Biphasic effects of moderate drinking on prolactin during lactation

Background: Contrary to the popular lore that encourages women to drink alcohol as an aid to lactation, we previously showed that alcohol consumption disrupted lactational performance and the hormonal milieu of the lactating mother in the short term. Methods: Thirteen lactating women participated in a 4‐session, double‐blind, 2 × 2 within‐subject study to test several hypotheses related to the effects of alcohol on prolactin (PRL) responses and milk yield over time. The two within‐subject factors were beverage condition (control or 0.4 g/kg dose of alcohol) and pumping condition (pumping occurred at fixed intervals once or twice during the 5.3‐hour session). Plasma PRL, blood alcohol concentrations (BAC), and milk yield were measured. Results: Alcohol consumption increased basal PRL levels (p < 0.0001) and modified the PRL response to pumping (p < 0.0001) but the directionality of the response depended on when pumping occurred along the BAC curve. Pumping enhanced PRL response when it occurred during the ascending BAC limb but blunted the response when it occurred during the descending limb, providing evidence that the effects were transient and of a biphasic nature. The slower the alcohol was metabolized, the greater the relative PRL response to breast pumping (p < 0.05). The dynamics of the PRL response between pumping sessions was also altered if women drank. If women pumped within the hour after drinking alcohol, the PRL response during the next pumping some 1.5 hours later, was delayed by a few minutes. Milk yield was significantly lower after drinking alcohol but such deficits were not significantly related to PRL or the speed at which alcohol was eliminated. Conclusions: Effects of alcohol on suckling‐induced PRL were biphasic in nature, but could not explain the deficits in lactational performance. Such findings provide further evidence that the dynamic changes in neuroendocrine state are integrally involved in alcohol’s effects over time and underscore the complexity of lactation.     

Acute Alcohol Intoxication Impairs the Hematopoietic Precursor Cell Response to Pneumococcal Pneumonia

Background: Alcohol abuse is associated with an increased incidence and severity of pneumonia. In both the general population and individuals consuming excess alcohol, Streptococcus pneumoniae is the most frequent lung infection pathogen. Alcoholic patients with pneumonia frequently present with granulocytopenia, which is predictive of increased mortality. The mechanisms underlying this impaired granulopoietic response to pneumococcal pneumonia have yet to be elucidated. Methods: Acute alcohol intoxication was induced in mice 30 minutes before intrapulmonary infection with S. pneumoniae. Bone marrow, lung, and blood samples were collected. Bone marrow cells were also isolated from naïve mice and treated in vitro with plasma from mice infected with S. pneumoniae. Results: Alcohol intoxication impaired the pneumococcal‐induced increase in granulocyte recruitment into the alveolar space, decreased bacterial clearance from the lung, and increased mortality. Pneumococcal pneumonia significantly increased bone marrow lineage^?c‐Kit⁺Sca‐1⁺ (LKS) cell number and colony‐forming unit—granulocytes and monocyte (CFU‐GM) activity of these cells. Both enhanced proliferation of LKS cells and re‐expression of Sca‐1 surface protein on downstream progenitor cells bearing lineage^?c‐Kit⁺Sca‐1^? surface markers accounted for the expansion of marrow LSK cells during pneumonia. Alcohol intoxication impaired these 2 mechanisms of LKS cell population expansion and was associated with a relative granulocytopenia during pneumococcal lung infection. Conclusions: Alcohol inhibits the hematopoietic precursor cell response to pneumonia, which may serve as a mechanism underlying the granulocytopenia and impaired host defense in alcohol abusers with bacterial pneumonia.     

Pharmacodynamic effects of intravenous alcohol on hepatic and gonadal hormones: influence of age and sex

Background: Growth hormone (GH)–insulin‐like growth factor‐1 (IGF‐1) axis and gonadal hormones demonstrate extensively associated regulation; however, little is known about the effects of acute alcohol exposure on these hormones. This study examined the effects of intravenous alcohol on the GH–IGF‐1 axis and gonadal hormone concentrations, and the influence of age and sex on their regulation. Methods: Forty‐eight healthy volunteers (24 men and 24 women each in the 21 to 25 and 55 to 65 year age groups) underwent a 2‐session single‐blinded study. Subjects received in randomized counter‐balanced order, alcohol infusions, individually computed based on a physiologically based pharmacokinetic model, to maintain a steady‐state (“clamped”) exposure of 50 mg% or saline for 3 hours in separate sessions. Blood samples collected at baseline and postinfusion in each session were assayed for levels of GH, IGF‐1, free testosterone, and estradiol. Results: Acute alcohol administration resulted in changes in gonadal hormones that differed by sex. Change in free testosterone showed a significant treatment × baseline interaction (p < 0.001), indicating that alcohol‐induced suppression of testosterone occurred predominantly in men. On the other hand, change in estradiol showed a significant treatment × sex interaction (p = 0.028), indicating that alcohol‐induced increases in estradiol occurred predominantly in women. There was a trend for alcohol‐induced decreases in IGF‐1 levels. Change in GH showed a significant main effect of baseline (p < 0.001) and a trend for treatment by baseline interaction, suggesting an alcohol‐induced decrease in individuals with high baseline GH values. There was also a significant main effect of sex (p = 0.046) indicating that men had greater changes in GH across treatment compared with women. Conclusions: Alcohol induced a complex pattern of hormonal responses that varied between younger and older men and women. Some of the observed sex‐based differences may help improve our understanding of the greater susceptibility to alcohol‐related hepatic damage seen in women.     

Cortical thickness, surface area, and volume of the brain reward system in alcohol dependence: relationships to relapse and extended abstinence

Background: At least 60% of those treated for an alcohol use disorder will relapse. Empirical study of the integrity of the brain reward system (BRS) is critical to understanding the mechanisms of relapse as this collection of circuits is implicated in the development and maintenance of all forms of addictive disorders. This study compared thickness, surface area, and volume in neocortical components of the BRS among nonsmoking light‐drinking controls (controls), individuals who remained abstinent and those who relapsed after treatment. Methods: Seventy‐five treatment‐seeking alcohol‐dependent individuals (abstinent for 7 ± 3 days) and 43 controls completed 1.5T proton magnetic resonance imaging studies. Parcellated morphological data were obtained for following bilateral components of the BRS: rostral and caudal anterior cingulate cortex, insula, medial and lateral orbitofrontal cortex (OFC), rostral and caudal middle and superior frontal gyri, amygdala and hippocampus as well as for 26 other bilateral neocortical regions. Alcohol‐dependent participants were followed over 12‐months after baseline study and were classified as abstainers (no alcohol consumption; n = 24) and relapsers (any alcohol consumption; n = 51) at follow‐up. Results: Relapsers and abstainers demonstrated lower cortical thickness in the vast majority of BRS regions as well as lower global thickness compared to controls. Relapsers had lower total BRS surface area than both controls and abstainers, but abstainers were not significantly different from controls on any surface area measure. Relapsers demonstrated lower volumes than controls in the majority of regions, while abstainers showed lower volumes than controls in the superior frontal gyrus, insula, amygdala, and hippocampus, bilaterally. Relapsers exhibited smaller volumes than abstainers in the right rostral middle and caudal middle frontal gyri and the lateral OFC, bilaterally. In relapsers, lower baseline volumes and surface areas in multiple regions were associated with a greater magnitude of post‐treatment alcohol consumption. Conclusions: Results suggest relapsers demonstrated morphological abnormalities in regions involved in the “top down” regulation/modulation of internal drive states, emotions, reward processing, and behavior, which may impart increased risk for the relapse/remit cycle that afflicts many with an alcohol use disorder. Results also highlight the importance of examining both cortical thickness and surface area to better understand the nature of regional volume loss frequently observed in alcohol use disorders. Results from this report are consistent with previous research implicating plastic neurobiological changes in the BRS in the maintenance of addictive disorders.     

Alcohol Stimulates Ciliary Motility of Isolated Airway Axonemes Through a Nitric Oxide, Cyclase, and Cyclic Nucleotide-Dependent Kinase Mechanism

Background: Lung mucociliary clearance provides the first line of defense from lung infections and is impaired in individuals who consume heavy amounts of alcohol. Previous studies have demonstrated that this alcohol‐induced ciliary dysfunction occurs through impairment of nitric oxide (NO) and cyclic nucleotide‐dependent kinase‐signaling pathways in lung airway ciliated epithelial cells. Recent studies have established that all key elements of this alcohol‐driven signaling pathway co‐localize to the apical surface of the ciliated cells with the basal bodies. These findings led us to hypothesize that alcohol activates the cilia stimulation pathway at the organelle level. To test this hypothesis we performed experiments exposing isolated demembranated cilia (isolated axonemes) to alcohol and studied the effect of alcohol‐stimulated ciliary motility on the pathways involved with isolated axoneme activation. Methods: Isolated demembranated cilia were prepared from bovine trachea and activated with adenosine triphosphate. Ciliary beat frequency, NO production, adenylyl and guanylyl cyclase activities, cAMP‐ and cGMP‐dependent kinase activities were measured following exposure to biologically relevant concentrations of alcohol. Results: Alcohol rapidly stimulated axoneme beating 40% above baseline at very low concentrations of alcohol (1 to 10 mM). This activation was specific to ethanol, required the synthesis of NO, the activation of soluble adenylyl cyclase (sAC), and the activation of both cAMP‐ and cGMP‐dependent kinases (PKA and PKG), all of which were present in the isolated organelle preparation. Conclusions: Alcohol rapidly and sequentially activates the eNOS→NO→GC→cGMP→PKG and sAC→cAMP→ PKA dual signaling pathways in isolated airway axonemes. These findings indicate a direct effect of alcohol on airway cilia organelle function and fully recapitulate the alcohol‐driven activation of cilia known to exist in vivo and in intact lung ciliated cells in vitro following brief moderate alcohol exposure. Furthermore, these findings indicate that airway cilia are exquisitely sensitive to the effects of alcohol and substantiate a key role for alcohol in the alterations of mucociliary clearance associated with even low levels of alcohol intake. We speculate that this same axoneme‐based alcohol activation pathway is down regulated following long‐term high alcohol exposure and that the isolated axoneme preparation provides an excellent model for studying the mechanism of alcohol‐mediated cilia dysfunction.     

Recollective experience in alcohol dependence: a laboratory study

Aims Alcohol dependence has been linked to dysfunction of fronto‐temporo‐striatal circuits which mediate memory and executive function. The present study aimed to explore the specificity of recognition memory changes in alcohol dependence. Design, setting and participants Twenty hospitalized alcohol‐dependent detoxified patients and 20 healthy control subjects completed a verbal list discrimination task. Measurements Hits and false alarm rates were analysed. Additionally, both the dual process signal detection model (DPSD) and the process dissociation procedure (PDP) were used to derive estimates of the contribution of recollection and familiarity processes to the recognition memory performance in patients and controls. Findings Alcohol‐dependent patients showed intact hit rates, but increased false alarm rates and an impaired ability to remember the learning context. Both the DPSD model and PDP estimates yielded significantly reduced recollection estimates in the alcohol‐dependent compared to control subjects. Whether or not familiarity was impaired, depended upon the sensitivity of the estimation procedure. Conclusion Taken together, the result pattern suggests a significant impairment in recollection and mild familiarity changes in recently detoxified, predominantly male, alcohol‐dependent subjects.     

Positron emission tomography imaging of mu- and delta-opioid receptor binding in alcohol-dependent and healthy control subjects

Background: The endogenous opioid system plays a significant role in alcohol dependence. The goal of the current study was to investigate regional brain mu‐opioid receptor (MOR) and delta‐opioid receptor (DOR) availability in recently abstinent alcohol‐dependent and age‐matched healthy control men and women with positron emission tomography (PET) imaging. Methods: Alcohol‐dependent subjects completed an inpatient protocol, which included medically supervised withdrawal and PET imaging on day 5 of abstinence. Control subjects completed PET imaging following an overnight stay. PET scans with the MOR‐selective ligand [¹¹C]carfentanil (CFN) were completed in 25 alcohol‐dependent and 30 control subjects. Most of these same subjects (20 alcohol‐dependent subjects and 18 controls) also completed PET scans with the DOR‐selective ligand [¹¹C]methylnaltrindole (MeNTL). Results: Volumes of interest and statistical parametric mapping analyses indicated that alcohol‐dependent subjects had significantly higher [¹¹C]CFN binding potential (BP_ND) than healthy controls in multiple brain regions including the ventral striatum when adjusting for age, gender, and smoking status. There was an inverse relationship between [¹¹C]CFN BP_ND and craving in several brain regions in alcohol‐dependent subjects. Groups did not differ in [¹¹C]MeNTL BP_ND; however, [¹¹C]MeNTL BP_ND in caudate was positively correlated with recent alcohol drinking in alcohol‐dependent subjects. Conclusions: Our observation of higher [¹¹C]CFN BP_ND in alcohol‐dependent subjects can result from up‐regulation of MOR and/or reduction in endogenous opioid peptides following long‐term alcohol consumption, dependence, and/or withdrawal. Alternatively, the higher [¹¹C]CFN BP_ND in alcohol‐dependent subjects may be an etiological difference that predisposed these individuals to alcohol dependence or may have developed as a result of increased exposure to childhood adversity, stress, and other environmental factors known to increase MOR. Although the direction of group differences in [¹¹C]MeNTL BP_ND was similar in many brain regions, differences did not achieve statistical significance, perhaps as a result of our limited sample size. Additional research is needed to further clarify these relationships. The finding that alcohol‐dependent subjects had higher [¹¹C]CFN BP_ND is consistent with a prominent role of the MOR in alcohol dependence.     

Apomorphine-induced growth hormone response is attenuated by ethanol but not dextromethorphan

BACKGROUND: Misuse of alcohol drinking is a major health problem. Alcohol decreases spontaneous growth hormone (GH) secretion, but the mechanism is unclear. The aim of this study was to test whether administration of alcohol (study 1) or a N-methyl d-aspartate (NMDA) receptor antagonist (study 2) attenuates the GH response to pharmacological dopaminergic stimulation. METHODS: The 2-session repeated measures design was conducted at the endocrine laboratory at the Department of Psychiatry at the Free University Berlin. Twenty healthy Caucasian males aged 35+/-10 years without a history of alcohol use disorders were tested using the Apomorphine (APO) challenge test. In study 1, we injected APO (0.01 mg/kg s.c.) 1 hour after oral administration of 1 g/kg ethanol and placebo, respectively. In study 2, the APO challenge was conducted after 0.3 mg/kg dextromethorphan (DXM) and placebo. The main outcome measures were the peak serum GH concentration and area under the time/concentration curve up to 120 minutes after APO. The effects of ethanol and DXM were tested using the Wilcoxon signed-rank tests. RESULTS: Compared with placebo, alcohol significantly decreased the APO-induced GH release (mean and SEM peak GH concentration 19.9+/-3.2 vs 6.2+/-1.9 ng/mL, p=0.002). Dextromethorphan did not change APO-induced GH response (22.5+/-5.4 vs 21.0+/-5.8 ng/mL, p=0.105). CONCLUSION: A single intermediate alcohol dose markedly reduces GH response to dopaminergic stimulation. Although alcohol is thought to stimulate dopaminergic function in certain pathways, but not necessarily in the hypothalamus, our results are in line with the alcohol effect on baseline GH secretion. Growth hormone suppression appears not to be mediated by ethanol's NMDA-antagonistic properties.     

Five-year outcomes of a brief alcohol intervention for adult in-patients with psychiatric disorders

Aims To compare 5 year outcomes (general hospital and mental health morbidity and mortality) among general hospital psychiatric in‐patients randomized to receive either an alcohol reduction motivational interview (MI) or information pack (IP), and compare these to matched controls. Design We recruited 120 patients aged 18–64 years who scored ≥8 on the Alcohol Use Disorders Identification Test (AUDIT). We selected matched controls from in‐patients not recruited but who reached the same AUDIT threshold. At 5 years, follow‐up data were collected via a state‐wide hospital record system. Findings There were no significant differences between the MI and IP groups in terms of ‘survival’ to their first alcohol‐related, other general hospital or mental health admission over 5 years. Matched controls had significantly more mental health in‐patient episodes (F[1,226] 4.4, P < 0.05) and greater length of hospital stay (F[1,226] 4.8, P < 0.05) than the combined MI‐IP group. Furthermore, the MI‐IP group had longer ‘survival’ times to both first general hospital (mean 583 versus 392 days) and mental health in‐patient (mean 788 versus 580 days) events. Collapsed across groups, dependent and harmful consumers had shorter ‘survival’ times than hazardous consumers (AUDIT classifications). Conclusions Alcohol interventions have medium‐term health benefits for those with mental health and alcohol use problems. Importantly, there were no differences in outcome between the intervention groups. The low cost of providing an IP makes it attractive as an alcohol intervention. The AUDIT provided an effective means of identifying those who are at risk of subsequent alcohol‐related admissions and may benefit from intervention.     

Probability and predictors of remission from life-time nicotine, alcohol, cannabis or cocaine dependence: results from the National Epidemiologic Survey on Alcohol and Related Conditions

Aim To estimate the general and racial/ethnic specific cumulative probability of remission from nicotine alcohol cannabis or cocaine dependence, and to identify predictors of remission across substances. Design Data were collected from structured diagnostic interviews using the Alcohol Use Disorder and Associated Disabilities Interview Schedule—DSM‐IV version. Setting The 2001–2002 National Epidemiological Survey of Alcohol and Related Conditions (NESARC) surveyed a nationally representative sample from US adults (n = 43 093) selected in a three‐stage sampling design. Participants The subsamples of individuals with life‐time DSM‐IV diagnosis of dependence on nicotine (n = 6937), alcohol (n = 4781), cannabis (n = 530) and cocaine (n = 408). Measurements Cumulative probability estimates of dependence remission for the general population and across racial/ethnic groups. Hazard ratios for remission from dependence. Findings Life‐time cumulative probability estimates of dependence remission were 83.7% for nicotine, 90.6% for alcohol, 97.2% for cannabis and 99.2% for cocaine. Half of the cases of nicotine, alcohol, cannabis and cocaine dependence remitted approximately 26, 14, 6 and 5 years after dependence onset, respectively. Males, Blacks and individuals with diagnosis of personality disorders and history of substance use comorbidity exhibited lower hazards of remission for at least two substances. Conclusions A significant proportion of individuals with dependence on nicotine, alcohol, cannabis or cocaine achieve remission at some point in their life‐time, although the probability and time to remission varies by substance and racial/ethnic group. Several predictors of remission are shared by at least two substances, suggesting that the processes of remission overlap. The lower rates of remission of individuals with comorbid personality or substance use disorders highlight the need for providing coordinated psychiatric and substance abuse interventions.     

Morphometry of dorsal raphe nucleus serotonergic neurons in alcoholism

BACKGROUND: Reduced serotonergic function is hypothesized in alcohol abuse and dependence. Serotonergic innervation of the cortex arises predominantly from the dorsal raphe nucleus (DRN). We sought to determine the number and morphometric characteristics of DRN serotonergic neurons postmortem in alcoholic individuals (n=9; age: 16-66 years; 8M:1F) compared with psychiatrically normal, nonalcoholic controls (n=6; age: 17-74 years; 4M:2F). METHODS: Brainstems were collected at autopsy, fixed and cryoprotected. Alcohol dependence or abuse was determined by psychological autopsy (DSM-IV), the presence of liver fatty changes or cirrhosis and/or high blood alcohol level. Tissue was sectioned at 50 microm (-25 degrees C). A series of 1:10 sections was immunoreacted with antiserum to tryptophan hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of serotonin. The total number of TPH-immunoreactive (IR) DRN neurons was determined by stereology. Neuron morphometry indices were determined using a video-based imaging system attached to a microscope. We identified TPH-IR neurons every 1,000 microm in each brainstem and measured neuron area, total cross sectional neuron area, and the total area and density of immunolabeled processes. RESULTS: Dorsal raphe nucleus neuron number (controls: 80,386+/-10,238; alcoholic individuals: 85,884+/-12,478) was not different between groups but TPH-IR was greater in alcoholic individuals throughout the rostrocaudal extent of the DRN. The volume of the DRN was 66+/-9 mm3 in controls and 55+/-5 mm3 in alcoholic individuals (p>0.05). The average size of DRN neurons did not differ between groups (353+/-12 microm2 for controls vs 360+/-15 microm2 for alcoholic subjects). However, the area occupied by neuron processes (area of processes/DRN area) was 2.2-fold greater in alcoholic individuals compared with controls (p<0.05). CONCLUSIONS: The increased area occupied by neuron processes in alcoholic individuals may represent sprouting and, together with greater TPH-IR, be a compensatory response to impaired serotonergic transmission or cumulative effects of alcohol on the serotonin system.     

Growth hormone release during insulin tolerance, clonidine, arginine and growth hormone releasing hormone tests in short normal children and adolescents.

This study was retrospectively performed in 574 short normal children and adolescents [328 underwent insulin tolerance test (ITT), 34 clonidine test (CLON), 64 arginine test (ARG), 19 GHRH test, 52 ITT+CLON, 30 GHRH+CLON, and 47 ITT+CLON+GHRH) in order to evaluate the effect of pubertal stage on GH response to different tests and to identify the most likely mechanism of action of different stimuli. GH peak was higher during GHRH than in all other tests. Sex or start of pubertal development did not cause any GH peak difference. Low-responder (GH peak less than 10 ng/ml) percentages were similar (ITT = 13.5%, CLON = 13.4%, ARG = 13.2%, GHRH = 10.6%) also when the subjects were divided according to sex and pubertal development. ITT+CLON showed discordant results in 42/99 subjects (30/42 = 71.4% were low-responders to ITT and 12/42 = 28.6% to CLON). GH peak appeared earlier during GHRH (85% less than 45 min) and later during CLON (78%: 60-120 min) than during all other tests; GH peak during ITT showed a wide variability of time. Negative correlations were found between GH peak during GHRH and chronological age, height and bone age and during CLON and chronological age. In conclusion our data show that these tests have similar GH secretagogue reliability.     

GH kinase activity in bovine anterior pituitary subcellular fractions

Growth hormone (GH) and prolactin (PRL) share significant structural homology. We have previously characterized the phosphorylation of bovine PRL and wish to determine whether a similar kinase activity phosphorylates bovine GH. Phosphorylation of bovine GH was performed using [α-³²P]ATP labeling of subcellular fractions. Bovine GH phosphorylation was dependent on Zn²⁺ or Cu²⁺ with apparent Km's of 0.9 and 1.0 mM, respectively, and a pH maxima of 7.0. The apparent Km's of bovine GH kinase activity for exogenous bovine GH and ATP were 30 μM and 376 μM, respectively. Exogenous bovine PRL served as a competitive substrate, increasing the apparent Km for bovine GH by threefold compared to the Km determined without exogenous bovine PRL. We conclude: 1) in vitro phosphorylation of bovine GH occurs under conditions that are consistent with those found in anterior pituitary cells, and 2) a similar kinase activity phosphorylates both bovine PRL and GH.     

Sexually dimorphic characteristics of clonidine-induced growth hormone release and autofeedback

The mechanism underlying the sexually dimorphic pattern of GH secretion in the rat has not been clearly elucidated. In this study differences in the regulation of GH secretion in males and females were analyzed by examining their sensitivity to alpha 2-adrenergic (alpha 2) stimulation and GH autofeedback. The model used in testing this system was the capacity of ovine (o) GH, injected into the third ventricle, to suppress the endogenous GH surge induced by clonidine (CLON), an alpha 2-agonist. In morning experiments, CLON (30 micrograms/kg BW, iv) was injected between 1000-1100 h in males. oGH (20 micrograms in 2 microliters vehicle) injected 3 h earlier inhibited the GH surge, which peaked 15 min after CLON injection in control animals receiving CLON alone. In females there was both no change in plasma GH levels and no difference between treatment groups in animals receiving 30, 50, 100, or 150 micrograms/kg CLON and saline controls. Preinjection of 20 micrograms oGH in proestrous or diestrous animals or 30 micrograms oGH in diestrous animals 3 h before CLON treatment did not depress plasma GH levels below those found in animals receiving CLON alone. Further, neither reducing the preinjection time to 2 h nor injecting 7, 13, or 20 micrograms oGH at this preinjection period suppressed basal or CLON-induced GH release. To facilitate comparisons in subsequent experiments the male protocol was followed. In evening experiments, CLON (injected between 2210-2240 h) stimulated a significant GH surge in diestrous females. However, preinjected oGH lowered basal GH levels but failed to suppress the CLON-induced GH surge. In somatostatin (SRIF) antiserum (anti-SRIF; 0.5 ml, iv)-treated adult diestrous animals, CLON induced a significant GH surge that was suppressed by oGH preinjection. In normal sheep serum-treated animals there was no significant response to either CLON alone or in combination with oGH. To determine the influence of ovarian hormones on GH release females were ovariectomized (OVXed) either pre- or postpubertally. After adult OVX, CLON induced an increase in GH release that was not suppressed by oGH pretreatment. In prepubertally OVXed animals CLON induced a substantial GH surge that was suppressed in animals preinjected with oGH. In prepubertally OVXed animals implanted with testosterone capsules the response to CLON and oGH was not significantly different from that after prepubertal OVX alone. Sham-operated animals responded to treatment in a manner similar to unoperated cycling females.(ABSTRACT TRUNCATED AT 400 WORDS)     

Ten-year trends (1992 to 2002) in sociodemographic predictors and indicators of alcohol abuse and dependence among whites, blacks, and Hispanics in the United States

Background: The objective of this paper is to examine 10‐year trends (1992 to 2002) in the number and type of indicators of DSM‐IV abuse and dependence among whites, blacks, and Hispanics in the United States. Methods: Data are from the 1991 to 1992 National Longitudinal Alcohol Epidemiologic Survey (NLAES; n = 42,862) and the 2001 to 2002 National Epidemiologic Study on Alcohol and Related Conditions (NESARC; n = 43,093). Both surveys used multistage cluster sample procedures to select respondents 18 years of age and older from the U.S. household population. Results: Increases in the prevalence of alcohol abuse between 1992 and 2002 seem associated with a rise in the prevalence of the indicator for “hazardous use.” which usually means reports of driving after drinking. The decrease in dependence was not associated with changes in a particular indicator. In addition, both in 1992 and 2002, 12.3 to 15.4% of the men and 5.2 to 7.9% of the women were diagnostic “orphans.” These respondents reported 1 or 2 indicators of alcohol dependence as present. Conclusions: The observed trends in number and types of indicators of DSM‐IV alcohol abuse and dependence were probably triggered by a complex interplay between individuals’ volume and pattern of drinking and reactions from the drinkers’ social environment. The close association between hazardous use of alcohol and the prevalence of abuse deserves further discussion. A medical diagnostic category should not be so dependent on a criterion that may be influenced by social situations. It is necessary to understand more about diagnostic “orphans” to better design interventions to address their problems.     

Age-correlated and ovary-dependent changes in relationships between plasma estradiol and luteinizing hormone, prolactin, and growth hormone in female C57BL/6J mice

Impairments in the estradiol (E2)-induced surge of LH occur as aging female rodents lose reproductive cycles. These and other impairments can be substantially attenuated by ovariectomy of the young adult. In female rats, plasma PRL tends to increase with age, whereas in male rats, GH tends to decrease; PRL is regulated by E2, whereas GH is probably not. To determine if age-correlated neuroendocrine impairments are accompanied by altered neuroendocrine sensitivity to E2, the relationships among plasma E2, LH, PRL, and GH were assessed in 6- and 12-month-old cycling and 18-month-old acyclic female C57BL/6J mice given E2 implants. An additional 18-month-old group, ovariectomized at 6 months of age, was examined to determine if age-correlated changes in sensitivity to E2 are ovary dependent. One week after ovariectomy, mice were given different sized E2 implants which generated a physiological range of plasma E2. Three weeks after implantation, plasma E2 correlated positively with implant size, uterine weight, and PRL, but correlated negatively with LH in each age group; age did not affect plasma E2 levels. The suppression of LH by E2 decreased progressively with age. Conversely, the elevation of PRL by E2 increased with age. These effects of age were largely prevented by ovariectomy at 6 months of age. Plasma GH decreased slightly with age, but was not significantly affected by E2; old mice ovariectomized when young had lower GH levels than previously intact old mice. GH also correlated positively with LH in all age groups. We conclude that neuroendocrine responses to E2 are altered with age even before estrous cycles are lost. Sensitivity to E2 may either increase or decrease, depending on the function. These effects of age can be attenuated by prolonged ovariectomy. Thus, chronic exposure to ovarian E2 during normal reproductive cycles may alter neuroendocrine sensitivity to E2, which may lead to age-correlated impairments in reproductive function.     

Prevalence and Correlates of Withdrawal‐Related Insomnia among Adults with Alcohol Dependence: Results from a National Survey

Insomnia during acute alcohol withdrawal (AWD) as well as persisting insomnia during postacute withdrawal is associated with relapse. Rates of insomnia in clinical samples of alcohol‐dependent patients range from 36% to 91%, but the prevalence of AWD‐related insomnia in the general population is unknown. The purpose of this study was to describe the prevalence of insomnia as a symptom of acute AWD and its correlates in a general population of alcohol‐dependent individuals. Data were analyzed from the 2001 to 2002 National Epidemiologic Survey on Alcohol and Related Conditions, which sampled 43,093 adults. The prevalence of AWD‐related insomnia among individuals with a lifetime diagnosis of alcohol dependence was 31.7%, which ranked fourth among the eight listed DSM‐IV withdrawal symptoms. Among individuals who met lifetime criteria for both alcohol dependence and AWD, the prevalence of insomnia was approximately 50%. Lifetime diagnoses of major depression and drug use disorders were significant correlates of AWD‐related insomnia in multivariate analyses. A less than 1‐year duration of the heaviest drinking period as well as the onset of alcohol dependence between ages 18 and 27 were negatively associated with AWD‐related insomnia. AWD‐related insomnia is a common symptom among alcohol‐dependent adults in the general population and is related to lifetime co‐occurring diagnoses, age at onset of alcohol dependence, and duration of heaviest drinking period. Its prevalence in the general population provides a representative base rate against which to compare the widely varying rates reported in clinical populations. Because of its relatively frequent prevalence and association with relapse, assessment and treatment of AWD‐related insomnia should be routinely considered in clinical settings. (Am J Addict 2010;19:238–244)     

A Within-Group Design of Nontreatment Seeking 5-HTTLPR Genotyped Alcohol-Dependent Subjects Receiving Ondansetron and Sertraline

Background: Serotonergic mechanisms are associated with the development of alcohol dependence (AD), however, studies evaluating serotonergic medications have produced conflicting results. One hypothesis suggests that differential response may be due to a functional polymorphism of the 5‐HTTLPR promoter region of the serotonin re‐uptake transporter (5‐HTT). The L/L genotype is postulated to be associated with early onset alcoholism and the S/S or S/L genotypes associated with late onset alcoholism. The aim of this study was to match and mismatch L/L, S/S, or S/L genotypes with administration of ondansetron and sertraline. Methods: Fifteen nontreatment seeking alcohol‐dependent individuals were randomized to 1 of 2 counterbalanced arms to receive either 200 mg/d of sertraline or ondansetron 0.5 mg/d for 3 weeks followed by an alcohol self‐administration experiment (ASAE), then received placebo for 3 weeks followed by a second ASAE. Participants then received the alternate drug for 2 weeks followed by a third ASAE. Results: At the first ASAE compared to sertraline, ondansetron significantly improved drinking outcomes for the L/L genotype for the ASAE volume consumed (100% reduction based on between‐subjects comparison, t = 2.35), and for drinks per drinking day during the 7 days prior to the ASAE (79% reduction and t = 4.34). Compared with ondansetron for S/S or S/L genotypes, outcomes at ASAE 1 for sertraline and S/S or S/L genotypes are opposite than hypothesized. Overall, subjects reduced drinking across their participation in the trial, as there appears to be an order effect. Conclusion: This study suggests that ondansetron may reduce alcohol consumption in alcohol‐dependent individuals who have the L/L genotype as measured naturalistically and during the ASAE. By contrast there was no support that sertraline reduces alcohol use in individuals who have S/S or S/L genotypes. Evidence in the literature suggests that AD in some individuals may be influenced by a gene by socio‐environmental interaction making pharmacological treatment with serotonergic drugs complex. Research must consider that typologies may predict successful treatment of AD in future trials.     

Hormonal responses during insulin-induced hypoglycemia in manic-depressed, unipolar depressed, and healthy control subjects

Early studies using the insulin tolerance test (ITT) in affective disorders reported a blunted GH response in some depressed patients. However, results from subsequent studies were less consistent. These discrepancies resulted in part from limited sample sizes causing diagnostic heterogeneity. In the present study we examined hormonal response patterns during the ITT in 25 bipolar patients (19 depressed and 6 hypomanic), 91 unipolar depressives, and 51 healthy volunteers to determine whether distinct neuroendocrine response patterns characterized specific diagnostic subgroups. We measured the glucose, GH, PRL, and cortisol responses during a 75-min ITT and observed a diminished cumulative GH response in bipolar hypomanic patients compared to bipolar depressives (P = 0.004) and healthy volunteers (P less than 0.001), and a larger cumulative GH response in bipolar depressives compared to unipolar patients (P = 0.02). No differences were observed in either PRL or cortisol responses among subject groups. The present findings suggest that GH responses during the ITT may be more complex than initially described and partially dependent upon affective disorder subtype. Thus, bipolar patients may have distinctive GH response patterns compared to those of unipolar depressives and healthy controls. Moreover, some of the difference observed in the GH response to the ITT may result from the phase of the manic-depressive illness. These data indicate differences in neuroendocrine substrates between affective disorder subtypes.