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

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 investigated was that short-sleep (SS) Ss might be more sensitive than long-sleep (LS) Ss to excitatory effects produced by low doses of depressants. In support of this hypothesis, SS Ss were more active in an open-field test after ethanol than were LS Ss. Two experiments were conducted, using 88 LS and 88 SS Ss. 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 Ss. A similar difference in the open-field activity of the selected lines was observed with pentobarbital. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of hypnotics on mice genetically selected for sensitivity to ethanol

It was previously shown that the rate of disappearance of blood ethanol was identical for two lines of mice selectively bred for differences in sleep-time after ethanol administration. The ED50 values for the loss of righting response with ethanol were significantly different at 3.64 g per kg for the SS line and 1.65 g per kg for the LS line. In the present study the mean sleep time is 367 sec for SS mice and 9342 sec for LS mice. The ED50 values remain essentially the same as previously reported. Unchanged LD50 values for ethanol, however, are not different at 4.8 g per kg for the SS and 4.5 g per kg for the LS line of mice. The ED50 value for loss for righting response following administration of methanol, butanol and t-butanol is approximately 2 fold greater for the SS line of mice than for the LS line. The ED50 values for sodium pentobarbital or ether in the 2 lines of mice for loss of righting response are virtually identical. In addition, the sleep-time values obtained after the administration of pentobarbital, chloral hydrate, trichloroethanol and paraldehyde are not significantly different. These data indicate that while the SS and LS lines of mice differ in central nervous system sensitivity to ethanol, methanol, butanol and t-butanol it is implied that they do no differ in central nervous system sensitivity to other hypnotic agents tested. Proof of this latter suggestion awaits determination of metabolic rates, and brain levels of these other depressants.     

Genetic determinants of sensitivity to ethanol in inbred mice.

Mice from 15 inbred strains (n?=?27–40 per strain) differed in sensitivity to ethanol-induced effects on open-field activity, hypothermia, rotarod ataxia, and anesthesia. Sensitivities to the different behavioral responses were generally uncorrelated. This suggests that the genetic determinants of behavioral sensitivity to one domain of ethanol effects are unrelated to those determining other responses. On the other hand, some variables were genetically related. For example, those strains sensitive to the loss of righting reflex induced by higher doses of ethanol showed reduced activity in the open field at lower doses and were more sensitive to ethanol-induced decreases in rearing. More generally, the pattern of results suggests that genetically influenced sensitivity to ethanol is not a monolithic phenomenon. Rather, it is specific to the particular response variable studied. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Subjective responses to intravenous nicotine: Greater sensitivity in women than in men.

Although approximately 45% of smokers in the United States are women, the influence of sex on nicotine dependence remains incompletely understood. Evidence from preclinical and clinical studies has indicated that there are significant sex differences in nicotine's effects. The authors' goal in this report was to determine whether men and women differ in their acute response to intravenous nicotine, which has not been examined in previous studies. Twelve male and 12 female smokers received saline followed by 0.5 mg/70 kg and 1.0 mg /70 kg nicotine intravenously. In response to nicotine, women, as compared with men, had enhanced ratings for drug strength, head rush, and bad effects. Women and men experienced similar suppression of smoking urges by nicotine as assessed by the Brief Questionnaire on Smoking Urges. Nicotine-induced heart rate and systolic and diastolic blood pressure increases were also similar in magnitude in men and women. The findings, consistent with those of several previous studies, support greater sensitivity of female smokers to some but not all of the subjective effects of nicotine. Further studies are warranted to examine the role of this differential nicotine sensitivity to development of nicotine dependence and response to nicotine replacement treatments in men and women. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ethanol-related traits in mice selectively bred for differential sensitivity to methamphetamine-induced activation.

Acute drug stimulation has been proposed to be an endophenotype for drug abuse. The authors previously reported the short-term selective breeding of lines of mice for low (LMACT) and high (HMACT) stimulation to methamphetamine (MA). These mice were used to examine whether common genes influence the locomotor response to MA and ethanol. Additionally, the authors tested these mice for ethanol drinking, locomotor sensitization, and clearance. LMACT mice were less stimulated by ethanol and consumed more ethanol than HMACT mice, but the lines did not differ in ethanol-induced sensitization. A small difference in ethanol clearance rate (0.1 mg/ml/h) likely had little impact on behavior. Some common genes may influence the locomotor response to MA and ethanol, as well as ethanol drinking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Corticosterone increases severity of acute withdrawal from ethanol, pentobarbital, and diazepam in mice

It has been suggested that withdrawal from several subclasses of central nervous system (CNS) depressants involves common underlying mechanisms. For example, mice genetically selected for severe ethanol withdrawal convulsions (Withdrawal Seizure Prone or WSP) have also been found to express severe withdrawal following treatment with barbiturates and benzodiazepines. Corticosteroids appear to modulate severity of withdrawal from CNS depressants. Therefore, it was hypothesized that corticosterone would enhance withdrawal convulsions following acute ethanol, pentobarbital, and diazepam in WSP mice. Corticosterone (20 mg/kg) administered following each of these drugs significantly increased severity of handling-induced convulsions during withdrawal. Corticosterone did not affect pre-withdrawal convulsion scores or handling-induced convulsions of drug-naive mice. These results suggest that withdrawal convulsions following acute ethanol, pentobarbital, and diazepam are sensitive to modulation by corticosterone and they support the hypothesis that stress may increase drug withdrawal severity.     

Acute functional tolerance to ethanol and fear conditioning are genetically correlated in mice

It has been speculated that tolerance to alcohol involves some form of neuronal plasticity that is similar to or the same as that mediating learning and memory. To investigate this possibility further, we tested the hypothesis that acute functional tolerance (AFT) to alcohol is genetically correlated to a Pavlovian learning task: fear conditioning. Mice selectively bred for differences in ability to acquire AFT were tested for fear conditioning. Subjects received a mild footshock paired to a broadband clicker and were tested 24 hr later for their freezing response to the conditioning chamber (context), to an altered chamber, and to the clicker. Both the original and replicate lines selected for high AFT (HAFT) were found to freeze significantly more than those selected for low AFT (LAFT) in response to the context and to the clicker. In a second experiment, an F2 population derived from the C57BL/6 (B6) and DBA/2 (D2) mouse strains were tested first for fear conditioning, followed 3 weeks later by AFT testing. AFT was defined as the difference between blood alcohol levels determined at the time of regain balance on a dowel rod first after 1.75 g/kg of ethanol and again after a subsequent dose of 2.0 g/kg. Consistent with results from HAFT and LAFT, freezing to context was found to be significantly positively correlated to AFT (r = 0.38, p = 0.04) in the F2 mice. The results suggest that co-variation in fear conditioning and AFT may be mediated by one or more of the same or at least tightly linked genes. Further dissection of this correlation may reveal neuronal mechanisms common to both AFT and fear conditioning.     

Electrophysiological responses to coarticulatory and word level miscues.

The influence of coarticulation cues on spoken word recognition is not yet well understood. This acoustic/phonetic variation may be processed early and recognized as sensory noise to be stripped away, or it may influence processing at a later prelexical stage. The present study used event-related potentials (ERPs) in a picture/spoken word matching paradigm to examine the temporal dynamics of stimuli systematically violating expectations at three levels: entire word (lexical), initial phoneme (phonemic), or in coarticulation cues contained in the initial phoneme (subphonemic). We found that both coarticulatory and phonemic mismatches resulted in increased negativity in the N280, interpreted as indexing prelexical processing of subphonemic information. Further analyses revealed that the point of uniqueness differentially modulated subsequent early or late negativity depending on whether the first or second segment matched expectations, respectively. Finally, it was found that word-level but not coarticulatory mismatches modulated the later-going N400 component, indicating that subphonemic information does not influence word-level selection provided no lexical change has occurred. The results indicate that acoustic/phonetic variation resulting from coarticulation is preserved in and influences spoken word recognition as it becomes available, particularly during prelexical processing. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Sensitivity to ethanol in inbred mice: Genotypic correlations among several behavioral responses.

Assessed the sensitivity of 20 inbred strains of mice for ethanol's effects on activity, body temperature, ataxia, balance, and the righting reflex. Genotypic correlations among the mean responses for the strains were estimated as indices of pleiotropic influences of genes on drug responses. Three major groups of genetic influence were detected: (a) hypothermic sensitivity to ethanol, (b) activity change, and (c) high basal activity. In the 1st group of variables, strains that had large reductions in body temperature after being given ethanol had high baseline temperatures, a pronounced ataxic response to ethanol, and a long-lasting loss of righting reflex. The 2nd group was composed largely of ethanol-induced increases and decreases in activity. Strains with larger increases in activity showed more rapid loss of balance after ethanol. The 3rd group indicated that high levels of basal activity in an open field and in the home cage were determined by the action of common genes. Strains with higher basal activity levels had reduced sensitivity to ambulatory ataxia following ethanol. Thus, there were substantial pleiotropic effects of common genes on several behavioral responses to ethanol. Conversely, the 3 major groups were not systematically correlated with one another to a major extent. This suggests the influence of 3 reasonably distinct sets of genes on these responses to ethanol. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sensitivity to cocaine and amphetamine among mice selectively bred for differential cocaine sensitivity

Recently developed Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) have been shown to be reliable for diagnosing and assessing TMD in U.S. and Swedish adult populations; however, few studies have focused on clinical examination methods and diagnostic criteria for use with children and adolescents. The present study used a sample of 50 Swedish children and adolescents, aged 12 to 18 years, to evaluate usefulness and reliability of existing and specially developed measures and methods for assessing and diagnosing TMD in youth. Subjects underwent repeated clinical exams by two calibrated examiners to assess signs and symptoms per the RDC/TMD, and they responded to a specially developed self-administered questionnaire that addressed location and frequency of TMD-related pain and symptoms, jaw function, effect of pain on daily activities, and use of pain medications. Interexaminer and intraexaminer reliability was assessed for clinical examination, questionnaire items, and diagnosis. Reliability values ranged from acceptable to excellent for the RDC/TMD clinical exam and questionnaire, and from good to excellent reliability for measuring virtually all modified clinical parameters of TMD assessed in these young patients.     

Individual differences in sensitivity to nicotine: implications for genetic research on nicotine dependence

Recent evidence suggests that cigarette smoking has a heritability index around 53%. While related research on underlying mechanisms also supports the idea that genetic factors contribute to nicotine dependence--as well as to cofactors such as substance use and mood disorders--the nature of the behavioral traits and biological capacity for reinforcement that constitutes vulnerability to nicotine dependence is not well understood. The present review explores the problem of why some people become highly nicotine dependent, others develop a pattern of occasional use, and still others avoid the drug entirely despite extensive exposure and widespread experimentation with tobacco in the population. Recent research--both infrahuman and human--suggests that vulnerability to nicotine dependence is related to high initial sensitivity to nicotine and that the development of tolerance is more rapid and self-administration more extensive in such individuals. Relevant findings from neuroscience and biobehavioral research are reviewed in order to identify variables and methodologies that might improve the reliability and validity of behavioral and molecular genetic studies on cigarette smoking. The integration of research in these areas may lead to new insights in the understanding of nicotine dependence as well as to improved techniques for prevention and treatment.     

Confirmation of quantitative trait loci for ethanol sensitivity in long-sleep and short-sleep mice

PURPOSE: To determine the efficacy of the combination of cisplatin, fluorouracil, and high-dose l-leucovorin (PFL) as organ-preserving induction therapy followed by radiotherapy in untreated patients with advanced squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: This was a phase II study of PFL in 47 patients with resectable stage III (n = 20) and IV (n = 27) M0 squamous cell carcinoma of the head and neck, including larynx (n = 20), hypopharynx (n = 14), and oropharynx (n = 13). The PFL regimen consisted of cisplatin 25 mg/m2 on days 1 through 5, fluorouracil 800 mg/m2 CI on days 2 through 6, and l-leucovorin 250 mg/m2 on days 1 through 6, all by continuous intravenous infusion every 21 to 28 days for three courses. The primary study endpoint was initial response to and local disease control rate with PFL as induction chemotherapy, with an aim to confirm the previously reported complete response rate of 60% to 70%. RESULTS: Of 47 patients enrolled, 46 were evaluable for response to PFL, 14 (30%) achieved a complete response, and 25 (54%) achieved a partial response, for an overall response rate of 84%. Of 39 patients evaluable for response after radiation therapy, 27 (69%) achieved a complete response and 11 (28%) a partial response. Local disease control was achieved in 37 of 46 (80%). Grade 3 or 4 toxic effects occurred frequently, with neutropenia in 27 (59%) of 46 evaluable patients, thrombocytopenia in 30%, mucositis in 41%, diarrhea in 13%, and nausea/ vomiting in 13%, but there were no treatment-related deaths. With a median follow-up of 35 months there have been nine recurrences (four local/regional and five distant) and 17 deaths (12 in patients with disease progression and five not directly related to the primary tumor). Second primary tumors have developed in six patients. At 3 years 62% of the patients remain alive with no disease progression, and the 3-year survival estimate with preserved organ function is 66%. CONCLUSION: PFL induction chemotherapy produced only a modest complete response rate, possibly due to suboptimal dose intensity, and was associated with substantial, although not life-threatening, toxicity. Newer regimens and treatment modalities are still needed in the management of advanced squamous cell carcinoma of the head and neck.     

Subjective responses to nicotine in smokers may be associated with responses to caffeine and to alcohol.

Sensitivity in responses to one drug may relate to sensitivity to other drugs, suggesting broad individual differences in characteristic responsivity across drugs. Data from two separate studies of smokers were reanalyzed to examine associations between acute subjective and cardiovascular effects of nicotine vs. caffeine and between nicotine vs. alcohol. Typical intakes of cigarettes, alcohol, and caffeine were included as covariates when they were correlated with the responses of interest. Significant associations between nicotine and caffeine were seen for most of the subjective measures and for blood pressure responses. Fewer significant associations were observed between nicotine and alcohol. Responses associated between nicotine and both of the other drugs tended to reflect psychomotor stimulation. These results suggest that smokers who are more responsive to some of nicotine's subjective and blood pressure effects are also more sensitive to the same effects of caffeine and, to a lesser extent, of alcohol. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pharmacologic actions of subtype-selective and novel GABAergic ligands in rat lines with differential sensitivity to ethanol

Alcohol-nontolerant (ANT) rats, produced by selective breeding for high sensitivity to motor-impairing effects of ethanol, have a point mutation in the cerebellar gamma-aminobutyric acid type A (GABAA) receptor alpha 6 subunit, which has been proposed to underlie enhanced sensitivity to benzodiazepine agonists as well. We compared ANT and alcohol-tolerant (AT) rats using behavioral and neurochemical methods to assess the significance of alpha 6- and non alpha 6-containing GABAA receptor subtypes. Motor performance in a tilting plane test was largely unaffected by a type I benzodiazepine receptor-preferring agonist, zolpidem [1-10 mg/kg, intraperitoneally (IP)], partial benzodiazepine agonists bretazenil and ZG-63 (both at 40 mg/kg, IP), and a novel broad-spectrum anticonvulsant loreclezole (40 mg/kg, IP) in both ANT and AT rats. In contrast, diazepam (10 mg/kg, IP) impaired performance of the ANT but not AT animals. These data, supported by results from brain regional autoradiography of [3H]Ro15-4513 and membrane binding of [3H]ZG-63 and [35S]TBPS as influenced by these ligands, strongly suggest that only ligands with full agonist actions on mutant (ANT) but not wild-type (AT) alpha 6-containing GABAA receptors are able to produce motor impairment in the ANT rats.     

Brown adipose tissue. III. Effect of ethanol, nicotine and caffeine exposure

Brown adipose tissue is known to be the most important organ for generating heat in non-shivering thermogenesis. Process of thermogenesis and thermoregulation may be affected by many drugs. The paper deals with actual literary data of effect of ethanol, nicotine and caffeine on brown adipose tissue, heat production and its regulation in experimental animals and in human.     

Increased sensitivity to the aversive effects of ethanol in PKCε null mice revealed by place conditioning.

Determining the intracellular signaling pathways that mediate the rewarding effects of ethanol may help identify drug targets to curb excessive alcohol consumption. Mice lacking the epsilon isoform of protein kinase C (PKCε) voluntarily consumed less ethanol than wild-type mice in two-bottle choice and operant self-administration assays. Decreased consumption may reflect either increased or decreased sensitivity to the rewarding effects of ethanol. Alternatively, decreased voluntary consumption may reflect a change in sensitivity to the aversive effects of ethanol. The authors used place conditioning to determine that PKCε null mice have an increased sensitivity to the aversive effects of ethanol but a decreased sensitivity to the rewarding effects of ethanol. Together these data suggest that PKCε null mice voluntarily consume less ethanol because they derive less reward and are more sensitive to the aversive effects of ethanol. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral, physiological, and neuroendocrine stress responses and differential sensitivity to diazepam in two Wistar rat lines selectively bred for high- and low-anxiety-related behavior

Two Wistar rat lines, selectively bred for high-anxiety-related behavior (HAB) and low-anxiety-related behavior (LAB) in the elevated plus-maze test, were tested for the susceptibility of their behavioral characteristics to anxiolytic treatment and for their endocrine and physiological reactivity to different stressors. Injection of 1 mg/kg diazepam failed to affect line differences in coping strategy but resulted in a marked (20-fold) decrease in plus-maze anxiety in HAB rats; whereas, the anxiolytic effect was less pronounced in LAB animals. Biotelemetrical measurements revealed that HAB and LAB rats do not significantly differ in their baseline body temperature, locomotor activity, food and water intake, or in stress-induced alterations of the diurnal rhythms in these parameters. However, line differences were found in acute changes in body temperature and locomotor activity following stress exposure, LAB rats responding with a greater, albeit shorter, increase in body temperature and activity than HAB animals. Basal ACTH and corticosterone plasma levels as well as pituitary reactivity to intravenously administered CRH (40 ng/kg) were similar in both lines, although, especially in response to plus-maze exposure, HAB rats tended toward higher ACTH secretion than LAB rats. These data confirm that animals with high or low basal levels of anxiety may be a promising model for studying the mechanisms of action of anxiolytic substances. Nevertheless, the endocrine findings support the notion that the reactivity of the hypothalamo-pituitary-adrenocortical system and anxiety-related behavior can be regulated independently.     

Greater sensitivity to subjective effects of nicotine in nonsmokers high in sensation seeking.

The personality characteristic of sensation seeking is associated with risk of smoking, perhaps because of greater initial sensitivity to nicotine. Young healthy nonsmokers (N?=?37) were administered 0, 10, and 20 μg/kg nicotine by nasal spray in 3 separate sessions, and subjective responses were assessed. Sensation-Seeking Scale (SSS) scores were then correlated with these responses. A comparison group of smokers (N?=?55) was included to determine whether sensation seeking was associated specifically with initial sensitivity to nicotine or with general sensitivity regardless of past nicotine exposure. SSS subscales, particularly Experience Seeking and Disinhibition, were correlated with subjective responses to nicotine in nonsmokers but generally not in smokers. These findings indicate that sensation seeking is associated with greater initial sensitivity to nicotine's subjective effects and may provide directions for further study of individual-differences characteristics that predispose people to the risk of becoming smokers. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Electrophysiological responses to evaluative priming: The LPP is sensitive to incongruity.

Previous studies examining event-related potentials and evaluative priming have been mixed; some find evidence that evaluative priming influences the N400, whereas others find evidence that it affects the late positive potential (LPP). Three experiments were conducted using either affective pictures (Experiments 1 and 2) or words (Experiment 3) in a sequential evaluative priming paradigm. In line with previous behavioral findings, participants responded slower to targets that were evaluatively incongruent with the preceding prime (e.g., negative preceded by positive) compared to evaluatively congruent targets (e.g., negative preceded by negative). In all three studies, the LPP was larger to evaluatively incongruent targets compared to evaluatively congruent ones, and there was no evidence that evaluative incongruity influenced the N400 component. Thus, the present results provide additional support for the notion that evaluative priming influences the LPP and not the N400. We discuss possible reasons for the inconsistent findings in prior research and the theoretical implications of the findings for both evaluative and semantic priming. (PsycINFO Database Record (c) 2011 APA, all rights reserved)