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Pharmacologic enhancement of central nervous system serotonin and dopamine functions has been postulated to improve maintenance of abstinence in patients with alcoholism. To test this hypothesis, patients with alcoholism who completed a 42-day inpatient treatment program were randomized to be administered, in a double-blind fashion, either 5-hydroxytryptophan and carbidopa, levodopa and carbidopa, or placebo for 1 year. Eight of 31 patients who entered the analysis remained abstinent from alcohol for 1 year; however, there was no significant effect of the treatment condition on maintenance of abstinence. Baseline psychologic measures showed that patients who abstained from alcohol had more education and higher scores on memory function tests. Measures of cerebrospinal fluid obtained before the start of the study indicated that all patients who had higher concentrations of the dopamine metabolite homovanillic acid relapsed, suggesting that further research is needed to elucidate the role of dopamine in alcoholism. Clinical Pharmacology and Therapeutics (1992) 52, 553–560; doi:10.1038/clpt.1992.184

OBJECTIVE Excessive exposure to glucocorticoids can have neurotoxic effects. The behavioral, cognitive, and neurochemical changes observed following the cessation of heavy drinking, therefore, may be associated with disturbances of the hypothalamic-pituitary-adrenal (HPA) axis. To investigate HPA axis disturbances during the ethanol withdrawal syndrome, the authors examined diurnal changes in plasma cortisol in six alcohol-dependent men following the abrupt discontinuation of alcohol intake. METHOD Plasma cortisol concentrations were quantified every 30 minutes for 24 hours in the early stage (1 day after cessation) and the middle to late stage (3 days after cessation) of the ethanol withdrawal syndrome as well as after the resolution of acute symptoms (8 days or more after cessation). RESULTS Plasma cortisol concentrations were almost twice as high during acute withdrawal as they were following recovery. The duration of the cortisol diurnal cycle on the first day of withdrawal was negatively correlated with the severity of withdrawal. CONCLUSIONS There is a marked activation of the HPA axis associated with the ethanol withdrawal syndrome. The authors hypothesize that this activation may account for some of the signs and symptoms of acute and subacute withdrawal. They discuss the potential long-term physiological effects of the episodic increases in cortisol associated with repeated episodes of ethanol withdrawal. The alterations in cortisol rhythmicity during early withdrawal may also have clinical implications.

In order to explore HPA axis organization and its relationship to central neuropeptide concentration in alcohol anamnestic disorder, we measured the plasma ACTH and cortisol response to oCRH administration and the CSF concentration of CRH and ACTH in a group of abstinent alcoholics with AAD and compred them with a group of carefully screened controls

Positron emission tomography is a neuroradiographic imaging technique that is beginning to be used to study cerebral pathophysiology in detoxified alcoholics. Localized cerebral glucose utilization in alcoholics at rest is not dramatically affected in comparison to the relatively large alterations in anatomic structure, cognition, and brain electrical activity. It is anticipated that future research studies will include cognitive challenges and utilization of PET ligands being developed to bind to specific receptors in the brain.

Forty-two alcoholic Korsakoff's syndrome (KS) patients (12 in study 1, 30 in study II) averaged slower tapping speeds than 35 alcoholic controls on the Halstead-Reitan manual finger tapping task. KS subjects also tapped slower than 26 normal volunteers in study II. Inverse relationships were found between finger-tapping speed dominant hand and verbal word fluency in one sample, and tapping speed and time to completion on Trail Making Part B and Tactual Performance Test in the other. The most powerful demographic predictors of tapping speed among age, education, length of abstinence, and affective state were age and education. Tapping speed was associated with cognitive tasks measuring frontal systems function (i.e., verbal fluency and Trail Making Part B) in KS subjects. There was no relationship between fine motor performance and general memory scores in the KS subjects. Decreased tapping speed for KS patients was postulated to result from compromised fine motor task initiation and persistence rather than mere slowing, as in Parkinson's disease. These findings suggest disruption of frontocerebellar systems that influence motor generation and set maintenance not previously explored in KS.

lthough it has been suggested for many years that A ethanol is directly toxic to the human brain,’ evidence in support of this contention has been largely correlative and descriptive. Historically, the ’70s may be viewed as the decade in which brain damage associated with alcoholism was “reified” using X-ray computed tomography, which could visualize shifts in ventricular and sulcal dimensions during prolonged drinking and abstinence.2 These radiographic findings appeared to parallel the cognitive abnormalities detected in many alcoholics by neuropsychologic testing.’ The ’80s witnessed important advances in the assessment of nervous system structure and function. Application of magnetic resonance imaging4 electrophy~iology,~ and positron emission tomography‘ to the study of alcoholic patients yielded important insights into the pathophysiology of brain damage in a\coho\ism, but a\so sewed to XighYight the complexity of this problem. For example, it was learned that certain electrophysiological abnormalities attributed to heavy alcohol intake were also present in the offspring of alcoholics prior to alcohol consumption.’ The present decade promises to be a time for important advances in understanding the pathophysiology of brain damage in alcoholics. Functional and structural brain imaging continue to improve rapidly, and powerful molecular genetic techniques offer the hope of identifying genetic mutations that predispose to certain neuropsychiatric complications of alcoholism. The purpose of this symposium is to focus on brain damage in alcoholics from the perspective of molecular pathophysiology. We have attempted to represent equitably different sides of the age-old debate concerning the relative contribution of alcohol neurotoxicityx.’ and sec

In Reply.— The comments of Drs McEntee and Mair raise a number of issues worthy of discussion. However, their underlying concern seems to be whether it is appropriate to conclude that an improvement of memory during treatment with fluvoxamine maleate in patients with Korsakoff's psychosis (KP) suggests an etiologic role of serotonergic mechanisms in alcoholic organic brain disease. They indicate that "more direct data," eg, diminished pretreatment levels of cerebrospinal fluid (CSF) 5-hydroxyin-doleacetic acid (5-HIAA) or improvement of memory test performance by treatment with selective serotonin agonists, would be required to substantiate the hypothesis of underlying serotonergic dysfunction in KP. Although the assessment in vivo of central serotonergic function is of considerable interest in understanding a wide range of psychiatric abnormalities,1,2it is uncertain whether CSF levels of 5-HIAA actually provide a measure of functionally active serotonin in periventricular brain regions.3Therefore, the absence of a significant correlation between

• We assessed the plasma corticotropin (adrenocorticotropic hormone) and cortisol responses to ovine corticotropin releasing hormone (oCRH) and the cerebrospinal fluid levels of CRH and corticotropin in alcoholics at various durations of abstinence and compared these variables with age-equivalent controls. Alcoholics who were tested at 1 week of abstinence (n = 11) demonstrated a significantly attenuated corticotropin response to oCRH compared with their response at 3 weeks of abstinence. Nine of these alcoholic patients demonstrated a significantly blunted corticotropin response at both 1 and 3 weeks of abstinence compared with controls (n =15). A markedly exaggerated corticotropin response to oCRH, associated with tachycardia, was exhibited by 2 alcoholics at both 1 and 3 weeks of abstinence. Alcoholics who were abstinent greater than 3 weeks did not differ in their response to oCRH compared with controls. Controls demonstrated a significant inverse correlation between baseline cortisol levels and the cortisol response to oCRH. This correlation was not evident in any of the alcoholic groups, including those patients who were abstinent greater than 6 months. There was a positive correlation between cerebrospinal fluid concentrations of CRH and corticotropin in all patient groups. These findings indicated that alcoholics have significantly altered hypothalamic-pituitary-adrenal axis functioning up to 3 weeks following the cessation of drinking, with a more subtle impairment present for greater than 6 months following abstinence.

Cerebrospinal fluid (CSF; n = 5) and plasma (n = 7) levels of norepinephrine (NE) and its major metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG) were examined in abstinent normotensive men with alcohol amnestic disorder during placebo and after 2 wk of clonidine treatment (6 or 12 micrograms/kg/day). Clonidine reduced concentrations of NE and both free and total MHPG in CSF and plasma. The CNS contribution to CSF free MHPG also decreased (as estimated from the differential reductions in CSF and plasma levels). Percent reductions in CSF and plasma NE were substantially greater than those for MHPG, suggesting diminished CNS and peripheral NE release and turnover. CSF levels of homovanillic acid (HVA), which is derived solely from CNS dopamine metabolism, rose in each patient, whereas the CSF serotonin metabolite, 5-hydroxyindoleacetic acid, did not change. Thus the increase in HVA cannot be attributed to inhibition of acid transport from brain to blood. Changes in central noradrenergic and dopaminergic activity correlated inversely; thus diminished NE release and enhanced dopamine metabolism may both contribute to the effects of clonidine in man.

To determine whether prenatal thiamine deficiency, a frequent concomitant of alcoholism, reduces the response to ethanol during adulthood in the rat as does ethanol exposure in utero (Abel et al. 1981), pregnant Sprague-Dawley rats received either control or thiamine deficient diets together with daily injections of the thiamine antagonist pyrithiamine. At 7 months of age, male offspring were exposed to precisely regulated ethanol vapor concentrations in an inhalation chamber for 24 h and blood ethanol concentrations (BECs) and ethanol-induced intoxication were determined. Prenatally thiamine deficient rats and controls were indistinguishable in terms of appearance, body and liver weights, and the ratios of liver to body weight and brain to liver weight. However, total body water was significantly greater, and BECs and behavioral impairment were decreased, in the experimental rats. These findings indicate that prenatal thiamine deprivation is associated with reduced pharmacologic effect of ethanol as a result of increases in its volume of distribution and rate of metabolism.

We have investigated a thiamine-dependent enzyme, transketolase, in cultured fibroblasts from 41 human subjects, including patients with alcoholism-associated Wernicke-Korsakoff syndrome (n = 3), familial chronic alcoholic males (n = 7), their sons (n = 7), nonalcoholic men (n = 7), their male offspring (n = 7), and three generations of an Amish family (n = 10) without any history of alcoholism. This study was undertaken to delineate whether transketolase abnormality (i.e., high Michaelis Menton constant (Km) for thiamine pyrophosphate), previously reported in patients with Wernicke-Korsakoff syndrome is prevalent among familial chronic alcoholic men and their sons without prior history of alcohol abuse but who are at high risk for alcoholism. Our data suggest that an inborn error (i.e., high Km of transketolase for thiamine pyrophosphate) predisposing to thiamine deficiency diseases similar to those reported in Wernicke-Korsakoff syndrome may occur in the general population. However, for some as yet unexplained reason(s) this variant seems to occur more frequently among familial chronic alcoholic men and their male offspring without any history of alcoholism. The inheritance pattern of this enzyme variant as revealed from an Amish pedigree study may be autosomal recessive as previously suggested.

EVERE chronic organic brain syndrome (OBS) is a S relatively common complication of alcoholism, occumng in about 10% of the cases.’ Alcoholism-associated OBS constitutes the second most common cause of adult dementia (approximately 10% following Alzheimer’s disease (40-60%).2 Although OBS in the alcoholic patient has variable presentations, some resear~hers~.~ have suggested that it may be conceptualized in terms of two clinically distinguishable syndromes: 1 ) alcoholic dementia (AD) and 2) alcoholic amnestic disorder (AAD) or Korsakoffs psychosis. AD is characterized clinically by global intellectual decline with deficits in abstracting ability, problem solving and memory, dysphasias and apraxias, electroencephalographic (EEG) abnormalities, cerebral and cerebellar atrophy, and ventricular dilation. Patients with AAD have disabling memory and behavioral abnormalities but with a relative sparing of intellectual functions. It has been thought that these two syndromes are neuropathologically distinguishable, but recent studies suggest that there may be considerable overlap.’ Nevertheless, AD has been associated with cortical neuropathological changes, whereas AAD is accompanied by subcortical periventricular lesiom6 While the clinical features and neuropathology of these syndromes may exist in some patients in relatively pure form, often AD and AAD coexist in some unrecognized proportion and likely interact to yield diverse clinical presentations.

Firstly, the contribution that cerebro-spinal fluid (CSF) studies have made to our understanding of the pathophysiology of alcohol withdrawal is addressed. Secondly, the developing literature, from our own studies and those of others, on abnormal CSF measurements in alcoholics and violent offenders is reviewed, with particular regard to impulsive murderers and arsonists. It is concluded that there is CSF evidence for increased norepinephrine function in alcohol withdrawal and an underlying serotonin hypofunction in impulsive disorders including some forms of alcoholism. Finally we report that patients with Korsakoff's syndrome may have central serotonin dysfunction since they show memory improvements during treatment with the serotonin uptake blocker fluvoxamine. Furthermore, these improvements correlate with the magnitude of change that fluvoxamine produces in CSF concentrations of the serotonin metabolite 5-HIAA.

Abrupt cessation of clonidine treatment in hypertensive patients may precipitate a withdrawal syndrome. Since this drug is likely to be more widely prescribed to normotensive patients with neuropsychiatric diseases, we studied neurochemical, cardiovascular, and behavioral changes upon placebo substitution in seven patients receiving clonidine (6 micrograms/kg/day for 3 weeks) for treatment of alcohol amnestic disorder. Urinary excretion of all major catecholamine metabolites returned to pretreatment levels 3-5 days after discontinuing clonidine, without significant overshoot. The percentage increase during clonidine withdrawal of the norepinephrine metabolite normetanephrine was greater than were those of vanillylmandelic acid, 3-methoxy-4-hydroxyphenylglycol (MHPG), or the epinephrine metabolite metanephrine. Excretion of the dopamine metabolites homovanillic acid and 3-methoxytyramine did not change. Total plasma MHPG, heart rate, and mean arterial pressure were significantly elevated above pretreatment values 72 h after the last dose of clonidine. There was an enhancement of episodic memory compared to predrug values but no other behavioral changes were noted during clonidine withdrawal. These findings are consistent with augmented catecholamine release and central noradrenergic activation which may produce psychopathology in some psychiatric patients during clonidine withdrawal.

The disposition of chlordiazepoxide (50 mg, intravenously), diazepam (0.143 mg/kg, orally), and oxazepam (0.429 mg/kg, orally) were studied in normal and alcoholic men before and after chronic disulfiram administration. Decreases in the plasma clearance of chlordiazepoxide (54%, p less than 0.05), diazepam (41%, p less than 0.05), and their active N-desmethyl metabolites were observed. Oxazepam has no important active metabolites and its net disposition is minimally altered by disulfiram. Oxazepam disposition is unaffected by age and liver disease. These considerations together with that of the short half-life of oxazepam (median, 6.1 hr) suggest that oxazepam may be the drug of choice if benzodiazepine therapy is used for patients taking disulfiram.

Pineal melatonin and serotonin content were determined during one to four days of continuous intoxication, and during the alcohol withdrawal syndrome. The nocturnal rise in pineal melatonin was blunted in continuously intoxicated animals, however this was found to be unrelated to duration of treatment. The initial dependent-intoxicated phase of the alcohol withdrawal syndrome produced a reduction of nocturnal pineal melatonin content with a concomitant elevation in pineal serotonin. The overt withdrawal phase of the alcohol withdrawal syndrome had no effect on pineal melatonin or serotonin content. This data suggests that ethanol may perturb pineal melatonin synthesis either directly, or indirectly by altered receptor function. Contrary to our expectations the pineal may not be a useful model to probe the physiology of increased noradrenergic neurotransmission produced by ethanol withdrawal.

There has been a continuing interest in the biological correlates of alcohol abuse and alcoholism, in part because structured clinical interviews and questionnaire-derived data are vulnerable to deliberate falsification and/or denial. Although alcoholics often report a history of specific complaints and diseases, many clinicians do not think that early alcohol abuse can be detected by evaluating this self-reported data. Although the search for a single biological marker for alcoholism has so far proved unsuccessful, several investigators have recently demonstrated that combinations of tests are more likely to identify alcoholics than single tests. Ideally, one would like to have a technique that would define when an individual is consuming too much alcohol, such that for one person it may be 4 drinks per day and for another it may be 6 drinks per day. Moreover, a clinically useful technique would identify binge drinkers as well as regular consumers, and would not be influenced by acute intoxication, age, other drug use, nonalcoholism-related medical conditions, or pathophysiology accompanying the alcohol withdrawal syndrome.

It has been suggested that the signs and symptoms of the ethanol withdrawal syndrome may be due to the increased production of an “inverse agonist” that binds to the central benzodiazepine (BZ) recognition site in the brain. Ro 15-1788 (a potent antagonist at the central BZ recognition site), diazepam, and Ro 15-1788 plus diazepam were administered to groups of rats undergoing overt ethanol withdrawal. Ro 15-1788 did not alter the severity of the ethanol withdrawal reactions, but antagonized the ameliorative effect of diazepam. The results of our studies suggest that 1. (1) the ethanol withdrawal syndrome is not produced by an endogenous ligand acting on the central BZ recognition site, and 2. (2) diazepam decreases the severity of the ethanol withdrawal syndrome, at least in part, by its action at the central BZ recognition site.

In order to assess some of the residue characteristics of the experimental carbamate acaricide, 3-methyl-5-isopropylphenyl-N-(n-butanoyl-)-N-methylcarbamate (promacyl) a 0.2 % aqueous emulsion was applied to cattle in a series of five trials and in a sixth, the technical product was added to the feed of stalled cattle. A method of analysis involving the formation of a derivative suitable for gas chromatographic analysis on electron capture detection mode was developed. Separate estimations of levels of the parent compound and the metabolites, 3-methyl-5-isopropylphenyl -N-methylcarbamate and 3-methyl-5- isopropylphenol, were carried out on fatty tissues and butterfat but for non-fatty tissues “total” levels, which were a combined estimate of 3-methyl-5-isopropylphenol itself and all substances hydrolysable to it, were estimated and quoted as Promacyl. The highest group average level of the parent compound was 0.9 part/million in fatty tissues 24 h after the last of 8 applications at 3 day intervals. In a single spray trial the maximum group average of 0.7 part/million in fatty tissues 24 h after treatment fell to 0.2 part/million after 5 days. Residues in butterfat, 7 h after a single dermal application showed a maximum level of 1.2 parts/million and this declined to 0.1 part/million on the seventh day after treatment. “Total” residues in non-fatty tissues were of the order of 1/10 those found in fatty tissues.

In a comparison of methods for estimating the cell-wall content of forage, each of three methods was compared separately with the other two in regression analyses. Subtraction of unextracted protein from cell-wall values removed differences in regression slopes. Parallel slopes, but different intercepts showed that different methods of extracting forage removed different amounts, rather than different proportions of non-protein, cell-wall material. With different extraction methods in use, cell-wall values are meaningful among laboratories using identical analytical procedures, and then only if interference from unextracted protein is excluded.

Memory may fail in a variety of ways. Patients with Korsakoff's syndrome demonstrate global memory deficits similar to those seen in patients with early progressive dementia. Korsakoff's patients, however, may recall rules and principles for organizing information and can gain access to their previously acquired knowledge (semantic memory), whereas recent memory may be grossly impaired. In contrast, dementia patients may have little access to previously acquired knowledge and therefore have great difficulty in organizing and encoding ongoing events. These contrasting forms of memory failure have implications for understanding the structure and mechanisms of memory and learning, particularly the relationship between episodic and semantic memory, as well as the development of therapeutic strategies for cognitive impairments.

Quadratic discriminant analysis of 25 commonly ordered clinical laboratory tests resulted in correct classification of 100% of nonalcoholic inpatients (n = 41), 100% of medical ward alcoholics as alcoholic (n = 63), and 95% of alcoholism treatment program participants as alcoholic (n = 274). Admission laboratory values for a random sample of 138 additional alcoholism treatment program participants were used to correctly classify 96% of them as alcoholics. Repeat analysis of these same laboratory tests after some 27 days of hospitalization resulted in 94% of the 138 patients still being classified as alcoholic, even though significant improvements in individual hepatic and hematologic laboratory values were noted. Classification was not changed with reanalysis after long-term abstinence (7 or 24 months), suggesting widespread and persistent alcohol-related alterations in organ system functioning with chronic alcohol abuse. Quadratic discriminant analysis of laboratory tests is an effective means of identifying people with present or past alcohol abuse but is not yet of value in detecting compliance with a treatment goal of abstinence.

Mean (+/- SEM) urinary excretion rate of the major melatonin metabolite 6-hydroxymelatonin (micrograms/day) was lower in 7 (2.8 +/- 1.0) of 8 men with Korsakoff's psychosis (KP) than in 15 healthy men (11.4 +/- 1.4). Treatment with the alpha 2-noradrenergic agonist clonidine decreased daily 6-hydroxymelatonin excretion (p less than 0.02). Reduced daily excretion of 6-hydroxymelatonin in KP reflects decreased melatonin synthesis in the pineal gland, perhaps as a residual effect of lesions due to past thiamine deficiency (Wernicke's encephalopathy).

The chronic effects of fluvoxamine (200 mg per day for 4 weeks) were studied in ten alcoholic organic brain syndrome patients in a double-blind cross-over design. Complete neuropsychological evaluation was performed as well as measurement of neurochemical changes in CSF. Fluvoxamine produced a small but significant improvement in memory performance. An analysis of fluvoxamine minus placebo difference scores showed a significant correlation between memory functioning and CSF 5HIAA levels. Alcohol amnestic syndrome patients who had the highest blood levels of fluvoxamine demonstrated the largest changes in CSF 5HIAA and improvement in memory performance under fluvoxamine. These findings implicate a role of serotonergic mechanisms in alcoholic organic brain syndrome and suggest that with individual titration of the drug dose, fluvoxamine might be a clinically useful agent in the treatment of this syndrome.

All-night sleep EEGs were compared in the following age-equivalent groups: seven men with Korsakoff's psychosis (KP), six men and two women with presumptive Alzheimer's disease, and six healthy men and three healthy women. KP patients had significantly increased intermittent time awake than both controls and Alzheimer patients, and shorter REM latency minus time awake than controls. Alzheimer patients had significantly reduced delta sleep than controls. Differences in the pattern of sleep EEG abnormalities may be due to different pathogenic mechanisms, but their utility in differential diagnosis requires further study.

Commonly used neuropsychological tests were administered to 91 detoxified alcoholics at the beginning of treatment. Statistically significant relationships were observed between test scores and post treatment consumption determined 8 months after completing treatment for 72 patients. The results varied depending upon the particular measure of posttreatment consumption evaluated and the type of statistical analysis used. The most consistent relationships were often counter to the notion that increased neuropsychological performance is correlated with a more favorable treatment outcome. Neuropsychological evaluation is of limited clinical utility in predicting posttreatment alcohol consumption.

The calcium antagonists nimodipine and dantrolene were compared with diazepam in an animal model of tolerance and physical dependence upon ethanol. Nimodipine and dantrolene were both effective in suppressing withdrawal tremors but diazepam was clearly superior to both agents. These results suggest that the ethanol with-drawal syndrome is only partially mediated by increased calcium flux.

Seven normotensive patients with alcohol amnestic disorder were treated with 2 micrograms/kg clonidine (C) three times daily for 1 wk. Four patients received 12 micrograms/kg/day during the subsequent week; three developed hypotensive symptoms at this dose and remained on 6 micrograms/kg/day. During a predrug placebo period and after 60 hr on each dose of C, urinary excretion rates of catecholamine metabolites were determined. C, 6 micrograms/kg/day, reduced the ratio of norepinephrine (NE) metabolites (mumol/24 hr) to normetanephrine (NM), vanillylmandelic acid (VMA), and 3-methoxy-4-hydroxyphenyl glycol (MHPG). The excretion of metanephrine (M) was not reduced significantly. The ratio M/NM and M/(VMA + MHPG) increased, indicating Cs effects are primarily noradrenergic. Reduction in NM/(VMA + MHPG) indicates disproportionate lowering of the O-methylated metabolite of NE compared to its deaminated metabolites, consistent with C inhibition of NE release. Patients with the highest predrug NM excretion had the greatest decrements with C. The dopamine metabolites 3-methoxytyramine and homovanillic acid were not decreased by C. C-induced reductions in the ratio NM/(VMA + MHPG), an index of NE release, correlated (n = 7) with reductions in supine systolic blood pressure, mean arterial pressure, and salivary flow rate.

We attempted to replicate previous reports of impaired central noradrenergic activity in patients with Korsakoff's psychosis. No differences were demonstrated in lumbar cerebrospinal fluid concentrations of norepinephrine or its major metabolite, 3-methoxy-4-hydroxyphenyl glycol (MHPG), or in the contribution of plasma to cerebrospinal fluid free MHPG in 6 patients with clinically well characterized Korsakoff's psychosis and 8 age-matched healthy, normal volunteers. Likewise, cerebrospinal fluid concentrations of the major metabolites of dopamine (homovanillic acid) and serotonin (5-hydroxyindoleacetic acid) were the same in patients and controls.

Six months after severe thiamine deficiency, when their body and liver weights had normalized, male Sprague-Dawley rats were exposed to constant ethanol vapor concentrations for 6 days in an inhalation chamber and blood ethanol concentrations (BECs) were determined. Previously induced thiamine deficiency was associated with about a 50% reduction of BECs and a significant increase in liver alcohol dehydrogenase (ADH) activity suggesting a persistent acceleration of ethanol metabolism. No significant changes were found in liver aldehyde dehydrogenase activity, plasma levels of thyroxine, testosterone, or estradiol, or brain or liver histology. Plasma growth hormone concentrations were about 60% lower in the experimental group than in controls, but this effect of previous thiamine deprivation did not correlate with changes in ADH activity. Therefore, it remains to be elucidated how thiamine deficiency-induced central nervous system alterations may contribute to the development of metabolic tolerance to ethanol.

Ethanol-induced intoxication and hypothermia were studied in rats approximately 7 months after severe thiamine deficiency, when treated rats appeared to have recovered their physical health. Previously induced thiamine deficiency without prior ethanol exposure significantly decreased the area under the curve plotted for the concentration of ethanol in blood and also decreased behavioral impairment and hypothermia due to ethanol exposure. Pathophysiologic changes resulting from thiamine deficiency may contribute to both the pharmacodynamic and pharmacokinetic tolerance to ethanol in chronic alcoholics.

Considering the magnitude of the problem, the treatment of alcoholism-associated chronic organic mental disorders has not been extensively studied. Alcoholic organic brain disease is heuristically viewed as the admixture of clinical syndromes of impairment [alcoholic amnestic disorder or Korsakoff’s psychosis (KP) and dementia associated with alcoholism (DAA)], each with its distinguishing cognitive, neuropathological, and neurochemical characteristics. Differences between KP and DAA are highlighted by studies that compare KP patients with those having Alzheimer’s disease or depression. Furthermore, treatment of cognitive deficits in KP and DAA may be modeled after strategies that have proved effective for these other neuropsychiatric disorders. Although abstinence and proper nutrition remain the cornerstones of treatment, pharmacological modification of neurotransmitter function and/or enhancement of cerebral metabolism combined with behavioral methods may also be beneficial. Serotonergic approaches to improve memory in detoxified alcoholics may also reduce alcohol intake, and this has implication for treatment of less impaired alcoholics.

Study of alcoholic chronic organic brain syndrome may have applicability to the large population of alcoholics with less severe cerebral dysfunction. Brain impairment in alcoholics may be conceptualized as two clinically and neuropathologically distinguishable organic brain syndromes: alcohol amnestic disorder or Korsakoff's psychosis (KP) and alcoholic dementia. Alcoholic organic brain disease may result from two interacting pathophysiological processes: nutritional (thiamine) deficiency and ethanol neurotoxicity. Subcortical periventricular lesions associated with KP result primarily from thiamine deficiency, whereas ethanol neurotoxicity and various secondary effects of alcoholism may contribute to the cortical neuropathological changes associated with alcoholic dementia. These two patterns of brain damage may be differentiable in individual alcoholics using cognitive tests and other measures of CNS function and, therefore, allow selection of a treatment strategy based on pathophysiological considerations. Studies in animals and humans suggest that a genetic predisposition to thiamine deficiency may contribute to alcoholism-associated dysfunction of brain and other organ systems and possibly have a causative role in the development of alcoholism.

The authors have investigated the function of the hypothalamic-pituitary-adrenocortical (HPA) axis during and after withdrawal from alcohol. 24 hour rhythms of cortisol were abnormal in that elevated levels were seen throughout the day in patients with moderate to severe, but not mild, withdrawal. This abnormality of circadian secretion of cortisol, which is similar to that seen in Cushing's syndrome and post-operative trauma, returned to normal after a period of one week of abstinence on their in-patient ward. Such excessive secretion of cortisol may explain some of the complications of chronic alcoholism.

• Ten patients with alcoholic chronic organic brain disease were categorized as having alcohol amnestic disorder, or Korsakoff's psychosis (n = 6), dementia associated with alcoholism (n = 3), or compensated alcoholic liver disease (n =1). All patients had severe deficits in memory for recently acquired information (episodic memory). Patients with alcohol dementia also showed global intellectual decline, including decreased performance on measures of semantic (knowledge) memory and reduction in levels of cerebrospinal fluid somatostatin. In a 4-week double-blind crossover design, the serotonin-uptake blocker fluvoxamine maleate (100 to 200 mg/d) was found to improve episodic memory in only the patients with alcohol amnestic disorder. These improvements in memory were significantly correlated with reductions in levels of cerebrospinal fluid 5-hydroxyindoleacetic acid, suggesting that facilitation of serotonergic neurotransmission may ameliorate the episodic memory failure in patients with alcohol amnestic disorder.

An aerial cache survey was unreliable in indicating population size or trend of beaver (Castor canadensis) on 2 prairie rivers in Montana. Accuracy in locating caches was high (about 90%) and constant among years and areas, but colony size varied among areas and years. Data on age, sex, and reproduction are needed to determine colony size and properly evaluate aerial cache-survey results. J. WILDL. MANAGE. 47(3):697-703 Aerial censuses of beaver using sign observed have been described by Swank and Glover (1948), Fuller (1953), Townsend and Newby (1955), Hay (1958), and Payne (1981). Aerial surveys of caches (submerged piles of branches stored in fall for winter food) agreed well with ground surveys of active colonies in Colorado (Hay 1958) and in Newfoundland (Bergerud and Miller 1977, Payne 1981), where beaver built dams and lodges. The aerial cache-survey technique was inaccurate on streams in British Columbia (Slough and Sadleir 1977), but has not been evaluated on prairie rivers where beaver build dams rarely, live in bank dens, and often secure their caches near the bank. Even if aerial surveys accurately determine the number of colonies present, changes in colony counts may not necessarily reflect changes in population size, because colony size can change from year to year (Townsend 1953, Bergerud and Miller 1977). To properly evaluate the reliability of aerial cache surveys for estimating beaver populations, the accuracy of observing caches and the relationship between colony counts and population size must be examined. This paper evaluates the aerial beaver-cache survey on 2 prairie rivers in southeastern Montana and compares cache counts to population numbers. We thank the following trappers who provided jaws and reproductive tracts from beaver: D. Delcamp, R. Brauer, W. McConnachie, M. and M. Howry, and D. Schaff. We also thank D. Palmisciano for estimating the age of beaver jaws and H. E. Hodgdon, J. S. Larson, H. S. Hash, and R. P. Brooks for constructive reviews of the manuscript. This is a contribution from Montana Federal Aid to Wildlife Restoration Project W-130-R.