety. Rather, individual anxiety may be exacerbated by disrupted sleep. To fully understand the relationship between anxiety and sleep-wake behavior, a more objective analysis of anxiety after stressor exposure is mandated.

Associations between self-control and dimensions of nicotine dependence: A preliminary report

OBJECTIVES According to ancient Chinese medicine, kudzu root has been used as an ingredient to treat alcohol intoxication for centuries. Kudzu root extract is effective at reducing alcohol intake in animals and in humans, both in a natural-settings laboratory environment and on an outpatient basis. In dependent populations, withdrawal from alcohol is associated with disturbed sleep. These disturbances to the quantity and quality of sleep likely impact relapse to drinking. Many medications used to treat alcohol dependence also affect sleep. Therefore, as a possible treatment for alcohol dependence, the impact of kudzu root extract on the sleep/wake cycle is an important aspect of its effectiveness. DESIGN This double-blind, placebo-controlled, crossover trial tested the effects of kudzu root extract on the sleep/wake cycles of moderate drinkers. RESULTS Kudzu extract had no effect on any of the sleep parameters measured, including sleep efficiency, sleep latency, total time asleep per night, number of waking episodes, time awake per episode, number of moving minutes, number of sleep episodes, time asleep per episode, and number of immobile minutes. CONCLUSIONS These data suggest that the administration of kudzu root extract does not disturb sleep/wake cycles of moderate drinkers, and as such its utility as an adjunct treatment for alcohol dependence remains free of any potential side-effects on sleep.

Tobacco and alcohol use disorders: Evaluating multimorbidity

BackgroundTranscutaneous electric acupoint stimulation (TEAS) avoids the use of needles, and instead delivers a mild electric current at traditional acupoints. This technique has been used for treating heroin addiction, but has not been systematically tested for other drugs of abuse. This study aims to investigate the effects of TEAS on drug addiction.MethodsVolunteers who were either cocaine-dependent (n = 9) or cannabis-dependent (n = 11) but were not seeking treatment for their dependence participated in a within-subject, single-blind study. Treatment consisted of twice daily 30-minute sessions of TEAS or sham stimulation for 3.5 days. The active TEAS levels were individually adjusted to produce a distinct twitching response in the fingers, while the sham stimulation involved 2 minutes of stimulation at threshold levels followed by 28 minutes of stimulation below the detection levels. The participants recorded their drug use and drug cravings daily. At 1 hour after the last morning session of TEAS or sham stimulation, a cue-induced craving EEG evaluation was conducted. Event-related P300 potentials (ERPs) were recorded, sorted, and analyzed for specific image types (neutral objects, non-drug-related arousing images, or drug-related images).ResultsTEAS treatment did not significantly reduce the drug use or drug cravings, or significantly alter the ERP peak voltage or latency to peak response. However, the TEAS treatment did significantly modulate several self-reported measures of mood and anxiety.ConclusionThe results of this pilot study with a limited sample size suggest that the acupoint stimulation techniques and protocol used in this trial alone do not significantly reduce cravings for or use of cocaine or cannabis. The findings that TEAS modulates mood and anxiety suggest that TEAS could be used as an adjunct in a multimodal therapy program to treat cocaine and cannabis dependence if confirmed in a full randomized controlled clinical trial.