Actions of sex hormones on the brain.

1. The brain is a target for sex steroid hormones. As a result of sex hormone actions on the brain various behavioral changes are observed in animal and man. This paper gives a brief overview over the multiple central nervous functions that are under modulatory control of sexual hormones and describes the complex sex steroid actions on the brain by giving an example for "activating" and "organizing" effects of estrogens on noradrenergic neurons in the brain of rats. 2. Estradiol-17 beta induced sex specific alterations in the turnover of noradrenaline in the preoptic area and mediobasal hypothalamus showing "female" or "male" responses. 3. Neonatal manipulations of female rat pups by testosterone, estradiol-17 beta or 4-hydroxyestradiol-17 beta defeminized the "female" response of the noradrenaline turnover in the preoptic area. 4. Defeminization was not observed when neonatal females received the non aromatizable sex steroid dihydrotestosterone. 5. Activating and organizing effects of sex steroids on animal brain as shown here for noradrenergic neurons are discussed in relation to the regulation of behavior in man. Special regard is given to psychic disorders that might be associated with abnormalities in the production or metabolism of or the response to gonadal hormones.     

Proton permeation through the myocardial gap junction

Although protons can directly or indirectly gate solute permeability of the myocardial gap junction, there is little information regarding their own permeation, despite their importance in the regulation of myocardial contractility and rhythm. By pipette-loading of acid into guinea pig isolated, ventricular myocyte pairs while imaging pH(i) confocally using SNARF fluorescence, we have observed that protons permeate the junctional region. Permeation is inhibited by glycyrrhetinic acid, an agent that also increases intercellular electrical resistance, suggesting H+ permeation via gap junctions. The rate of spread of acid between cells appears to be limited by junctional permeation rather than by cytoplasmic diffusion. Mathematical analyses, combined with experiments using SNARF as a proton carrier, suggest that gap junctional H+ transmission may be accomplished physiologically by the permeation of intrinsic "proton-porter" molecules. We propose that proton flux through gap junctions will contribute to the dissipation of regional acid loads within the myocardium. This represents a mechanism for the local control of myocardial pH(i).     

Formation and metabolism of catecholestrogens in depressed patients

The evidence that catecholestrogens are formed in the brain and exert behavioral effects in animal models suggest that these steroids might have psychotropic activities. In the present investigation, the formation and metabolism of catecholestrogens were studied in depressed patients. Twenty-four-hr urine samples were collected from 6 male patients (59 +/- 8 years) with endogenous retarded depression (subtype primary, endogenous, and recurrent according to Research Diagnostic Criteria) and from 12 male control subjects (51 +/- 4 years). The patients were treated with the monoamine oxidase inhibitor tranylcypromine (10-40 mg/day for 3-4 weeks). The concentrations of primary estrogens, 4- and 2-hydroxyestrogens and 2-methoxyestrogens, were measured in the urine samples after multiple chromatographic separation steps by radioimmunoassay. In the depressed patients, the excretion rates of 4-hydroxyestrogens were significantly lower than in control subjects. The ratio 2-methoxyestrogens:2-hydroxyestrogens as an index for 2-O-methylation was 3.8 +/- 1.6 in patients and 1.8 +/- 0.7 in controls. The increased methylation and reduced 4-hydroxylation rates of patients were not affected by treatment with tranylcypromine though the psychopathological state was improved by 46%. Therefore, it seemed unlikely that the observed alterations were pathognomonically relevant in these depressed patients. The alterations in the formation and methylation of catecholestrogens show that the depressed patients exhibited remarkable metabolic disturbances. The functional role of these disturbances remains to be clarified.     

THE WATERY EYE - MANAGEMENT AND RESULTS

The physiology of tear drainage has been clarified by the use of lacrimal scintillography, introduced within the last decade. During the same time, anatomical depiction of the drainage pathways has been enhanced by utilisation of refined contrast-medium radiology. The results of surgery from the Unit of Ophthalmic Plastic and Reconstructive Surgery, Sydney Eye Hospital, 1973–1977, in patients with a chronically wet eye, and evaluated preoperatively on a clinical basis only, are reviewed, and the potential benefit of X-rays and scintigrams appraised in retrospect. Of 150 wet eyes undergoing D.C.R. ± some form of intubation, 89% achieved success with the first operation, and 7% achieved success with one subsequent procedure. The success rates at first operation within the three groups were: DCR 92%, DCR + canalicular intubation 81%, DCR + Jones conjunctivorhinostomy tube 90%. An apparent selection error of ?.3% was elicted which accurate X-ray and scintigram conceivably could have avoided.     

Treatment of alcohol withdrawal syndrome with gabapentin.

Four in-patients with moderate alcohol-withdrawal syndromes benefited from treatment with gabapentin administered in an add-on fashion to clomethiazole. In comparison with the amount of clomethiazole required as estimated using a specially developed score during previous detoxifications of these patients at our hospital, gabapentin (400 mg q.i.d.) clearly reduced the amount of clomethiazole needed now Gabapentin, an anticonvulsant with favorable pharmacokinetic properties and tolerability, and with no known risk of dependence, may therefore be a useful new drug in the treatment of alcohol withdrawal. We believe that the potential value of gabapentin in alcohol withdrawal deserves further controlled studies.     

Effects of prepulses and d-amphetamine on performance and event-related potential measures on an auditory discrimination task

Rationale: Prepulse inhibition (PPI) of the startle reflex is a measure of sensorimotor gating, that is the processing of the startle stimulus (S2) is inhibited by the interfering processing of a closely preceding prepulse (S1). It has been demonstrated that PPI is disrupted in a variety of mental disorders and that several neurotransmitter systems, including dopamine, participate in the modulation of sensorimotor gating. Previous studies have also shown that a task-relevant S1 enhances PPI in healthy subjects but not in schizophrenic patients. These findings indicate an influence of attentional processes on sensorimotor gating and an impairment of this modulation in schizophrenia. Objective: Assuming a dopamine-mediated suppression of S1 processing as a mechanism of resource management and selective attention, which might be impaired in certain mental disorders, the present study investigated the effects of the indirect dopaminergic agonist d-amphetamine on prepulse-altered S2 discrimination and event related potentials (ERPs). Methods: Twelve healthy volunteers were tested in a double-blind, placebo-controlled experimental design. Here, S2 is the target in a difficult Go/NoGo auditory discrimination task. Results: Confirming our previous results, S2 processing is ”accentuated” by a weak acoustic prepulse in healthy subjects, thus leading to a lower rate of errors of omission but also to more false alarms (i.e. a liberal response bias). This performance change correlated with a prepulse-induced increase in the amplitude of the P3 ERP towards non-targets (”prepulse-induced non-target positivity”; PINTP). In addition, the results of the present study show that under prepulse conditions amphetamine disrupts ”S2 accentuation” associated with a dose-related reduction of the P2 component of the S1 response and a plasma level related reduction of PINTP. Conclusions: These data suggest an involuntary attentional shift towards S1 processing with increasing dopamine-release similar to that observed in patients with schizophrenia or OCD. It is concluded that sensory gating alters selective attention via dopaminergic modulation. Received: 30 March 1998 / Final version: 10 February 1999     

Gabapentin's acute effect on mood profile -- a controlled study on patients with alcohol withdrawal

RATIONALE: Delayed beneficial effects of gabapentin on mood were frequently reported in various patient populations. This is the first controlled study which addressed acute effects of gabapentin on mood. METHODS: Analysis of the German version of Profile of Mood States (POMS) throughout a randomised placebo-controlled, double-blinded study of gabapentin on acute alcohol withdrawal [Bonnet, U., Banger, M., Leweke, F.M., Specka, M., Müller, B.W., Hashemi, T., Nyhuis, P.W., Kutscher, S., Burtscheidt, W., Gastpar, M. 2003. Treatment of acute alcohol withdrawal with gabapentin -- results from a controlled two-center trial. J Clin Psychopharmacol 23, 514-519]. In addition, subjective severity of alcohol withdrawal was determined by the Essen Self-Assessment of Alcohol Withdrawal Scale (ESA) to control effects of concurrent withdrawal on POMS. Ratings were performed at intake (baseline), day 1 (study medication 400 mg q.i.d.), day 2 (study medication 400 mg q.i.d.) and day 7 (no study medication). RESULTS: Analyses could be performed on 46 out of 59 randomised subjects. Within the first two days of the study, a significant stronger increase in the POMS-vigour subscore occurred in the gabapentin group. A subgroup analysis suggests that gabapentin's effect on vigour largely results from a stronger improvement of vigour in a small group of 11 patients with co-morbid mild depression (according to ICD-10: dysthymia or depressive adjustment disorder). There were no significant differences between the treatment groups regarding the other POMS-subscores (dejection, fatigue, anger) ruling out an overall fast effect on mood. Moreover, ESA-measures were not significantly altered indicating a missing effect of 400 mg gabapentin q.i.d. on acute alcohol withdrawal itself. After tapering off study medication, no more significant differences between gabapentin and placebo group were observed on vigour, strongly suggesting that the initial effect results from a pharmacological gabapentin action. CONCLUSION: Gabapentin selectively accelerated the improvement of the vigour-subscore of patients with acute alcohol withdrawal within 48 h. This effect was independent from the subjective severity of withdrawal and especially marked in patients with co-morbid mild depression.     

Concomitant endocrine and immune alterations during alcohol intoxication and acute withdrawal in alcohol-dependent subjects

Although both alcohol intoxication and withdrawal have been demonstrated to produce significant endocrine alterations, no data exist on the effects of acute withdrawal on immune functions. Therefore, the current study investigated the effect of alcohol intoxication and acute withdrawal on plasma cortisol, prolactin and catecholamines, and blood leukocyte subset distribution in alcohol-dependent subjects. Nine male alcoholics admitted to the university clinic for alcohol dependence and 9 age-matched controls participated in the study. Blood was drawn from the alcohol-dependent subjects at 10:30 a.m. on day 0 (chronic alcohol intoxication), at the same time during acute alcohol withdrawal (day 1) and following the resolution of acute withdrawal (day 7). Blood was drawn from age- and gender-matched healthy control subjects at the corresponding time points. Plasma was then analyzed for hormone concentrations and blood examined for leukocyte subsets by flow cytometry. Alcohol-dependent patients displayed significantly elevated plasma cortisol during intoxication and withdrawal, which decreased to control levels following resolution of acute withdrawal. Small elevations of plasma prolactin and catecholamines were also observed during intoxication. Furthermore, alcohol-dependent subjects showed reduced absolute numbers of CD4(+) and CD8(+) T cells and natural killer cells compared with healthy controls across all time points. In contrast, although monocyte numbers were lower in alcohol-dependent patients during intoxication, acute alcohol withdrawal increased the number of monocytes in patients. Thus, alcohol dependence produces a general suppression of leukocyte subset populations in blood. However, resolution of acute alcohol withdrawal is associated with a return of plasma cortisol to control levels, and a concomitant increase in peripheral blood monocyte numbers.     

Treatment of acute alcohol withdrawal with gabapentin: results from a controlled two-center trial

A few case reports and data from animal experiments point to a possible efficacy of gabapentin (GP) in the treatment of alcohol withdrawal syndrome (AWS). Because of ethical considerations, the efficacy of GP in acute AWS was tested in an add-on fashion to clomethiazole (CLO). Given that the symptom-triggered amount of CLO required to limit AWS within the first 24 hours is related to the severity of AWS, we tested this amount of CLO during placebo (P) or GP (400 mg qid) under double blind, randomized conditions. Sixty-one patients (P = 29/GP = 32) suffering from alcohol dependence (ICD-10) and without any other psychiatric condition or psychotropic medication were included. The groups were not significantly different in baseline characteristics (eg, demographic data, severity of AWS). Both ITT and completer analyses revealed no significant differences between the groups considering the primary effectiveness measure: amount of CLO required in the first 24 hours (P = 6.1 +/- 5.4/GP = 6.2 +/- 4.7 capsules). In addition, premature discontinuations (P = 3/GP = 2) and decreases in Mainz Alcohol Withdrawal Scores were not significantly different in the first 48 hours of AWS (secondary effectiveness measures). Tolerability of combined CLO/GP was studied throughout the whole treatment comprising a 5-day lasting reduction part subsequent to the first 48 hours. Throughout the whole 7-day treatment a total of 5 and 2 patients dropped out and 6 and 5 patients reported adverse clinical events in the P and GP groups, respectively. All together, GP (400 mg qid) was no better than P in saving initial consumption of CLO or decreasing initial Mainz Alcohol Withdrawal Scores suggesting that GP was ineffective in the management of acute AWS in this model. The combination of GP and CLO was safe.