Zonisamide, topiramate, and levetiracetam: efficacy and neuropsychological effects in alcohol use disorders.

The anticonvulsant topiramate not only decreases ethanol consumption in alcohol dependence (AD) but also may produce several adverse events including cognitive impairment. Zonisamide is a structurally related anticonvulsant that is a promising agent for the treatment of AD and may have greater tolerability than topiramate. This study evaluated the effects of zonisamide (400 mg/d) on alcohol consumption and its neurotoxic effects in subjects with AD. A double-blind placebo-controlled clinical trial was conducted using 2 comparator anticonvulsant drugs, topiramate (300 mg/d) and levetiracetam (2000 mg/d), which does not impair cognition. Study medications were administered for 14 weeks, including a 2-week taper period. Medication adherence was facilitated using Brief Behavioral Compliance Enhancement Treatment. The neurotoxicity of the study drugs was assessed using neuropsychological tests and the AB-Neurotoxicity Scale. Compared with placebo, both zonisamide and topiramate produced significant reductions in the drinks consumed per day, percent days drinking, and percent days heavy drinking. Only the percent days heavy drinking was significantly decreased in the levetiracetam group. The topiramate cell was the only group that had a significant increase on the mental slowing subscale of the Neurotoxicity Scale compared with placebo at study weeks 11 and 12. Topiramate and zonisamide both produced modest reductions in verbal fluency and working memory. These findings indicate that zonisamide may have efficacy in the treatment of AD, with effect sizes similar to topiramate. Both of these drugs produced similar patterns of cognitive impairment, although only the topiramate group reported significant increases in mental slowing.

Dorsal subcoeruleus nucleus (SubCD) involvement in context-associated fear memory consolidation.

The neurobiological mechanisms of emotional memory processing can be investigated using classical fear conditioning as a model system, and evidence from multiple lines of research suggests that sleep influences consolidation of emotional memory. In rodents, some of this evidence comes from a common finding that sleep deprivation from 0 to 6 h after fear conditioning training impairs processing of conditioned fear memory. Here, we show that during a 6-h session of sleep-wake (S-W) recording, immediately after a session of context-associated fear conditioning training, rats spent more time in wakefulness (W) and less time in slow-wave sleep (SWS) and rapid eye movement (REM) sleep. This context-associated fear conditioning training-induced reduction in SWS lasts for 2 h, and the REM sleep reduction lasts throughout the entire 6-h post-training S-W recording period. Interestingly, these reductions in SWS and REM sleep during this 6-h period did not impair memory consolidation for context-associated fear conditioning. The results of this study show, for the first time, that lesions within the dorsal part of the subcoeruleus nucleus (SubCD), which were unintentionally caused by the implantation of bipolar recording electrodes, impair consolidation of context-associated fear conditioning memory. Together, the results of these experiments suggest that emotional memory processing associated with fear conditioning can be completed successfully within less than a normal amount of sleep, but it requires a structurally and functionally intact SubCD, an area in the brain stem where phasic pontine wave (P-wave) generating cells are located.

The Kv7 potassium channel activator retigabine decreases alcohol consumption in rats.

BACKGROUND: Activation of Kv7 potassium channels may decrease the reactivity of mesolimbic dopaminergic neurons that are implicated in mediating the reinforcing effects of ethanol. OBJECTIVES: The objective of this study was to determine whether the administration of the Kv7 potassium channel opener retigabine would decrease ethanol intake in Long Evans rats. METHODS: A limited access two-bottle choice model of alcohol (10% solution) consumption was used in this study. A separate group of animals was tested to evaluate the actions of retigabine on sucrose (5% solution) consumption to determine whether this drug might produce non-selective impairment of the ability of rats to drink liquids. Animals were treated with either vehicle or increasing doses (2.5-7.5 mg/kg SC) of retigabine administered over a 3-day period. RESULTS: Compared to vehicle, retigabine at a dose of 7.5 mg/kg produced a reduction in the amount of ethanol consumed. These effects did not occur in association with significant changes in water consumption. A significant time effect was found for the actions of retigabine in sucrose-drinking rats with a trend for an increase in sucrose intake with the highest dose of retigabine administered. CONCLUSIONS: These results indicate that the administration of retigabine may produce a decrease in ethanol consumption by rats at doses that do not significantly reduce the drinking of either water or a sucrose solution. These findings are consistent with the hypothesis that activation of Kv7 channels facilitates the reduction of alcohol consumption in the rat.

Concealment and fabrication by experienced research subjects.

BACKGROUND: Subjects who enroll in multiple studies have been found to use deception at times to overcome restrictive screening criteria. Deception undermines subject safety as well as study integrity. Little is known about the extent to which experienced research subjects use deception and what type of information is concealed, withheld, or distorted. PURPOSE: This study examined the prevalence of deception and types of deception used by subjects enrolling in multiple studies. METHODS: Self-report of deceptive behavior used to gain entry into clinical trials was measured among a sample of 100 subjects who had participated in at least two studies in the past year. RESULTS: Three quarters of subjects reported concealing some health information from researchers in their lifetime to avoid exclusion from enrollment in a study. Health problems were concealed by 32% of the sample, use of prescribed medications by 28%, and recreational drug use by 20% of the sample. One quarter of subjects reported exaggerating symptoms in order to qualify for a study and 14% reported pretending to have a health condition in order to qualify. LIMITATIONS: Although this study finds high rates of lifetime deceptive behavior, the frequency and context of this behavior is unknown. Understanding the context and frequency of deception will inform the extent to which it jeopardizes study integrity and safety. CONCLUSION: The use of deception threatens both participant safety and the integrity of research findings. Deception may be fueled in part by undue inducements, overly restrictive criteria for entry, and increased demand for healthy controls. Screening measures designed to detect deception among study subjects would aid in both protecting subjects and ensuring the quality of research findings.

Withdrawal from chronic, intermittent access to a highly palatable food induces depressive-like behavior in compulsive eating rats.

The increased availability of highly palatable foods is a major contributing factor toward the development of compulsive eating in obesity and eating disorders. It has been proposed that compulsive eating may develop as a form of self-medication to alleviate the negative emotional state associated with withdrawal from highly palatable foods. This study was aimed at determining whether withdrawal from chronic, intermittent access to a highly palatable food was responsible for the emergence of depressive-like behavior. For this purpose, a group of male Wistar rats was provided a regular chow diet 7 days a week (Chow/Chow), whereas a second group of rats was provided chow for 5 days a week, followed by a 2-day access to a highly palatable sucrose diet (Chow/Palatable). Following 7 weeks of diet alternation, depressive-like behavior was assessed during withdrawal from the highly palatable diet and following renewed access to it, using the forced swim test, the sucrose consumption test, and the intracranial self-stimulation threshold procedure. It was found that Chow/Palatable rats withdrawn from the highly palatable diet showed increased immobility time in the forced swim test and decreased sucrose intake in the sucrose consumption test compared with the control Chow/Chow rats. Interestingly, the increased immobility in the forced swim test was abolished by renewing access to the highly palatable diet. No changes were observed in the intracranial self-stimulation threshold procedure. These results validate the hypothesis that withdrawal from highly palatable food is responsible for the emergence of depressive-like behavior, and they also show that compulsive eating relieves the withdrawal-induced negative emotional state.

The efficacy of mirtazapine in the treatment of cocaine dependence with comorbid depression.

BACKGROUND: Prior findings concerning the use of mirtazapine in the treatment of a variety of substance use disorders and its antagonistic actions at the serotonin 5-HT(2A) receptor suggest that this drug may have efficacy in the treatment of cocaine dependence in the presence of a depressive disorder. METHODS: Depressed cocaine-dependent subjects received either mirtazapine (target dose 45 mg daily) or placebo for 12 weeks. Urine concentrations of benzoylecgonine and self-report were used to assess cocaine consumption. Depression and sleep quality were evaluated using the Hamilton Depression Rating Scale (HAM-D) and the Pittsburgh Sleep Quality Index, respectively. RESULTS: Cocaine consumption during the treatment period did not differ significantly between the mirtazapine (n = 11) and placebo (n = 13) groups in this study. In week 4 sleep latency was significantly lower in the active medication than in the placebo group. Positive effects of mirtazapine treatment on early insomnia were suggested by an item analysis of the HAM-D. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The results of this study suggest that mirtazapine is superior to placebo in improving sleep in patients with comorbid depression and cocaine dependence, but is not more effective than placebo in reducing cocaine use.

Open label trial of the tolerability and efficacy of zonisamide in the treatment of alcohol dependence.

OBJECTIVES: The objectives of this study are to assess the tolerability and efficacy of the anticonvulsant zonisamide in an open label trial of the treatment of alcohol dependence. METHODS: In this trial, zonisamide (400-mg daily) was administered to alcohol-dependent subjects (ADS) (n = 16) over 13 weeks. The mean daily consumption of standard alcoholic drinks and performance on a verbal fluency task, the COWAT, and on a measure of attention and visuomotor speed, the DSMT were assessed, and the occurrence of adverse events was monitored weekly. RESULTS: The mean number of drinks consumed daily was significantly reduced from baseline levels during the treatment period. Performances on the COWAT and on the DSMT were not significantly reduced by zonisamide treatment. Overall, zonisamide was well tolerated by the study subjects. CONCLUSION: These results indicate that zonisamide administration may not impair verbal fluency in ADS, and are consistent with other studies that found zonisamide administration may reduce alcohol intake.

Deep brain stimulation of the nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug seeking in rats.

Increasing evidence suggests that deep brain stimulation (DBS), which is currently being used as a therapy for neurological diseases, may be effective in the treatment of psychiatric disorders as well. Here, we examined the influence of DBS of the nucleus accumbens shell on cocaine priming-induced reinstatement of drug seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.25 mg, i.v.) 2 h daily for 21 d and then cocaine-seeking behavior was extinguished by replacing cocaine with saline. During the reinstatement phase, DBS was administered bilaterally to the nucleus accumbens shell through bipolar stainless steel electrodes. Biphasic symmetrical pulses were delivered at a frequency of 160 Hz and a current intensity of 150 muA. DBS began immediately after a priming injection of cocaine (0, 5, 10, or 20 mg/kg, i.p.) and continued throughout each 2 h reinstatement session. Results indicated that only the higher doses of cocaine (10 and 20 mg/kg) produced robust and reliable reinstatement of cocaine seeking. DBS of the nucleus accumbens shell significantly attenuated the reinstatement of drug seeking precipitated by these higher cocaine doses. Additional experiments indicated that this DBS effect was both anatomically and reinforcer specific. Thus, DBS of the dorsal striatum had no influence on cocaine reinstatement and DBS of the accumbens shell did not affect the reinstatement of food seeking. Together, these results suggest that DBS of the nucleus accumbens shell may be a potential therapeutic option in the treatment of severe cocaine addiction.

The anticonvulsant zonisamide reduces ethanol self-administration by risky drinkers.

OBJECTIVE: The purpose of this study is to examine the effects of zonisamide on ethanol self-administration and subjective effects in risky drinkers using a human laboratory paradigm. METHOD: We conducted a double-blind, placebo-controlled study of the effects of zonisamide 100 mg on ethanol self-administration and urge to drink in risky drinkers (N = 10) ( [1] ). RESULT: During the second hour of a 2-hour self-administration session ethanol consumption was 50% lower in the zonisamide group as compared to the placebo group. Urge to drink was also significantly lower under the zonisamide condition. CONCLUSION: These results indicate that a single dose of zonisamide reduces urge to drink and the quantity of ethanol self-administered by risky drinkers during their second hour of access to alcohol. SCIENTIFIC SIGNIFICANCE: Zonisamide may help individuals drinking at risky levels reduce their intake of alcohol.

Zonisamide decreases ethanol intake in rats and mice.

Several anticonvulsant agents, including topiramate and valproate, have been found to reduce alcohol consumption in rodent models of drinking. The question of whether the novel anticonvulsant agent, zonisamide, shares similar actions in either mice or rats was investigated in the present experiments. In an initial experiment, the consumption of a 10% ethanol-5% sucrose solution, available for one hour, by Wistar rats treated with lactose, topiramate, or zonisamide was determined. In a second experiment, the intake of a 10% ethanol/water solution, accessible for two hours, by C57BL/B6N mice treated with either zonisamide or vehicle was assessed. In the rat, 50 mg/kg (PO) doses of either topiramate or zonisamide produced significant, but moderate decreases in ethanol/sucrose intake. The administration of a 50 mg/kg (IP) dose of zonisamide to mice resulted in a marked lowering in ethanol consumption. These results provide evidence that zonisamide administration will decrease ethanol consumption by both mice and rats in limited access models of drinking, and might, like topiramate, be useful as a medication for alcoholism.

Pharmacokinetics and pharmacodynamics of multiple sublingual buprenorphine tablets in dose-escalation trials.

In this investigation, the pharmacokinetic and pharmacodynamic properties were determined of multiple doses of sublingual tablets containing either buprenorphine alone or buprenorphine and naloxone. Subjects were experienced opiate users who received escalating doses (4-24 mg) of buprenorphine either alone or in combination with naloxone. Peak concentration (Cmax) and area under the concentration-time curves (AUCs) increased for both buprenorphine and naloxone with escalating doses. Significant differences were found across the range of doses administered for dose-adjusted Cmax for both tablet formulations and for the dose-adjusted AUCs for the buprenorphine-naloxone tablets. For both formulations, the maximal buprenorphine-induced decreases in respiratory rate and pupil diameter did not vary significantly across doses. Several of the subjective effects of buprenorphine did not increase as the dose of buprenorphine administered was increased. These findings are consistent with the ceiling effect associated with the partial agonist actions of buprenorphine. They also indicate a lack of dose proportionality for buprenorphine sublingual tablets, at least during the times at which levels of this agent are highest.

Nociceptive threshold and analgesic response to morphine in aged and young adult rats as determined by thermal radiation and intracerebral electrical stimulation.

The present experiment compared the nociceptive threshold and analgesic response to morphine in young (4-5 months) and aged (24 months) rats using peripheral thermal stimulation and intracerebral electrical stimulation. Responses to thermal stimuli were assessed using both the classical tail-flick procedure in which latency of response is the dependent variable and a new method in which threshold in calories of heat is the dependent variable. In the intracerebral nociceptive threshold procedure, electrical stimuli were delivered via an electrode implanted in the mesencephalic reticular formation (MRF), a pain pathway, and the animals were trained to terminate the stimulation by turning a cylindrical manipulandum embedded in one wall of the experimental chamber. For the classical tail-flick method, the aged rats required a greater intensity of stimulation to produce a basal response latency that was between 2.5 and 3.5 s. Using the new psychophysical method for determining the tail-flick threshold, the aged rats' basal thresholds were significantly higher than that of the young rats. However, the basal thresholds obtained by direct stimulation of the MRF failed to show a significant age effect, suggesting that the registration of pain is not different between young and aged rats. These age-related differences in baseline tail-flick response may be due to changes in the spinal reflex associated with aging. Although, there was no difference in the analgesic effects of morphine between young and aged rats using the latency of the tail-flick response, evidence for decreased analgesic response was seen using the tail-flick threshold measure and the intracerebral stimulation threshold method.

Efficacy screening trials of paroxetine, pentoxifylline, riluzole, pramipexole and venlafaxine in cocaine dependence.

AIMS: The two studies presented here were conducted to assess the efficacy of paroxetine, pentoxifylline, riluzole, venlafaxine and pramipexole as medications for the treatment of cocaine dependence. DESIGN: A multi-arm, modified blinded, placebo-controlled design was used. SETTING: The studies were conducted at the Boston VA Healthcare System and the Boston University School of Medicine Medication Development Research Unit (MDRU). PARTICIPANTS: Participants met criteria for cocaine dependence during a 2-week screening period. INTERVENTION: Following random assignment to one of the treatment groups, subjects received active medication or placebo for 8 weeks in combination with cognitive behavioral counseling. In the first study the efficacy of the antidepressant paroxetine (20 mg daily), the phosphodiesterase inhibitor pentoxifylline (1200 mg daily) and the glutamate release inhibitor riluzole (100 mg daily) was assessed. The antidepressant venlafaxine (150 mg daily) and the dopamine agonist pramipexole (1.5 mg daily) were evaluated in the second study. MEASUREMENTS: Urine benzoylecgonine (BE) concentrations, self-report of cocaine use and global impression scores served as primary outcome measures. Secondary measures included assessments of cocaine craving and psychiatric functioning. Adverse events were monitored during the treatment period. FINDINGS: None of the active medications produced greater reductions in urine BE concentrations over the treatment period than did placebo. There were trends for BE levels to become reduced in the pentoxifylline group during the first 4 weeks of treatment and for Addiction Severity Index (ASI) drug composite scores to be lower in the pentoxyfylline group at end-point compared to the placebo group. Significant within-group reductions in reported cocaine use and craving were found for all treatment groups, but none of the active medications were superior to placebo on these measures. The accuracy of self-reported cocaine use declined over the study period. Overall, the active medications were well tolerated. CONCLUSIONS: This study does not support the use of paroxetine, pentoxifylline, riluzole, venlafaxine or pramipexole for the treatment of cocaine dependence. However, these results need to be interpreted with caution because of the small size and lack of homogeneity of the experimental groups.

The homeostatic regulation of REM sleep: A role for localized expression of brain-derived neurotrophic factor in the brainstem.

Homeostatic regulation of REM sleep plays a key role in neural plasticity and deficits in this process are implicated in the development of many neuropsychiatric disorders. Little is known, however, about the molecular mechanisms that underlie this homeostatic regulation process. This study examined the hypothesis that, during selective REM sleep deprivation (RSD), increased brain-derived neurotrophic factor (BDNF) expression in REM sleep regulating areas is critical for the development of homeostatic drive for REM sleep, as measured by an increase in the number of REM sleep transitions. Rats were assigned to RSD, non-sleep deprived (BSL), or total sleep deprivation (TSD) groups. Physiological recordings were obtained from cortical, hippocampal, and pontine EEG electrodes over a 6h period, in which sleep deprivation occurred during the first 3h. In the RSD, but not the other conditions, homeostatic drive for REM sleep increased progressively. BDNF protein expression was significantly greater in the pedunculopontine tegmentum (PPT) and subcoeruleus nucleus (SubCD) in the RSD as compared to the TSD and BSL groups, areas that regulate REM sleep, but not in the medial preoptic area, which regulates non-REM sleep. There was a significant positive correlation between RSD-induced increases in number of REM sleep episodes and increased BDNF expression in the PPT and SubCD. These increases positively correlated with levels of homeostatic drive for REM sleep. These results, for the first time, suggest that selective RSD-induced increased expression of BDNF in the PPT and SubCD are determinant factors in the development of the homeostatic drive for REM sleep.

Payment expectations for research participation among subjects who tell the truth, subjects who conceal information, and subjects who fabricate information.

Multiple models guide researchers' payment practices but few studies have assessed subjects' expectations for payment. Payments in excess of subjects' expectations may result in undue inducement, while payments below these expectations may be associated with exploitation. Data on subjects' payment expectations will help inform practices to avoid undue inducement and exploitation. This study examined subjects' expectations for payment for common research procedures and explored the relationship between subjects' honesty and payment expectations. One-hundred subjects who participated in two or more studies in the last year reported the minimum payment they expect for completing study procedures. They were also asked about their use of deception while screening for studies. Subjects expected $20 on average to complete the least risky and least burdensome procedure. Subjects' expectations for payment consistently increased with greater procedure risks. Subjects who denied using deception to enroll in studies refused more procedures than subjects who reported using deception. Among subjects who used deception, the rate of procedure refusal increased with procedure risks, suggesting that these subjects have some risk aversion and may act to protect themselves from undue inducement. Although subjects expect greater payments for more risky procedures, ethical considerations for limiting undue inducement may prevent researchers from meeting subjects' expectations. Subjects who use deceptive practices appear to be more risk-tolerant than subjects who deny using deception; nonetheless, these deceptive subjects also exercise some risk aversion when they refuse higher-risk procedures. These subjects may be able to protect themselves from undue inducement by refusing procedures that exceed their risk tolerance.

Effects of cue exposure on brain glucose utilization 8 days after repeated cocaine administration.

Relapse to cocaine use may involve exposure to cocaine-associated environmental cues. The present experiment tested the hypothesis that basal local cerebral metabolic rate for glucose (LCMR(glu)), as measured by the 2-deoxy-D-[l-(14)C]glucose (2-DG) autoradiography, would change in the presence of cocaine conditioned cues at 8 days after the last of seven daily cocaine injections (30 mg/kg). This dose regimen results in sensitization to the locomotor effects of cocaine. Cocaine was administered to two groups of rats while saline was administered to a third. In the conditioned group, the rats were placed into the 2-DG experimental chamber immediately after cocaine injection. Rats in the non-conditioned group were placed into their home cage after cocaine administration. A control group received only saline. The 2-DG experiment was conducted in non-drugged animals 8 days after treatment completion. The interaction between treatment status and brain region was significant. Mean basal LCMR(glu) was significantly lower in 12 brain regions in the conditioned group as compared to the control group, but was significantly lower in only four areas in the non-conditioned group. Regions in which there were significant changes in the conditioned group included the basolateral amygdala, subiculum, medial thalamus, lateral habenula and the substantia nigra pars compacta. LCMR(glu) was significantly reduced in the ventrolateral orbital cortex and rostral nucleus accumbens in both experimental groups. These findings indicate that repeated cocaine administration can cause protracted decreases in basal LCMR(glu), decreases that are more widespread in the brain during exposure to cocaine-associated cues.

Increased sensitization to morphine-induced oral stereotypy in aged rats.

Sensitization develops to the stereotypic biting behavior that appears with the repeated administration of high dose morphine to rats. Because there is evidence that this behavior is dopamine-mediated and that there are age-related changes in dopamine systems, we compared the development and expression of morphine-induced biting behavior in aged (24 months) and young rats (5 months). Animals were treated with four sensitizing 10 mg/kg doses of morphine or saline, followed by three weekly challenges with 4 mg/kg doses of morphine or saline. By the fourth sensitizing morphine dose and after the administration of each low dose challenge, the biting time was significantly greater for aged than for young morphine pre-treated rats. After the first weekly low dose challenge, the aged but not young animals expressed more biting than when they did after the last 10 mg/kg dose. These results indicate that sensitization to morphine-induced oral stereotypy is significantly greater in aged as compared to young rats. Age-related enhanced sensitivity to morphine-induced oral stereotypy might be related to age-induced increases in vulnerability to opioid-induced insults to the basal ganglia, and may be a model for certain diseases of this pathway.

Effects of morphine on brain-stimulation reward thresholds in young and aged rats.

Mesolimbic opioid systems are altered with aging; however, the effects of these changes on the rewarding actions of opioids have not been examined. The present experiment assessed differences in the responsiveness of brain reward pathways in young and aged rats to the effects of morphine using the brain-stimulation reward (BSR) model. Aged (24 months) and young (5 months) male F344/BNF1 rats were stereotaxically implanted with a bipolar stainless steel electrode into the lateral hypothalamic (LH) region of the medial forebrain bundle. Thresholds were determined using the rate-independent psychophysical method. Each animal was tested after the administration of saline or morphine at 0.5, 1, 2.5, 5 and 10 mg/kg doses. A significant difference in the mean baseline threshold between aged (99.8+/-6 microA) and young rats (149.1+/-14 microA) was observed. Although in both groups morphine lowered the BSR threshold, there were no significant differences between the groups except at the 10-mg/kg dose, the difference did approach significance. This study indicates that there are baseline differences in the rewarding threshold in the two groups, that morphine lowers the threshold in young and aged animals and that the hedonic effects produced by morphine, for the most, part remain preserved in aged animals.

The effects of cocaine on the rate independent brain stimulation reward threshold in the mouse.

Interest in the development of mouse models of drug abuse liability has increased with the introduction of selective gene expression. In the rat, the ability of drugs to lower brain stimulation reward (BSR) thresholds often correlates with high abuse liability. Measurement of BSR thresholds using rate-independent methods decreases the influence of impaired motor performance on threshold determination that may confound studies of mutant mice. In the present experiment, the effects of cocaine on mouse BSR thresholds were assessed using a modification of the rate-independent psychophysical method of limits as current intensity was systematically varied in a series of descending and ascending discrete trials. Bipolar electrodes were implanted into the medial forebrain bundle of male C57Bl/6N mice and the effects of intraperitoneal saline and cocaine (5.0-30.0 mg/kg) on BSR thresholds were assessed using a within-subject crossover design. Threshold was defined as the intensity at which the mouse would respond in 50% of the trials. Threshold levels were significantly lowered below levels of control following cocaine administration with the maximum lowering following a 20.0-mg/kg dose. These findings indicate that cocaine increases the sensitivity of the mouse to BSR, and that BSR thresholds can be determined using rate-independent methods in this species.

Mechanisms underlying sleep-wake disturbances in alcoholism: focus on the cholinergic pedunculopontine tegmentum.

Sleep-wake (S-W) disturbances are frequently associated with alcohol use disorders (AUD), occurring during periods of active drinking, withdrawal, and abstinence. These S-W disturbances can persist after months or even years of abstinence, suggesting that chronic alcohol consumption may have enduring negative effects on both homeostatic and circadian sleep processes. It is now generally accepted that S-W disturbances in alcohol-dependent individuals are a significant cause of relapse in drinking. Although significant progress has been made in identifying the socio-economic burden and health risks of alcohol addiction, the underlying neurobiological mechanisms that lead to S-W disorders in AUD are poorly understood. Marked progress has been made in understanding the basic neurobiological mechanisms of how different sleep stages are normally regulated. This review article in seeking to explain the neurobiological mechanisms underlying S-W disturbances associated with AUD, describes an evidence-based, easily testable, novel hypothesis that chronic alcohol consumption induces neuroadaptive changes in the cholinergic cell compartment of the pedunculopontine tegmentum (CCC-PPT). These changes include increases in N-methyl-d-aspartate (NMDA) and kainate receptor sensitivity and a decrease in gamma-aminobutyric acid (GABAB)-receptor sensitivity in the CCC-PPT. Together these changes are the primary pathophysiological mechanisms that underlie S-W disturbances in AUD. This review is targeted for both basic neuroscientists in alcohol addiction research and clinicians who are in search of new and more effective therapeutic interventions to treat and/or eliminate sleep disorders associated with AUD.