Age modifies the effect of ethanol on behavior: Investigations in adolescent, adult and aged rats.

The number of older people is increasing in most if not all countries in the world. In addition, the amount of alcohol consumption in the aged population is increasing and the consumption pattern is often in a binge fashion. However, little is known if the effects of alcohol, either acute or chronic exposure, vary in the older population compared to younger populations. The current mini-review will provide an overview of the effects of acute and chronic ethanol exposure at three different periods of development: adolescent, adult and aged on multiple different commonly studied behaviors. The overall conclusion is that biological age of the subject is a critical factor in understanding the effects of ethanol across the lifespan.

Gut T cell-independent IgA responses to commensal bacteria require engagement of the TACI receptor on B cells.

The gut mounts secretory immunoglobulin A (SIgA) responses to commensal bacteria through nonredundant T cell-dependent (TD) and T cell-independent (TI) pathways that promote the establishment of mutualistic host-microbiota interactions. SIgAs from the TD pathway target penetrant bacteria, and their induction requires engagement of CD40 on B cells by CD40 ligand on T follicular helper cells. In contrast, SIgAs from the TI pathway bind a larger spectrum of bacteria, but the mechanism underpinning their production remains elusive. Here, we show that the intestinal TI pathway required CD40-independent B cell-activating signals from TACI, a receptor for the innate CD40 ligand-like factors BAFF and APRIL. TACI-induced SIgA responses targeted a fraction of the gut microbiota without shaping its overall composition. Of note, TACI was dispensable for TD induction of IgA in gut-associated lymphoid organs. Thus, BAFF/APRIL signals acting on TACI orchestrate commensal bacteria-specific SIgA responses through an intestinal TI program.

Neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one modulates electrophysiological and behavioral actions of ethanol.

Neuroactive steroids are synthesized de novo in brain, yet their physiological significance remains elusive. We provide biochemical, electrophysiological, and behavioral evidence that several specific actions of alcohol (ethanol) are mediated by the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP; allopregnanolone). Systemic alcohol administration elevates 3alpha, 5alpha-THP levels in the cerebral cortex to pharmacologically relevant concentrations. The elevation of 3alpha,5alpha-THP is dose- and time-dependent. Furthermore, there is a significant correlation between 3alpha,5alpha-THP levels in cerebral cortex and the hypnotic effect of ethanol. Blockade of de novo biosynthesis of 5alpha-reduced steroids using the 5alpha-reductase inhibitor finasteride prevents several effects of ethanol. Pretreatment with finasteride causes no changes in baseline bicuculline-induced seizure threshold but reverses the anticonvulsant effect of ethanol. Finasteride pretreatment also reverses ethanol inhibition of spontaneous neural activity in medial septal/diagonal band of Broca neurons while having no direct effect on spontaneous firing rates. Thus, elevation of 3alpha,5alpha-THP levels by acute ethanol administration represents a novel mechanism of ethanol action as well as an important modulatory role for neurosteroids in the CNS.

Age-related differences in neurosteroid potentiation of muscimol-stimulated 36Cl(-) flux following chronic ethanol treatment.

Alcoholism and alcohol abuse create costly social and economic problems in many nations. Recent studies indicate that alcohol exposure during adolescence may convey unique risks for subsequent neurocognitive deficits and problem drinking. Although GABA(A) receptor function is one of the principle neurochemical targets of ethanol action in the adult brain, little is known about the effects of alcohol on this system during adolescence. Adolescent (30-day-old) and adult (90-day-old) male rats were intermittently exposed to ethanol for 1 month. At various times after the end of the exposure period, synaptoneurosomes were prepared from their cerebral cortices. GABA(A) receptor-mediated 36Cl(-) influx was measured in the absence and presence of the neurosteroid 3alpha,21-dihydroxy-5alpha-pregnan-20-one (THDOC). In tissue from ethanol-exposed animals, sensitization to the potentiating effects of the neurosteroid was apparent 5 and 12 days after ethanol withdrawal. This sensitization was more apparent at the low concentrations of THDOC in animals pretreated with ethanol as adolescents. Sensitization to the potentiating effects of a neurosteroid is an enduring phenomenon, persistent long after the acute phase of ethanol withdrawal, and may be indicative of long-term changes in GABA(A) receptor function. Enhanced neurosteroid sensitization in animals pretreated as adolescents is consistent with the notion that adolescence is a period of unique sensitivity to the effects of ethanol. This uniqueness may now be extended to the chronic effects of ethanol.

The role of GABA(A) receptors in the acute and chronic effects of ethanol.

GABA(A) receptors are sensitive to ethanol in distinct brain regions and are clearly involved in the acute actions of ethanol, ethanol tolerance, ethanol dependence and ethanol self-administration. Data from a variety of perspectives such as molecular, cellular and behavioral analysis have elucidated the role of GABA(A) receptors in these processes. GABA(A) receptor activation mediates many of the behavioral effects of ethanol including motor incoordination, anxiolysis and sedation. The actions of ethanol at GABA(A) receptors are influenced by endogenous modulators such as the neuroactive steroids. Sensitization to these compounds influences ethanol dependence and withdrawal and may explain gender differences in the molecular effects of ethanol. Furthermore, GABA(A) receptors may also play a role in ethanol self-administration via the mesolimbic reward system. Ethanol tolerance and dependence may be explained, in part, by changes in the function of GABA(A) receptors. We have proposed that alterations in native GABA(A) receptor subunit assembly could alter the functional properties of these receptors. However, post-translational modifications or other post-synaptic mechanisms may also explain changes in GABA(A) receptor function. Genetic animal models of ethanol dependence have also identified GABA(A) receptor genes as likely mediators of the behavioral adaptations associated with ethanol dependence and withdrawal. A better understanding of the effects of ethanol at GABA(A) receptors has highlighted important potential mechanisms involved in the development of alcoholism.

Prenatal exposure to ethanol disrupts spatial memory: effect of the training-testing delay period.

The present study investigated how variations in the period of delay between training and testing in the Morris water maze task affect the use of spatial memory in adult rats that were prenatally exposed to ethanol. Previous results utilizing the Morris water maze task have shown that prenatal, or early postnatal, exposure to ethanol produces deficits in the use of spatial memory, a type of memory that is dependent on an intact hippocampus. However, in these prior studies the delay period between the training of animals and the testing of spatial memory is typically fixed at only 1 day. In the current study, which utilized a revised training procedure within the Morris water maze task, the period of delay between training and testing was altered such that it was either 1 day or 3 days. Following the 3-day delay, different levels of prenatal exposure to ethanol impaired the use of spatial memory. In contrast, following the 1-day delay, prenatal exposure to ethanol failed to impair the use of spatial memory. The present study thus shows that prenatal exposure to ethanol differentially affects spatial memory in the Morris water maze task depending on the period of delay between training and testing.

Gender impacts behavioral and neurochemical adaptations in ethanol-dependent rats.

Previous investigations have found gender differences in the effects of chronic ethanol exposure on ethanol withdrawal behaviors as well as GABA(A) receptor gene expression. The present investigation extended these studies with additional behavioral and neurochemical measures of ethanol dependence and withdrawal. No significant gender differences in the elevated plus-maze assessment of ethanol withdrawal anxiety behaviors were found. However, the neuroactive steroid, 3alpha,5alpha-THP, increased exploratory behavior in ethanol withdrawn female, but not male, rats. GABA(A) receptor binding assays showed potent competition of [35S]TBPS binding by 3alpha,5alpha-THP. Control females displayed a decreased affinity for 3alpha,5alpha-THP compared to control males, as evidenced by a nearly 30% increase in the IC50 value. There was no significant effect of ethanol withdrawal on 3alpha,5alpha-THP modulation of [35S]TBPS binding. However, gender differences were observed in the effects of chronic ethanol exposure on GABA(A) receptor subunit peptide levels in the hypothalamus. Female rats had a significant increase in peptide levels for the alpha2 and alpha3 but not alpha4 subunit, whereas male rats displayed a significant increase in alpha4 and alpha3 but not alpha2 subunits compared to pair-fed control levels. Chronic ethanol-induced alterations in gene expression in the hypothalamus did not coincide with previous findings in the cerebral cortex. In particular, male rats showed an increase in alpha1 subunit peptide levels in the hypothalamus, whereas significant decreases in this subunit have been observed in the cerebral cortex. Both female and male rats showed significant increases in the alpha3 subunit in the hypothalamus but not the cerebral cortex. Taken together, these studies provide additional support for gender-selective effects of chronic ethanol-elicited adaptations at the molecular level.

Effects of sweetened ethanol solutions on ethanol self-administration and blood ethanol levels.

The enhancement of voluntary self-administration of ethanol by sucrose or saccharin was tested in conjunction with measurements of blood ethanol levels. Adult male rats were given access to both tap water and one of five solutions: 0.125% saccharin, 10% sucrose, ethanol, saccharin+ethanol, or sucrose+ethanol. The rats receiving the sucrose+ethanol solution drank consistently more ethanol (>5 g/kg/day) than did the rats receiving the saccharin+ethanol solution (<3 g/kg/day) or ethanol only (<2 g/kg/day). Both sweetened solutions produced higher ethanol consumption during these periods than ethanol alone. However, no significant differences in blood ethanol levels were found between the sucrose+ethanol and saccharin+ethanol conditions, when tested at different intervals on Day 44 or Day 45 of ethanol consumption. Following 45 days of consumption, no change in the bicuculline seizure threshold was observed in the ethanol-consuming rats compared to the controls. In a separate study using 90 naive rats, rats were gavaged with ethanol (1, 2, or 3 g/kg) containing either 10% sucrose (n=10 for each dose of ethanol), 0.125% saccharin (n=10 for each dose of ethanol), or ethanol alone (n=10 for each dose of ethanol), and blood was collected from the tip of the tail 30, 60, 180, 300, and 540 min later and analyzed for ethanol concentrations. Sucrose significantly decreased the resultant blood ethanol levels at several time points following gavage. These results indicate that sucrose can significantly alter blood ethanol levels and that chronic self-administration of a sweetened ethanol solution for 6 weeks does not produce ethanol dependence.

Fimbria/fornix lesions facilitate the learning of a nonspatial response task.

The spatial cognitive map theory of O'Keefe and Nadel (1978) predicts that lesions of the hippocampal system should impair learning on spatial tasks but not learning on nonspatial tasks. However, there is evidence that such lesions can facilitate learning on certain nonspatial tasks. Their theory does not predict such facilitation. Nevertheless, it is reasonable to expect that animals possessing a spatial cognitive map would have an inherent bias to engage a mapping strategy and thus be at a disadvantage on certain nonspatial tasks in comparison with animals without the mapping capacity and bias. In the present study, fimbria/fornix lesions impaired learning on a spatial task, but actually facilitated learning on a nonspatial task of equal difficulty. Thus, brain lesions that interfere with map functioning can facilitate learning on tasks for which a mapping strategy interferes with task solution. The results require a modification of the spatial cognitive map theory.

Threatening and otherwise inappropriate letters to members of the United States Congress.

The authors examine the characteristics of threatening and otherwise inappropriate communications sent to members of the U.S. Congress by a sample of 86 subjects, 20 of whom threatened assassination. We quote excerpts from these letters and provide quantitative data on such variables as the volume, duration, form, and appearance of such communications; the enclosures; the subjects' perceived relationships to the recipients; the thematic content of the communications; and the messages and threats communicated. Comparisons between 43 subjects who pursued encounters with members of Congress and 43 who did not revealed 17 factors associated with such pursuit. In this population, threateners were significantly less likely to pursue an encounter than inappropriate letter writers who did not threaten, regardless of the type of threat or the harm threatened. Inappropriate letters to members of Congress are compared with those directed to Hollywood celebrities. Mentally disordered persons writing to public figures often mention and sometimes threaten public figures other than those to whom the letters are addressed, which raises important issues regarding notification of endangered third parties and the sharing of information among protective agencies.

High-throughput behavioral phenotyping in the expanded panel of BXD recombinant inbred strains.

Genetic reference populations, particularly the BXD recombinant inbred (BXD RI) strains derived from C57BL/6J and DBA/2J mice, are a valuable resource for the discovery of the bio-molecular substrates and genetic drivers responsible for trait variation and covariation. This approach can be profitably applied in the analysis of susceptibility and mechanisms of drug and alcohol use disorders for which many predisposing behaviors may predict the occurrence and manifestation of increased preference for these substances. Many of these traits are modeled by common mouse behavioral assays, facilitating the detection of patterns and sources of genetic coregulation of predisposing phenotypes and substance consumption. Members of the Tennessee Mouse Genome Consortium (TMGC) have obtained phenotype data from over 250 measures related to multiple behavioral assays across several batteries: response to, and withdrawal from cocaine, 3,4-methylenedioxymethamphetamine; "ecstasy" (MDMA), morphine and alcohol; novelty seeking; behavioral despair and related neurological phenomena; pain sensitivity; stress sensitivity; anxiety; hyperactivity and sleep/wake cycles. All traits have been measured in both sexes in approximately 70 strains of the recently expanded panel of BXD RI strains. Sex differences and heritability estimates were obtained for each trait, and a comparison of early (N = 32) and recent (N = 37) BXD RI lines was performed. Primary data are publicly available for heritability, sex difference and genetic analyses using the MouseTrack database, and are also available in GeneNetwork.org for quantitative trait locus (QTL) detection and genetic analysis of gene expression. Together with the results of related studies, these data form a public resource for integrative systems genetic analysis of neurobehavioral traits.

Effects of acute and chronic ethanol exposure on spatial cognitive processing and hippocampal function in the rat.

Animals, including rats, have a predisposition to process and use spatial information to organize and guide behavior. The hippocampus and related structures are critically involved in this function, and, consequently, it has been proposed that one function of the hippocampus is to construct "spatial cognitive maps" of environments. Lesions to the hippocampus or its connections produce a pattern of alterations in behavior which include shifts from the use of spatial information to guide behavior to the use of cue- or taxon-based information to guide behavior. Recently it was demonstrated that ethanol interacts with a specific group of neurotransmitter systems, i.e., N-methyl-D-aspartate receptors and GABA(A) receptors that exist in high proportions in the hippocampus and related structures. In this review, we seek to summarize the literature demonstrating that one effect of acute and chronic ethanol exposure is to produce behavioral alterations that are strikingly similar to those found following lesions to the hippocampal system. Furthermore, cellular and anatomical alterations resulting from similar ethanol exposure paradigms will be reviewed and offered as possible mechanisms for producing the alterations in behavior. Finally, several unanswered questions concerning the interaction between ethanol and spatial cognitive processing will be identified.

Ethanol-induced impairments in spatial working memory are not due to deficits in learning.

BACKGROUND: Acute ethanol administration impairs spatial reference memory and spatial working memory. However, the experimental designs previously used to test spatial working memory fail to make a distinction between the acquisition, or learning, of spatial information and the retention of this information. This study demonstrates that acute ethanol administration impairs spatial working memory, by using a novel experimental design that eliminates the confound between the learning of new spatial information and the testing of this information. METHODS: Long-Evans male rats received three forced trials to the same place for food reward on an elevated radial arm maze. Subjects were then given six free-choice trials in the first acquisition session, followed by a 30-min consolidation period before an additional six free-choice trials were administered-the retention session. Animals were trained to a criterion of five of six correct in both the acquisition and retention over 2 consecutive days. Once criteria were obtained, subjects received either saline or one of three ethanol doses immediately after the acquisition session to investigate whether ethanol alters retention of the learned spatial information. RESULTS: Acute ethanol administration impaired spatial working memory. Rats tested under saline and low-dose ethanol (1.0 g/kg) made significantly more place choices than rats tested under moderate- or high-dose ethanol (1.5 and 2.0 g/kg, respectively). Ethanol produced a temporary impairment in that no significant differences were found when subjects were retrained and retested 24 hr after initial testing. CONCLUSIONS: These results demonstrate that acute ethanol administration impairs spatial working memory and that such a deficit is not contingent on a learning impairment. These results support earlier findings that acute ethanol administration impairs spatial working memory but provide a significant advance by validating a novel training procedure that allows for direct investigation of working memory. Ethanol's impairment of both spatial working memory and spatial reference memory strengthens the similarities between memory impairments due to ethanol administration and memory impairments due to hippocampal lesions.

The deliberate misdiagnosis of major depression in primary care.

OBJECTIVE: Because the correct diagnosis of a psychiatric condition can jeopardize reimbursement and other benefits, physicians deliberately substitute alternative diagnoses. We estimated the prevalence of alternative coding for major depression by primary care physicians and the reasons for its occurrence. DESIGN: Cross-sectional mail survey with telephone follow-up of nonresponders. SETTING: Primary care practices in communities across the nation. PARTICIPANTS: Physicians were eligible to participate if they were randomly selected from membership lists of two professional organizations of primary care clinicians. Four hundred forty-four physicians (70.0% of eligible physicians and 89.5% of eligible physicians we could locate) completed the survey by mail or telephone. MAIN OUTCOME MEASURE: Substitution of an alternative code for major depression within a 2-week period. RESULTS: Of our respondents, 50.3% (SE, +/- 2.5%) reported that they had substituted another diagnostic code during a 2-week period for one or more patients whom they recognized met the criteria for major depression in the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. Thirty-one percent of depressed patients received alternative codes. The most common reasons for these substitutions involved physician uncertainty about the diagnosis and problems with reimbursement for services if a diagnosis of major depression was coded. CONCLUSION: The practice of deliberately substituting another diagnostic code for major depression is widespread among primary care providers. Physicians who employ deliberate misdiagnosis circumvent inequitable policies for particular patients, but the impact of substitution on the health care system as a whole deserves more careful consideration.

Effects of pH on the kinetics of redox reactions in and around the cytochromebf complex in an isolated system.

Rate-coefficients describing the electron transfer reactions between P700 and plastocyanin, between cytochromef in cytochromebf complexes and plastocyanin, and between decyl plastoquinol and cytochromebf complexes were determined as a function of pH in the range 4-10 from flash-induced absorbancy changes at four wavelengths. The reactions between P700 and plastocyanin, and between cytochromef and plastocyanin were optimised when there was electrostatic interaction between ionised acidic groups in plastocyanin with a pKa of 4.3-4.7 and ionised basic constituents in P700 (assumed to be in the PSI-F subunit) and in cytochromef, with a pKb of 8.9-9.4. The basic groups are thought to be lysine rather than arginine. This mechanism agrees with that inferred from effects of ionic strength changes on rate-coefficients. The relation between the second-order rate-coefficient for decyl plastoquinol oxidation by thebf complex and pH was characterised by a pKa of 6.1. This is interpreted as showing that the anion radical form of that quinol, which has a pKa of 6, and which becomes progressively protonated when pH is changed from 7 to 5, is essential to reduce cytochromeb-563 (low potential) during quinol oxidation. Above pH 9, permanent effects were observed on this rate-coefficient, which were absent in the reactions between P700, plastocyanin and cytochromef.

The kinetics of reactions around the cytochrome bf complex studied in an isolated system.

The kinetics of oxidation and reduction of P700, plastocyanin, cytochrome f and cytochrome b-563 were studied in a reconstituted system consisting of Photosystem I particles, cytochrome bf complex and plastocyanin, all derived from pea leaf chloroplasts. Decyl plastoquinol was the reductant of the bf complex. Turnovers of the system were initiated by laser flashes. The reaction between oxidised P700 and plastocyanin was non-homogeneous in that a second-order rate coefficient of c. 5×10(-7) M(-1) s(-1) applied to 80% of the P700(+) and c. 0.7×10(7) M(-1) s(-1) to the remainder. In the presence of bf complex, but without quinol, the electron transfer between cytochrome f and oxidised plastocyanin could be described by a second-order rate coefficient of c. 4×10(7) M(-1) s(-1) (forward), and c. 1.6×10(7) M(-1) s(-1) (reverse). The equilibrium coefficient was thus 2.5. Unexpectedly, there was little reduction of cytochrome f (+) or plastocyanin(+) by electrons from the Rieske centre. With added quinol, reduction of cytochrome b-563 occurred. Concomitantly, electrons appeared in the oxidised species. It was inferred that either the Rieske centre was not involved in the high-potential chain of electron transfer events, or that, only in the presence of quinol, electrons were quickly passed from the Rieske centre to cytochrome f (+). Additionally, the presence of quinol altered the equilibrium coefficient for the cyt f/PC interaction from 2.5 to c. 5. The reaction between quinol and the bf complex was describable by a second-order rate coefficient of about 3×10(6) M(-1) s(-1). The pattern of the redox reactions around the bf complex could be simulated in detail with a Q-cycle model as previously found for chloroplasts.

Fine points aside: data are data.

Movement responses by 5 1/2- to 6 1/2-year-old children on the Holtzman Inkblot Test were reported on by Lockwood et al. in volume 45 of this Journal. Criticism of the findings discussed in that article by J. Swartz, Reinehr, and C. Swartz was published in the December, 1981, volume of the Journal. The present article rebuts their criticism and emphasizes the significance of the original findings which reflect new and highly discrepant normative M response data from that previously available.

Two studies of the movement responses in young children: new and highly discrepant norms.

The Holtzman Ink Blot Test was administered to 5- to 6-year-old children and analyzed for movement response. The range and frequency of movement response in both an original and replication study are significantly greater than would have been anticipated for this age group based upon available normative data. NO significant differences were found in the frequency of Human Movement and Animal Movement responses. No sex difference among subjects was found in the range and frequency of movement responses produced. These new findings call into question previously reported data as well as some of the theoretical presumptions underlying the production of movement responses by young children.