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.

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.

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.

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.

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.

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 effects of venlafaxine and cognitive behavioral therapy alone and combined in the treatment of co-morbid alcohol use-anxiety disorders.

The effects of the antidepressant venlafaxine (VEN-225 mg daily) and transdiagnostic cognitive behavioral treatment (CBT) alone and in combination on alcohol intake in subjects with co-morbid alcohol use disorders (AUDs) and anxiety disorders were compared. Drinking outcomes and anxiety were assessed for 81 subjects treated for 11 weeks with one of 4 conditions: 1) VEN-CBT, 2) VEN-Progressive Muscle Relaxation therapy (PMR), 3) Placebo (PLC)-CBT and 4) a comparison group of PLC-PMR. For subjects who reported taking at least one dose of study medication, the Time×Group interaction was significant for percent days of heavy drinking and drinks consumed per day. For the measure of percent days heavy drinking, the paired comparison of PLC-CBT versus PLC-PMR group indicated that the PLC-CBT group had greater drinking reductions, whereas other groups were not superior to the comparison group. In Week 11, the proportion of subjects in the PLC-CBT group that had a 50% reduction from baseline in percent days heavy drinking was significantly greater than those in the comparison group. Of the 3 "active treatment" groups only the PLC-CBT group had significantly decreased heavy drinking when contrasted to the comparison group. This finding suggests that the transdiagnostic CBT approach of Barlow and colleagues may have value in the management of heavy drinking in individuals with co-morbid alcoholism and anxiety.

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.

Haloperidol overdosing in the treatment of agitated hospitalized older people with delirium: a retrospective chart review from a community teaching hospital.

BACKGROUND: Practice guidelines recommend the use of low dose haloperidol when medication is needed to treat delirium with acute agitation in hospitalized older people. Despite this, high dose haloperidol may frequently be used and result in higher rates of complications. OBJECTIVE: To describe dosages and effects of haloperidol used in the initial treatment of delirium with acute agitation in hospitalized older people, and prescriber use of low and high dose haloperidol. METHODS: Retrospective chart reviews were performed from June 2008 to May 2009 in a community teaching hospital located in Upland, PA, USA. Patients aged 65 years and older with acute agitated delirium were included. Patients admitted to ICU and those with psychiatric conditions were excluded. Data were collected on haloperidol dosing, responses, sedation, length of stay, and concurrent use of lorazepam. RESULTS: A total of 261 charts of patients who received haloperidol were reviewed and 56 patients met inclusion criteria (14 males, 42 females). The mean age of subjects was 83 years. The recommended starting dose of haloperidol (0.5 mg) was administered to 35.7 % of the patients. An initial dose of more than 1 mg was received by 37.5 % of the patients. The remaining 26.8 % of patients received 1 mg. The relative risk of sedation was significantly greater for subjects receiving more than 1 mg of haloperidol in 24 h. The length of hospitalization was not predicted by haloperidol doses or lorazepam but by the number of days of agitation. CONCLUSIONS: Higher than recommended initial doses of haloperidol were frequently used in the treatment of delirium with acute agitation in hospitalized older people. We found no evidence to suggest that higher dosages were more effective in decreasing the duration of agitation or the length of hospital stay. Low dose haloperidol appears to be as effective as and safer than higher doses in the treatment of acute agitation in this older population.

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.

Medial forebrain stimulation enhances intracranial nociception and attenuates morphine analgesia suggesting the existence of an endogenous opioid antagonist.

The purpose of this experiment was to test in the rat the hypotheses that activation of the brain reward system would attenuate the effects of intracranial nociceptive stimulation and would potentiate the antinociceptive effects of morphine. In this experiment pain (nociception) was generated by electrical stimulation of a brain pain pathway, the mesencephalic reticular formation (MRF) of the rat. Reward pathway stimulation was to the medial forebrain bundle at the level of the lateral hypothalamus (MFB-LH). Current thresholds for escape from MRF stimulation were determined using a modification of the psychophysical methods of limits. MRF stimulation was delivered concurrently with different intensities of non-contingent MFB-LH stimulation. The effects of morphine and saline were determined under all stimulation conditions. Contrary to expectation MFB-LH stimulation significantly lowered MRF stimulation escape thresholds. Morphine administration elevated MRF thresholds in the absence of MFB-LH stimulation. However, this effect was blocked by concurrent MFB-LH stimulation. These findings, which mimic the effects of the opiate antagonist naloxone, i.e., potentiating of pain and antagonism of morphine's analgesic effects, suggest the presence of an endogenous opiate receptor antagonist.

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.

Deep brain stimulation of the nucleus accumbens reduces ethanol consumption in rats.

Recent studies have shown that deep brain stimulation (DBS) of the nucleus accumbens (NAcc) has an inhibitory effect on drug-seeking behaviors including reinstatement responding for cocaine. The objective of the present study was to expand on these findings by assessing the effects of DBS on behaviors related to alcohol consumption. The specific aim of this study was to determine whether DBS delivered to either the shell or core of the NAcc would reduce ETOH intake in rats using a two-bottle choice limited access procedure. Long Evans rats were induced to drink a 10% ethanol solution using a saccharin fading procedure. Bipolar electrodes were implanted bilaterally into either the core or shell of the NAcc. During testing animals received DBS 5 min prior to and during a 30-minute test session in which both ETOH and water bottles were accessible. Current was delivered at amplitudes ranging from 0 to 150 microA. ETOH consumption was significantly reduced from baseline levels at the 150 microA current for both shell and core electrode placements. A significant current effect was not found for water consumption for either site. These results provide evidence that DBS delivered either to the nucleus accumbens core or shell subregions can significantly reduce ethanol intake in the rat.

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 effects of levetiracetam on alcohol consumption in alcohol-dependent subjects: an open label study.

The aim of this open-label pilot study was to assess the efficacy and safety of the novel anticonvulsant agent, levetiracetam, for the treatment of alcohol dependence. A maximal dose of 2000 mg was administered daily for 10 weeks to alcohol dependent subjects (n = 20). Mean reported ethanol intake declined significantly from 5.3 to 1.7 standard drinks per day. Levetiracetam was well tolerated by most subjects.

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.

Effects of low dose cocaine on REM sleep in the freely moving rat.

Cocaine administration can be disruptive to sleep. In compulsive cocaine users, sleep disruption may be a factor contributing to relapse. The effects of cocaine on sleep, particularly those produced by low doses, have not been extensively studied. Low dose cocaine may stimulate brain reward systems that are linked to the liability of abusing of this drug. This study was designed to assess the effects of the acute administration of low to moderate cocaine doses on sleep in the rat. Polygraphic recordings were obtained from freely moving, chronically instrumented rats over a 6-h period after the administration of either cocaine (as a 2.5-10 mg/kg intraperitoneal dose) or saline. Following cocaine administration, time spent by the rats in wakefulness increased and slow wave sleep decreased in a dose-dependent manner, compared to controls. These changes lasted between 1 to 3 h following the cocaine administration. Rapid eye movement (REM) sleep was decreased during a 2- to 3-h period following the injection of 5 and 10 mg/kg doses of cocaine. In contrast, REM sleep increased during the periods 2-4 h after the administration of 2.5 and 5 mg/kg doses of cocaine. These results indicate that sleep can be significantly altered by low doses of cocaine when administered subacutely.