Sensitivity to low doses of ethanol and pentobarbital in mice selected for sensitivity to hypnotic doses of ethanol.

These experiments assessed sensitivity to low doses of ethanol and pentobarbital in mice that had been selectively bred with respect to ethanol sleep time (the length of time an animal remains on its back following a hypnotic dose of ethanol). The hypothesis under investigation was that short-sleep (SS) mice might be more sensitive than long-sleep (LS) mice to excitatory effects produced by low doses of depressants. In support of this hypothesis SS mice were more active in an open-field test after ethanol than were LS mice. The lines did not differ in performance on a rotating-rod apparatus after these same doses of ethanol, suggesting that the difference in open-field activity was not attributable to a greater impairment of locomotor activity in LS mice. A similar difference in the open-field activity of the selected lines was observed with pentobarbital.     

Ethanol-induced grooming in mice selectively bred for differential sensitivity to ethanol

In rats, excessive grooming follows the application of several forms of stress. The injection of alcohol may be considered as a stressor, since it increases plasma corticosterone levels. The present study examines the effects of ethanol injections on grooming in two lines of mice selected for differences in their hypnotic response to ethanol, i.e., the long sleep (LS) and short sleep (SS) lines developed at the Institute for Behavior Genetics at the University of Colorado at Boulder. Various subhypnotic doses of ethanol produced excessive grooming in the SS line, but this did not occur in the LS line. The SS mice also displayed more "novelty-induced" grooming compared to the LS mice after repeated exposure to the testing situation. The increase in excessive grooming in both the ethanol-induced and the novelty-induced excessive grooming situations was most apparent in the second half of the observation period.     

Electrophysiological responses to ethanol, pentobarbital, and nicotine in mice genetically selected for differential sensitivity to ethanol

Cortical electroencephalographic (EEG) changes induced by ethanol (4.3 and 1.4 g/kg, ip), pentobarbital (50 and 16 mg/kg), and nicotine (1.0 g/kg) were examined in long-sleep (LS) and short-sleep (SS) mice that were genetically selected for differential sleep times induced by a hypnotic dosage of ethanol. Ethanol (4.3 g/kg) caused EEG changes that paralleled the behavioral differences, whereas no differences between selected lines were observed following the activating dose (1.4 g/kg). Data support the notion that the known difference in ethanol sleep times is due not to greater SS sensitivity to ethanol activation but rather to greater LS sensitivity to ethanol hypnosis. No differences between selected lines were observed following 50 mg/kg pentobarbital, which again parallels previous behavioral data. The SS mice were more responsive to pentobarbital activation (16 mg/kg). Nicotine more severely reduced EEG power and heart rate in LS mice; a continuous iv infusion of nicotine elicited a distinct pattern of behavioral stereotypy for each selected line, with more profound motor and reflex depression in LS mice. The lines do not differ in rate of nicotine metabolism, hence they must differ in central nervous system sensitivity to nicotine. Thus, lines of mice selectively bred for differential sensitivity to ethanol also display marked differences in electrophysiological and behavioral responses to nicotine.     

Alcohol intake in selected lines of mice: importance of sex and genotype.

Mice selected by McClearn and Kakihana for differences in ethanol-induced sleep time were used as subjects. In Experiment 1, mice from the long-sleep (LS) and short-sleep (SS) lines were offered a choice of water or solution GS consisting of 3% glucose and .16% sodium saccharin (w/v); or a choice of water or solution GS + E that contained GS solution plus 4% ethanol (w/v). In Experiment 2, mice from the first experiment were provided with a three-way choice among water, solution GS, and solution GS + E. In both experiments, SS mice (alcohol-insensitive) consumed more GS + E than LS mice (alcohol-sensitive). In addition, female mice drank considerably more GS + E solution than male mice. Thus, consumption of sweetened ethanol in both a two-way choice (water and GS + E) and a three-way choice (water, GS, and GS + E) is dependent on both genotype and sex. High genetic sensitivity to ethanol was associated with low consumption, and vice versa. Although females consumed more alcohol than males, famales of these lines have not been previously found to show lower sensitivity to acute alcohol administration.     

Dissociated control as a signature of typological variability in high hypnotic suggestibility

This study tested the prediction that dissociative tendencies modulate the impact of a hypnotic induction on cognitive control in different subtypes of highly suggestible individuals. Low suggestible (LS), low dissociative highly suggestible (LDHS), and high dissociative highly suggestible (HDHS) participants completed the Stroop color-naming task in control and hypnosis conditions. The magnitude of conflict adaptation (faster response times on incongruent trials preceded by an incongruent trial than those preceded by a congruent trial) was used as a measure of cognitive control. LS and LDHS participants displayed marginally superior up-regulation of cognitive control following a hypnotic induction, whereas HDHS participants’ performance declined. These findings indicate that dissociative tendencies modulate the influence of a hypnotic induction on cognitive control in high hypnotic suggestibility and suggest that HS individuals are comprised of distinct subtypes with dissimilar cognitive profiles.     

Effects of alpha and beta adrenergic antagonists on aggressive behavior in male mice

The effects of a variety of alpha and beta adrenergic antagonists were examined on the social encounters of isolated male mice with anosmic male partners. A range of alpha antagonists, including phentolamine, prazosin, and yohimbine, all suppressed social aggression. A range of beta antagonists, including propranolol, atenolol, metaprolol, and ICI 118, 551, also reduced this type of attack. Ethological assessment of the lowest effective dose of these adrenergic antagonists revealed a marked inhibitor action on offensive, social, and nonsocial behavior, while defensive responses and immobility were enhanced. It is concluded that the noradrenergic system has a significant non-specific role in mediating intermale aggression via both alpha and beta adrenergic receptor subtypes. © 1993 Wiley-Liss, Inc.     

Ethanol impairs memory of a simple discrimination in adolescent rats at doses that leave adult memory unaffected

Adolescent rats are less sensitive than adults to the hypothermic, anxiolytic, motor impairing, hypnotic, and lethal effects of ethanol. In vitro experiments nevertheless suggest that hippocampal neural activity is more affected by ethanol in preweanling or adolescent rats than in adults. These data are complemented by in vivo results showing that pretraining ethanol impairs learning in adolescent rats at doses that do not affect adult learning. In order to determine if posttraining ethanol affects memory differently in adolescents than in adults, Sprague-Dawley albino rats of both ages were trained in an appetitively motivated odor discrimination in which they were required to dig in scented sand for sweetened cereal reward. Immediately after training subjects received intraperitoneal injections of 0, 0.5, or 1g/kg ethanol (12.6%). At test, 48h later, subjects were presented with unbaited discriminanda and the time (s) spent digging in the S+ and S- was measured. Adolescents, but not adults, showed impaired discrimination performance if training was followed by ethanol. A subsequent experiment discounted the possibility that impaired adolescent performance was due to ethanol-induced conditioned taste or odor aversions. It thus appears that relative to adults, memory in adolescent rats is more strongly affected by ethanol in a test of appetitive conditioning that excludes ethanol's effects on sensory and motivational influences during the learning experience.     

The effects of atropine and adrenergic antagonists on behavioral arousal in rats

Two experiments investigated the mechanism for changes in measures of behavioral arousal inhibition in rats following administration of atropine. In Experiment 1, 40-day-old rats were given administrations of atropine sulfate, the alpha-, beta-adrenergic blocker labetalol, or both. The drugs, either alone or in combination, increased transport response intensity, whereas both together increased dorsal immobility durations. In Experiment 2, rats were given atropine, the beta-adrenergic antagonist propranolol, the alpha-adrenergic antagonist phentolamine, or a combination of two of the drugs. Propranolol blocked atropine-induced increases in transport response, and phentolamine was without effect. Phentolamine, when combined with atropine, increased dorsal immobility durations. Results are discussed with respect to aspects common to both transport response and dorsal immobility.     

The Effects of Atropine and Adrenergic Antagonists on Behavioral Arousal in Rats

Two experiments investigated the mechanism for changes in measures of behavioral arousal inhibition in rats following administration of atropine. In Experiment 1, 40-day-old rats were given administrations of atropine sulfate, the α-, β-adrenergic blocker labetalol, or both. The drugs, either alone or in combination, increased transport response intensity, whereas both together increased dorsal immobility durations. In Experiment 2, rats were given atropine, the β-adrenergic antagonist propranolol, the α-adrenergic antagonist phentolamine, or a combination of two of the drugs. Propranolol blocked atropine-induced increases in transport response, and phentolamine was without effect. Phentolamine, when combined with atropine, increased dorsal immobility durations. Results are discussed with respect to aspects common to both transport response and dorsal immobility.     

Compositional Semantics and Normative ‘Ought’

According to the paradigm view in linguistics and philosophical semantics, it is lexical semantics (LS) plus the principle of compositionality (PC) that allows us to compute the meaning of an arbitrary sentence. The job of LS is to assign meaning to individual expressions, whereas PC says how to combine these individual meanings into larger ones. In this paper I argue that the pair LS?+?PC fails to account for the discourse-relevant meaning of normative ‘ought’. If my hypothesis is tenable, then the failure of LS?+?CS extends to normative language in general. The reason I offer that this is so is that semantics for normative language is, in an important respect, a substantive semantics (SS). The ‘substantive’ in question means that the meaning of normative vocabulary in use is driven by metanormative views associated with a particular normative concept. SS rejects the model LS?+?CS and replaces it with a discourse-relevant semantics built around an interactional principle that ascribes to a particular surface syntactical form of ‘ought’ sentences a logical form that represents its discourse-salient normative content. In the paper I shall sketch how SS works and why it is worth serious consideration.

     

Psychological treatment of hypnotic-dependent insomnia in a primarily older adult sample

Objective

This study tested cognitive behavior therapy (CBT) in hypnotic-dependent, late middle-age and older adults with insomnia.

Method

Seventy volunteers age 50 and older were randomized to CBT plus drug withdrawal, placebo biofeedback (PL) plus drug withdrawal, or drug withdrawal (MED) only. The CBT and PL groups received eight, 45 min weekly treatment sessions. The drug withdrawal protocol comprised slow tapering monitored with about six biweekly, 30 min sessions. Assessment including polysomnography (PSG), sleep diaries, hypnotic consumption, daytime functioning questionnaires, and drug screens collected at baseline, posttreatment, and 1-year follow-up.

Results

Only the CBT group showed significant sleep diary improvement, sleep onset latency significantly decreased at posttreatment. For all sleep diary measures for all groups, including MED, sleep trended to improvement from baseline to follow-up. Most PSG sleep variables did not significantly change. There were no significant between group differences in medication reduction. Compared to baseline, the three groups decreased hypnotic use at posttreatment, down 84%, and follow-up, down 66%. There was no evidence of withdrawal side-effects. Daytime functioning, including anxiety and depression, improved by posttreatment. Rigorous methodological features, including documentation of strong treatment implementation and the presence of a credible placebo, elevated the confidence due these findings.

Conclusions

Gradual drug withdrawal was associated with substantial hypnotic reduction at posttreatment and follow-up, and withdrawal side-effects were absent. When supplemented with CBT, participants accrued incremental self-reported, but not PSG, sleep benefits.     

Reactivity and aggression in the rat: induction by alpha-adrenergic blocking agents injected ventral to anterior septum but not into lateral septum.

Intracranial injections were made bilaterally through permanently implanted cannulas ending in the lateral septum or in the region ventral to the anterior septum. The rats were first screened with injections of a local anesthetic, lidocaine, which blocks both synaptic and axonal conduction. Those animals that showed an increase in reactivity and aggression were then injected with a synaptic transmitter blocking agent. The results showed that transmitter blocking agents reproduced the effect of the local anesthetic only in the region ventral to the anterior septum and that alpha-adrenergic (phentolamine, tolazoline), but not beta-adrenergic (propranolol, hydralazine), cholinergic (atropine, hyocine), or dopaminergic (haloperidol) blocking agents were effective. These results suggest that synapses in the forebrain system controlling reactivity and aggression are alpha-asrenergic and are located in the region ventral to the anterior septum just lateral to the diagonal band of Broca. The septum itself may be involved only to the extent that it is traversed by fibers of passage.     

Acute effects of viloxazine HCl and flurazepam when given alone and in combination on sleep EEG: A double-blind interaction study with normals

Viloxazine, an aryl-oxypropanolamine type β-adreno-receptor antagonist, has been used in the treatment of depression. In a double-blind drug interaction study with flurazepam, a commonly used benzodiazepine hypnotic, viloxazine administered alone decreased the amount of time spent in REM sleep, increased the amount of time in the “light” stages of sleep, and increased the number of transitions to awake. However, no interactive effects of the combined administration of viloxazine and flurazepam could be detected.     

Effects of sleep deprivation on free-operant avoidance

Two studies examined effects of sleep deprivation on free-operant avoidance by rats. In Experiment 1, a 5-s shock-shock (SS) interval and 20-s response-shock (RS) interval produced baseline performances, which were reestablished after each experimental manipulation. Once baselines were established, animals were exposed to 24, 48, or 96 hr of sleep deprivation and equivalent periods of home cage and food restriction as a control condition. Compared to baseline, sleep deprivation increased response rates by increasing the proportion of brief interresponse times (IRTs); response rates changed little in the control conditions. Percentage of shocks avoided did not systematically change across conditions. In Experiment 2, the RS interval was manipulated (10, 20, and 40 s), while the SS interval (5 s) and level of sleep deprivation (48 hr) were held constant. Across RS intervals, sleep deprivation increased response rates via a shift toward brief IRTs. In addition, sleep deprivation increased the percentage of shocks avoided as an inverse function of RS intervals.     

The behavioral treatment of insomnia an alternative to drug therapy.

The use of hypnotic drugs to treat insomnia is criticized because of (a) tolerance effects, (b) carry-over effects, (c) alterations in sleep patterns, (d) rebound effects, and (e) attributional effects. Behavioral treatments represent a more viable alternative and are reviewed under four headings: (a) systematic desensitization: (b) applied relaxation; (c) attribution-based therapies; and (d) classical conditioning therapies. The behavioral therapies are predicated upon three views of insomnia: first, that insomnia results from excessively high levels of arousal prior to and during sleep; second, that insomnia occurs when the sleep environment lacks sufficient stimulus control over sleeping; and finally, that insomnia is often enhanced and maintained by exacerbation cycles in which worries about not falling asleep interfere even further with one's sleep.     

Selective autonomic blockade of conditioned and unconditioned cardiovascular changes in rhesus monkeys (Macaca mulatta).

Changes in heart rate and in systolic and diastolic blood pressures were examined in eight rhesus monkeys during six sessions of differential classical conditioning. The conditioned stimuli consisted of tones differing in frequency and the unconditioned stimuli consisted of tail shock. Both the conditioned responses (CRS) and unconditioned responses (UCRs) consisted of increases in heart rate and in systolic and diastolic pressures, but blood pressure CRs sometimes occurred in the absence of heart rate CRs. Graded doses of the selective blocking agents propranolol, phentolamine, and atropine methylnitrate were systemically administered to four of the monkeys prior to additional conditioning sessions. The results suggested that the CRs and UCRs were mediated by both sympathetic and parasympathetic influences.     

Hypnotic discontinuation in chronic insomnia: impact of psychological distress, readiness to change, and self-efficacy.

OBJECTIVE: To compare individuals who were successful in discontinuing hypnotic medications against those who were not on measures of insomnia severity, medication withdrawal symptoms, psychological symptoms, perceived health, readiness to change and self-efficacy. DESIGN: Secondary analyses of a randomized clinical trial comparing a hypnotic taper intervention with or without self-help treatment for insomnia. MAIN OUTCOME MEASURES: Self-report measures of insomnia severity, medication withdrawal symptoms, depression and anxiety symptoms, physical and mental health, stages of change, readiness to change, decisional balance, and general and situational self-efficacy. RESULTS: There were no significant differences at baseline between medication-free individuals and those still using sleep medication at the end of a taper intervention. Group differences emerged midway through the 8-week withdrawal program and were accentuated after the intervention; participants who remained medication-free during the next six months had less severe insomnia and anxiety symptoms, a more positive perception of their health and higher self-efficacy to refrain from hypnotic use in various situations. Contrary to expectations, there were no differences between drug-free and nondrug-free participants on both readiness to change and stages of change. CONCLUSIONS: Chronic users of hypnotic medications entered a taper intervention with equal levels of psychological distress, health, self-efficacy, and readiness to change. Successful hypnotic discontinuation was associated with overall improvement of insomnia, anxiety and distress symptoms, perceived health and self-efficacy. More intensive and individualized therapeutic attention may be warranted for individuals experiencing worsening of insomnia symptoms, more withdrawal symptoms and psychological distress, and lower self-efficacy during medication discontinuation.     

Self-efficacy and compliance with benzodiazepine taper in older adults with chronic insomnia.

Better understanding of compliance with BZD taper is warranted. Compliance with a taper program and perceived self-efficacy (SE) in being able to comply with hypnotic reduction goals was monitored weekly in 52 older adults (mean age: 63.0 years) with chronic insomnia (average duration: 21.9 years) who underwent a 10-week physician-supervised medication tapering. One group received cognitive- behavior therapy for insomnia during discontinuation, whereas the other did not. Compliant patients showed higher SE ratings at Weeks 6, 8, 9, and 10. Medication-free patients at the end of the treatment also reported higher mean SE ratings at those 4 weeks. Differences remained significant when withdrawal symptoms and sleep efficiency were controlled for. These results have important clinical implications because SE may indicate key time points when patients are experiencing more difficulty during discontinuation.     

Chronic propranolol induces deficits in retention but not acquisition performance in the water maze in mice

Agents that alter adrenergic receptors, such as "beta-blockers," also alter memory storage. However, reports suggest that beta-adrenergic receptor antagonists, such as propranolol, have conflicting behavioral effects with acute vs chronic dosing. This study was designed to evaluate the effects of chronic propranolol on retention for a spatial learning task. Adult male ICR mice were given daily injections of propranolol (2, 4, 8, or 12 mg/kg ip) or 0. 9% NaCl for 15 days prior to, and during, trials in a Morris water maze. Mice received five massed acquisition (escape) trials in each of three daily sessions, followed by a single 60-s probe trial on the fourth day. The location of the submerged platform was constant for each animal over acquisition trials, but varied across animals; starting position varied across trials. A 5 (dose) x 3 (trial blocks) mixed factorial ANOVA for escape time yielded a significant trial blocks effect only (p <.001), showing performance improving over sessions. Time spent in the target quadrant on the probe trial was shorter under all doses of propranolol when compared to vehicle group (all p <.001), indicating poorer retention of prior platform location. This effect, however, was not dose-related. Swim speed was not significantly affected by propranolol. These data demonstrate that chronic dosing with propranolol can impair retention of spatial learning, which cannot be attributed to reduced arousal or motor function.     

The effect of home or novel environment on the facilitation of passive avoidance by post-training ethanol

Passive avoidance behavior of mice is improved when mice are injected with ethanol immediately after footshock training. Further study has shown that avoidance can be affected by ethanol injections given within 1 h, but not at 90 or 180 min, after training. The present study was conducted to investigate the possibility that events which occur in the homecage during this sensitive period may influence the effect of ethanol on subsequent avoidance. Male Swiss-Webster mice were housed either singly in a novel environment for 90 min or returned to their (group) homecage following one-trial, step-through, passive avoidance training (0.1 mA footshock) and intraperitoneal injection of 3.0 g/kg ethanol (15% v/v) or saline. As in previous studies, when ethanol-treated mice were returned to their homecage, avoidance was significantly increased at 24 h compared to the behavior of saline-treated mice. However, when mice were isolated in the novel environment for 90 min immediately following treatment, the memory facilitating effects of ethanol were not observed. The avoidance behavior of mice injected with saline was the same regardless of their post-training environment. Also, the number of mice (6 or 10) housed per homecage did not significantly influence the effects of ethanol or post-training environment on avoidance. These findings indicate that environmental factors may interact with the effects of ethanol to modify avoidance behavior. The possible influence of variables such as aggression, thermoregulation, and behavioral arousal on the effects of ethanol in this paradigm are discussed.