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Rats on a chronic intermittent ethanol (CIE) regimen showed a persistent reduction in seizure threshold to the convulsant drug pentylenetetrazol (PTZ). CIE rats were given ethanol by intubation on an alternate day schedule and tested at selected intervals for seizure threshold with PTZ. A significant reduction in seizure threshold, a sign of withdrawal, was observed 20 hr after the first dose. The severity of withdrawal intensified on repetition of the ethanol administration and depression-hyperexcitability cycle, with the seizure threshold reaching a maximum decrease after 12 doses and remaining reduced up to 60 doses. The reduction in seizure threshold persisted for at least 40 days of no alcohol following the 60th dose. The long-lasting decrease in seizure threshold following CIE treatment resembled the "kindling" phenomenon produced by chronic administration of PTZ (25 mg/kg, 3 times/week). The CIE rats developed, in addition, a tolerance to the anticonvulsant action of ethanol, which occurred well after the decrease in PTZ seizure threshold, and a tolerance to the hypothermic effect of ethanol, which developed rapidly. PTZ kindled rats that had never been exposed to ethanol also exhibited tolerance to the hypothermic effect of ethanol. We propose that kindling contributes to the mechanism of the development of dependence on central nervous system depressants like benzodiazepines, barbiturates, and alcohol, drugs that act on the gamma-aminobutyric acid-A receptor chloride ion channel complex. Repeated episodes of depression and withdrawal hyperexcitability are postulated to produce kindling during the repeated withdrawal episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

A single dose of mianserin (a 5HT1C/5HT2 antagonist), administered 1 hr, 48 hr, or 7 days before testing, was evaluated for its efficacy in alleviating or preventing the occurrence of anxiogenic behaviors observed during ethanol withdrawal. Other behavioral experiments using selected drug interactions were conducted to examine whether the effect of mianserin was related to a long-term modification of 5-hydroxy-tryptamine (5HT) receptor function. Rats were fed a liquid diet containing 4.5% ethanol for 4 days. They were tested on the elevated plus-maze (EPM) 12 hr (acute withdrawal) and 5 days (protracted withdrawal) after the last ethanol dose. Ethanol withdrawal induced a pattern of "anxiogenic" behavior that consisted of reduced activity (total entries) and a reduced proportion of open arm activity. Mianserin, injected as a single dose given either 1 hr (0.16-5 mg/kg, ip) before testing or given (20 mg/kg, ip) on the morning of the 3rd day of ethanol administration, i.e., 48 hr and 7 days before testing, dose-dependently prevented or reversed the ethanol withdrawal induced reduction in open-arm activity. In contrast, the 5HT1C/5HT2 receptor agonist (+/- )-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOl) did not affect behaviors in the EPM in ethanol-naive rats, nor in those undergoing ethanol withdrawal. However, although there was a marked tolerance to DOl-induced body shakes (a measure of 5HT2 function) during withdrawal, DOl reversed the action of mianserin in the EPM. The 5HT1 receptor agonist, 5HT2 receptor antagonist 1-naphthyl-piperazine (1-NP) reduced open-arm activity in ethanol-naive rats and this action was enhanced during withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

We recently proposed that alcoholics suffer from a functional defect within the basal ganglia/limbic striatum or its modulation by dopaminergic projections from the ventral tegmentum, and that inhibition of striatal output caused by the prodopaminergic effects of alcohol ingestion induces or exacerbates craving and impaired control over alcohol consumption in alcoholic individuals. To test this hypothesis, 16 subjects with a diagnosis of alcohol dependence or abuse were studied in a double-blind, placebo-controlled experiment in which the effects of the D-2 antagonist haloperidol on measures of craving and impaired control were assessed before and after administration of a priming dose of alcohol. Subjects were pretreated with 0.015-0.025 mg/kg haloperidol (experimental condition) or 2 ml normal saline (control condition), and subsequently consumed 0.4-0.6 g/kg ethanol as their preferred alcohol-containing beverage. Significant increases in subjectively rated craving for alcohol and perceived difficulty resisting additional alcohol consumption occurred following the priming dose of alcohol when subjects were pretreated with saline. In contrast, no significant changes in reported ability to resist additional alcohol occurred when subjects were pretreated with haloperidol, and reported levels of craving decreased relative to baseline following haloperidol pretreatment. Subjects also consumed about 25% less optionally available alcohol when pretreated with haloperidol than when pretreated with saline. These findings support the hypothesis that craving and impaired control are induced or exacerbated by the prodopaminergic effects of alcohol consumption.

EMG abnormalities such as short muscle twitches and marked increase of muscle tone can be identified during REM sleep. We compared the polysomnographic parameters of ten alcoholic patients who were sober and medication-free for at least four weeks, five methadone-substituted politoxicomanic patients (MSP) and ten healthy control patients. The alcoholics and the MSP showed significantly more twitches than the control patients, and the MSP had significantly more tonus increase than the alcoholics and the controlled. The polysomnographic measures differed significantly between the groups in sleep architecture. The alcoholics had significantly less slow-wave sleep (SWS) and more REM sleep, the MSP had a longer REM latency and more of stage 2. Dividing all subjects along the median of the two EMG abnormalities, the group which showed a high number of twitches had significantly less SWS with a compensatory increase of stage 2. The two EMG measures, which were scored additionally, may provide a useful additional information in the differentiation of sleep disturbances in alcoholic and methadone-substituted patients. The interaction between the occurrence of these EMG abnormalities and the other polysomnographic measures in our study needs further clarification.

Mouse lines have been genetically selected to be alcohol Withdrawal Seizure Prone (WSP) or Resistant (WSR). The selection index is the severity of withdrawal handling-induced convulsions seen after removal of mice from chronic exposure to ethanol vapor. Behavioral, pharmacological, and neurochemical results from a replicated bidirectional selection project are reviewed. In reciprocal F1 crosses of the WSP and WSR lines, substantial dominance for resistance to withdrawal was found in both replicated sets of lines. WSP and WSR mice differ principally, and markedly, in traits related to the severity of withdrawal from alcohols and other drugs with depressant properties. This suggests that genes influencing severity of withdrawal from chronic ethanol exposure also pleiotropically influence genetic susceptibility to dependence on other drugs of abuse. However, the results of WSP vs. WSR comparisons for traits related to ethanol sensitivity and tolerance development suggest control in large part by genes different from those influencing withdrawal severity.

Prior experience with ethanol (EtOH) withdrawal may sensitize an individual to subsequent withdrawal episodes. It has been hypothesized that the progressive intensification of the EtOH withdrawal syndrome following repeated episodes of EtOH intoxication and withdrawal may represent the manifestations of a "kindling" mechanism. The purpose of this study was to develop an animal model of EtOH withdrawal that is sensitive to the effects of prior withdrawal experience. Adult male C3H mice were chronically exposed to EtOH vapor in inhalation chambers prior to withdrawal testing. A multiple withdrawal (MW) group received 3 cycles of 16 hr EtOH vapor separated by 8-hr periods of abstinence; a single withdrawal (SW) group received a single bout of EtOH exposure (16 hr); a third group (SW-CONT) experienced a single withdrawal episode after receiving the equivalent amount of EtOH intoxication as the MW group (16 x 3 = 48 hr), but in a continuous (uninterrupted) fashion; and a fourth group (C) served as controls, not receiving any EtOH exposure throughout the study. Severity of the withdrawal response was assessed by scoring handling-induced convulsions hourly for the first 10 hr and then at 24 hr postwithdrawal. The results indicated that the severity of EtOH withdrawal seizures was significantly greater in animals that had a prior history of withdrawal episodes (MW group) in comparison to a separate group of animals that were tested following a single withdrawal from the same 16-hr intoxication period (SW group).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of long-term treatment with ethanol was investigated on the function of gamma-aminobutyric acid A (GABAA) and N-methyl-d-aspartic acid (NMDA) receptors. Rats were rendered ethanol-dependent by repeated forced administration of a 20% ethanol solution (12 to 18 g/kg/day po) for 6 days and tested while still intoxicated or at different time intervals after withdrawal. t-[35S]Butylbicyclophosphorothionate (35S-TBPS) binding was increased by 30% in cortical homogenates of rats killed 1 to 3 hr after last ethanol administration, when compared with saline-treated animals. However, GABA-stimulated 36Cl- uptake and its enhancement by flunitrazepam was decreased in the ethanol-treated animals. 35S-TBPS binding and 36Cl- influx measured 9 to 24 hr following the last ethanol injection, when withdrawal signs were present, were unmodified with respect to saline-treated rats. Moreover, the effects of both isoniazid and FG 7142 on 35S-TBPS binding were unchanged in ethanol-dependent rats tested at 1 to 3 and 9 to 24 hr, compared with controls. In contrast, ethanol-withdrawn rats tested at 9 to 24 hr showed a dramatic enhancement in their sensitivity to the convulsant action of isoniazid (50 to 250 mg/kg, sc). The same animals were also more susceptible to the convulsant action of NMDA (0.5 to 5 micrograms/5 microliters/rat intracerebroventricularly) and kainic acid (12 mg/kg, ip), and this effect was paralleled by an enhancement (+25%) in the density of 3H-MK 801 recognition sites in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of short-term (15 days) and long-term (60 days) ethanol treatment and withdrawal on agonist-stimulated phosphoinositide (Pl) hydrolysis, serotonin receptor subtypes (5HT1A and 5HT2), and alpha 1-adrenergic receptors were studied in rat cerebral cortex. Short-term ethanol treatment had no significant effect on serotonin (5HT), norepinephrine (NE), and calcium ionophore (A23187)-stimulated [3H]-inositol-1-phosphate ([3H]-IP1) formation and 5-HT2 receptors as measured by 125I-lysergic acid diethylamide (125I-LSD) binding, in rat cerebral cortex. However, 15 days of ethanol treatment, followed by 24 hr of withdrawal resulted in a decrease in Bmax of 125I-LSD binding without significant change in KD, as well as a decrease in 5HT-stimulated [3H]-IP1 formation in rat cerebral cortex. 5HT1A and alpha 1-adrenergic receptors were determined by using [3H]-8-hydroxy-2-(di-N-propylamino)tetralin and [3H]-prazosin as radioligand, respectively. We also observed that long-term ethanol treatment had no significant effect on Bmax and KD of 5HT2, 5HT1A, and alpha 1-adrenergic receptors, as well as NE and A23187-stimulated [3H]-IP1 formation, but significantly decreased the 5HT-stimulated [3H]-IP1 formation in rat cerebral cortex. It is possible that a decrease in 5HT-induced PI turnover after long-term ethanol exposure may be due to a decrease in coupling of 5HT2 receptors to G protein or PLC enzyme, whereas the decrease in 5HT-induced PI turnover after withdrawal may be due to a decrease in functional 5HT2 receptor number.

The effects of alcohol on the central nervous system can be subdivided into three main categories: the effects of acute intoxication (drunkenness, acute encephalopathy, stroke), the effects of tolerance and ethanol withdrawal (delirium tremens, seizures) and the delayed manifestations of chronic alcohol consumption (cerebellar degeneration, Wernicke's encephalopathy, dementia).

The effect of alcohol dependence induced by ethanol inhalation on GABA-dependent 36Cl- influx into membrane vesicles prepared from the mouse brain has been examined. Ethanol, flunitrazepam and salsolinol induced a significant facilitation of the GABA-dependent 36Cl- influx into membrane vesicles obtained from the normal mouse brain. Ethanol inhalation induced the facilitation of GABA-dependent 36Cl- influx at 3-12 hr after the initiation of inhalation, but this facilitation returned to a normal level within 12 hr. In membrane vesicles obtained from the brain of an alcohol-dependent mouse at 7 days after the initiation of ethanol inhalation, not only was there a significant decrease of the GABA-dependent 36Cl- influx but there occurred also the disappearance of the activating effects of ethanol, flunitrazepam and salsolinol on the influx. This decrease in GABA-dependent 36Cl- influx was found to be recovered within 8 hr after the withdrawal of ethanol inhalation. On the other hand, behavioural withdrawal signs such as tonic-clonic convulsions with grimaces and heads thrown back appeared at 8 hr after the withdrawal of ethanol inhalation and continued for 8-16 hr. These results suggest that the observed functional deteriorations at cerebral GABAA receptors such as the decrease of GABA-dependent 36Cl- influx and the disappearance of the activating effects of ethanol, flunitrazepam and salsolinol on the influx may contribute to the preparation of the exhibition of ethanol withdrawal signs and/or the establishment of functional tolerance to alcohol, but are not directly related to the exhibition of alcohol withdrawal signs.

The relationship between dexamethasone suppression test (DST) response, depressive symptoms and liver function tests was investigated in 15 male alcohol-dependent patients for 2 weeks during alcohol withdrawal. Six of the patients relapsed into drinking within the investigation period. There was no association between DST response and relapse, which suggests that abnormal DST response has no predictive value for relapse into drinking. About 50% of the patients had abnormal DST responses during the first week of alcohol withdrawal. There was no relationship between DST response and depression or depressive symptoms. Depression remitted within 1-2 weeks, whereas DST responses remained abnormal for at least 2 weeks in 2 of the non-relapsing 9 patients. Abnormal DST response in alcohol withdrawal is unlikely to be due to alterations in liver function but may be attributable to the effect of alcohol on the hypothalamic-pituitary-adrenocortical axis.

Withdrawal of rats from chronic ethanol (2-5 g/kg, every 6 hr for 6 days) resulted in withdrawal symptomatology and dramatic fall in extracellular dopamine (DA) in the ventral striatum as measured by microdialysis. The changes in DA output paralleled the withdrawal symptomatology and both phenomena were reversed by a challenge ethanol dose (5 g/kg orally). The results suggest that the decrease in DA output may be responsible for the aversive symptoms of withdrawal.

Growth hormone (GH), blood pressure, and pulse rate responses to clonidine (100 micrograms IV) were studied three times during the first week of alcohol withdrawal in 19 alcohol-dependent patients. Fifteen healthy men were used as controls. The results suggest reduced sensitivity of the alpha-2-adrenoceptors involved in GH secretion for at least 1 week after the end of alcohol intake. In contrast, very short-lasting subsensitivity was found in the alpha-2-adrenoceptors regulating blood pressure.

One of ethanol's actions after acute exposure is anticonvulsant activity whereas withdrawal from chronic ethanol exposure increases convulsant activity. An increase in neuronal transmission in the GABAergic pathways from striatum to the substantia nigra (SN) and a decrease in GABAergic transmission from SN to superior colliculus (SC) both appear to play a major role in inhibiting seizure propagation. If this is the case, then the changes in seizure sensitivity caused by ethanol may be expected to affect GABAergic transmission in opposite ways in SN and SC. We measured the effects of in vitro ethanol on pre- and postsynaptic indices of GABA transmission using SN and SC tissue from both ethanol-naive rats and rats given ethanol in their drinking water for 24 days and then withdrawn for 24 hr, a treatment that decreases seizure latency. While ethanol inhibited 3H-GABA release from slices of SC at low concentrations (20-100 nM), much higher concentrations were required to inhibit release from SN (100-500 mM). In fact, release from SN was increased by low concentrations of ethanol. Ethanol in vitro (20-1000 mM) also inhibited specific binding of 35S-TBPS to the GABAA receptor but this effect was similar in both potency and efficacy in SC and SN. Next, the in vitro effects of ethanol were measured in rats that had consumed an average of 9.8 g ethanol/kg body weight/day and were then withdrawn for 24 hr. Ethanol inhibition of 3H-GABA release from SC was significantly less in ethanol-treated rats compared to controls whereas the inhibitory effect of ethanol was increased in SN from ethanol-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

A complex pattern of changes in the field potentials recorded from mouse hippocampal slices, prepared after chronic ethanol treatment in vivo, has previously been demonstrated in this laboratory. In the present study, recordings from slices prepared immediately after 2 weeks of ethanol treatment, showed only an increase in paired pulse potentiation, compared with controls, whereas recordings made immediately after 16 weeks of ethanol administration showed decreases in the thresholds for single and multiple population spikes, increases in paired pulse potentiation and epileptiform activity. In hippocampal slices prepared after 24 hr withdrawal, following 16 weeks of ethanol treatment, there were no signs of hyperexcitability in the field potentials. Ratings of convulsive behaviour were increased in mice during a 12-hr period after withdrawal from 16 weeks of ethanol treatment. Corresponding behaviour ratings for the mice given ethanol for 2 weeks, or those withdrawn for 24 hr after 16 weeks ethanol treatment, were not significantly different from control values. It was concluded that epileptiform activity seen in hippocampal slices after prolonged ethanol administration may contribute to the ethanol withdrawal hyperexcitability seen in vivo.

Delirium tremens is linked with a chronic depression of the central nervous system by alcohol and a compensatory hyperactivity of neurotransmitters. A sudden stoppage of alcohol intake induces excessive production of these transmitters. Firstly appearing is a noradrenergic hyperactivity which may be responsible not only for reducing the magnesium blood level but also for activating the other transmitter systems. A magnesium blood level lower than 1 mmol.l-1 involves a risk of seizures and requires IV magnesium sulfate. Noradrenergic hyperactivity can be prevented by IV alcohol associated with sedation best achieved by IV clomethiazole in alcoholic solution. Should these preventive measures fail, noradrenaline action in the central nervous system can be blocked by clonidine. Should hallucinations become manifest, linked to dopaminergic hyperactivity, haloperidol is indicated. Benzodiazepines may be useful, particularly carbamazepine, for their depressing effect on gaba-ergic hyperactivity.

Alcohol-induced delirium tremens (DT) is a well-known disease with an unpredictable, either favorable or fatal, spontaneous course. The cardinal symptoms are disorientation, hallucinations and autonomic lability. The pathogenesis of DT is still unknown, and the numerous hypothesis have spawned as many therapeutic approaches. Drugs with a cross-tolerance to alcohol have so far proved best. Benzodiazepines and clomethiazole have been considered the drugs of first choice for the past 20 years and more. Improvements in intensive care has helped lower the mortality rate to 3 to 8%. Major tranquilizers with a strong antipsychotic effect and anti-epileptic agents can effectively expand the sedative management of DT. Cerebral convulsions at the beginning of DT appear to dispose the patient to a prolonged course, and preexisting or concomitant disease affecting other organs (complicated DT) clearly prolongs the duration of delirium. The risks and contraindications of clomethiazole are emphasized. The course and outcome of DT is unpredictable--in our patients we found a mortality rate of 3.7% and 12.3% end up in a defective state.

The spectrum and time course of different symptoms during alcohol withdrawal may be caused by the involvement of various neurotransmitter systems that are differentially vulnerable to the effects of ethanol. Withdrawal symptomatology results from increased activity of excitatory mechanisms (NMDA-receptor, catecholamines among others) and from reduced functioning of inhibitory receptors (GABAA-, alpha 2-adreno-receptor among others). The neuronal mechanisms are subject to different dynamics of restitution following intoxication. Some of these probably contribute to long-lasting changes in CNS functions by "kindling" processes. Therapeutic guidelines are deduced from results of basic research and clinical trials. It is concluded that clomethiazole and benzodiazepines are superior in treating delirium tremens and certain risk-patients, whereas carbamazepine and clonidine may be helpful in moderate withdrawal syndromes or as adjunctive agents. However, the need for improved methodological standards of method in clinical research is evident.

We examined the effect of various treatment schedules with ethanol on the development of tolerance and the severity of withdrawal in rats. Tolerance to ethanol was examined after a challenge dose of ethanol using rectal temperature, dowel performance, and tail flick response; open field activity and the startle response were determined during withdrawal. Animals treated daily with ethanol developed greater tolerance, and also lost it faster, compared with animals subjected to repeated cycles of 3 days of ethanol treatment followed by 3 drug-free days. Also, the severity of withdrawal was greater in animals treated daily with ethanol. In the second study, we examined the development of tolerance and withdrawal severity of animals subjected to three different schedules of daily ethanol administration. Overall, the animals receiving continuous infusion of ethanol showed the most severe withdrawal and had, except for dowel performance, the fastest loss of tolerance to ethanol.

The suppression of heart rate variation reflects cardiac autonomic nervous dysfunction and is known to be associated with a poor prognosis or sudden death in diabetic patients. We investigated consecutive changes in the heart rate variation in 51 alcoholics using the coefficient of variation of R-R interval (CVRR). To correct for age effects, a ratio of CVRR to the standard predicted value (CVP) was calculated. On the whole, CVRR/CVP was suppressed on admission and on the 7th day of abstinence and increased on the 30th day. However, alcoholics could be divided into two groups by their CVRR/CVP on the 30th day: one group with transient autonomic dysfunction whose CVRR/CVP was more than 0.8 (n = 32), and the other group with persistent autonomic dysfunction whose CVRR/CVP was less than 0.8 (n = 19). Withdrawal hypertension occurred more frequently (63% vs. 19%) and mean systolic pressure (159 +/- 24 mmHg vs. 138 +/- 17 mmHg) was higher in the latter group than in the former, suggesting that persistent autonomic damage might, at least in part, contribute to withdrawal hypertension. To investigate further the relationship between the persistent autonomic damage and other complications, the CVRR/CVP on the 30th day of abstinence was analyzed in an additional 85 alcoholics (total n = 136). Persistent suppression of the CVRR/CVP was more frequently found in alcoholics with leg paresthesia (64%, n = 22), the Wernicke-Korsakoff syndrome (73%, n = 11), or diabetes mellitus (69%, n = 68), than in alcoholics without these complications (31%, n = 35).(ABSTRACT TRUNCATED AT 250 WORDS)

In 12 patients with developing alcohol withdrawal syndrome after abdomino-thoracic surgical procedures who were treated with Clonidine, short latency somatosensory evoked potentials were recorded. Clonidine leads to a good sedation, anxiolysis and moderated the psychotic symptoms. However, there was no significant correlation between the Clonidine medication and the SEP results over the time of drug administration concerning the primary cortical response N20 and the following N20/P25 wave. Therefore, the short-latency SEP-recording cannot provide a reliable monitoring of the good sedative effect of Clonidine in alcoholic withdrawal. The SEP responses after Clonidine are like those of morphine and are thought to have a similar central mode of action.

Withdrawal from both acute and chronic ethanol (EtOH) exposure is associated with increased neural excitability and increased activity of the hypothalamic-pituitary-adrenal axis. There is some evidence that glucocorticoids are necessary for EtOH withdrawal seizure expression. Lines of mice that were selected for severe (WSP) and minimal (WSR) EtOH withdrawal (as estimated from handling-induced convulsion scores) have been shown to differ in their stress response following an acute dose of EtOH. In this study we provide evidence that these lines of mice also differ in their sensitivity to the excitatory effects of glucocorticoids. EtOH withdrawal seizures of WSP mice were significantly increased by chronic and acute corticosterone treatment, whereas those of the WSR mice were unaffected. Neural excitability was decreased in the WSP mice when aminoglutethimide, a glucocorticoid synthesis blocker, was administered. Thus, it appears that genetic differences in EtOH withdrawal seizure severity may be due, in part, to differences in sensitivity to the excitatory effects of glucocorticoids.

We reviewed the histories of 340 men and 60 women who were admitted for alcohol detoxification to determine if hospitalizations unrelated to detoxification increased the prevalence of seizures observed in these patients. Previous investigations on this cohort suggested that recurrent detoxification admissions increased the probability of seizure histories. Detoxification and non-detoxification hospitalizations were calculated from patient reports and chart reviews on patients admitted for alcohol detoxification. Discriminant analysis of each type of hospitalization and total hospitalizations for each sex revealed an increased risk of seizure activity correlating with non-detoxification hospitalizations, but the correlation was weaker than that observed for detoxification admissions and for total admissions. This correlation between hospitalizations and seizure prevalence supports the hypothesis that recurrent alcohol withdrawal may have a kindling effect.

The earliest description of clinical magnesium deficiency was reported in 1934. In 1954, Flink reported alcoholism as a cause of magnesium deficiency. This has been confirmed by low serum and tissue levels, balance studies, low exchangeable 28Mg and parenteral Mg retention tests. Alcohol causes urinary Mg wastage, but other mechanisms related to alcoholism contribute to the magnesium deficiency including malnutrition, gastrointestinal losses, phosphate deficiency, acidosis and/or alkalosis, vitamin D deficiency and free fatty acidemia associated with alcohol withdrawal. Mg replacement therapy is recommended to prevent some of the serious sequelae of magnesium deficiency.

Statistical analysis of the interpeak latencies of brainstem auditory evoked potentials (BAEP) shows that a delayed IPL I-V is a very sensitive indicator for an early diagnosis of Wernicke's encephalopathy. In cases of uncomplicated delirium tremens no significant deviations of BAEP were found.

We previously found that, in the hippocampal formation as well as other central nervous system regions, withdrawal from alcohol following long periods of ingestion did not impede the ethanol-induced degenerative changes, including cell loss: on the contrary, neuronal degeneration was found to be increased in withdrawn rats. By grafting withdrawn rats either with immature hippocampal blocks or with suspensions of cultured astrocytes, we hoped to arrest the process of cell loss or even reverse it, because it is known that grafted material might display trophic and eventually protective effects in conditions of brain damage. The dentate granule and hippocampal CA3 pyramidal cells were counted both in the grafted hemisphere and in the contralateral one. Grafts of astrocyte suspensions did not interfere with the ongoing process of cell death in withdrawn rats. Conversely, grafts of hippocampal tissue impeded the degeneration observed in the granule and pyramidal cells of the grafted hemisphere, although in the contralateral one the cell loss persisted. We therefore conclude that the protective effect displayed by solid grafts might be a local process dependent on the release of diffusible trophic agents. We cannot explain the absence of any effect displayed by astroglial grafts, inasmuch as in different experimental situations such an effect was described.

Serotonin (5-HT) receptor subtypes were investigated during severe ethanol intoxication and withdrawal. Ethanol was administered intragastrically five times a day for 4 days (12 g/kg per day). 5-HT receptor subtypes were studied: (1) in severely intoxicated animals (mean blood ethanol concentration (BEC) = 4.7 g/l); (2) during the withdrawal reaction; and (3) in a control group. The maximal density of [3H] 8-hydroxy-2-(di-n- propylamino)tetralin [( 3H] 8-OH-DPAT) binding (Bmax) to 5-HT1a receptors was decreased by 25 and 17% in the hippocampus during chronic ethanol intoxication and withdrawal, respectively. [3H]Ketanserin binding to 5-HT2 receptors in the cortex, (-)[125I]-iodo-cyanopindolol [( 125I]CYP) binding to 5-HT1b receptors in the striatum and hypothalamus, and [3H] 8-OH-DPAT binding in the cortex were not affected by chronic ethanol administration. Previous in vitro experiments have shown that 5-HT1a receptors in the hippocampus are inhibitory. The down-regulation of these receptors may play a role in physical ethanol dependence, by inducing hyperexcitability of the hippocampus.

A study was made of the clinical picture of autonomic-somatic++ components of alcoholic abstinence and delirium as well as of the role of cardiovascular (hemodynamic) deviations. Using tetrapolar chest rheography the main types of hemodynamic disorders were described on a material of a random examination of 137 patients with stage II and III alcoholism. Of these, 64 patients were with the abstinent syndrome and 73 with the delirious syndrome according to the growth of the status gravity. Analysis of the clinical picture of the disease was first performed over time on the basis of the clinico-hemodinamic + parameters and phases of hemodynamic decompensation. The role of alcoholic cardiomyopathy in the general structure of the cardiovascular and somatovegetative manifestations was shown as dependent on variants of abstinence and delirium. Based on three clinico-hemodynamic++ types equivalent to the types of hemodynamic disorders, a new approach was applied to the differentiated treatment of alcoholic patients depending on their individual features, using optimally computed drug doses influencing the hemodynamics.

In alcohol withdrawal, abnormalities occur in a number of neurotransmitter systems: there is reduced inhibitory function, and increased activity of excitatory systems. The former, indicated by reduced GABA and alpha-2-adrenoceptor activity, acts in conjunction with, and is exacerbated by, the latter, which itself may be due to the potentiation of NMDA activity by depletion of magnesium, and overactivity of catecholaminergic and CRF neurones. These dysfunctions produce immediate effects and may also contribute to the long-term changes in brain excitability by a kindling-like process. It is possible that early and active treatment may oppose this process. Present strategies for treatment of alcohol withdrawal enhance GABA and alpha-2 inhibitory, or reduce excitatory, mechanisms. Future possibilities include the use of CRF and/or NMDA antagonists.

The purpose of these experiments was to determine whether or not tolerance develops to the effect of 3.0 g/kg ethanol on total and regional splanchnic blood flow in male Wistar rats. The animals were given the Lieber-DeCarli liquid diet containing ethanol for 10 days; ethanol-fed animals were withdrawn 24 hr prior to experiments. Regional blood flow and cardiac output (CO) were measured by the reference microsphere technique after an intraperitoneal injection of 3.0 g/kg of ethanol. Acute ethanol administration produced early nonsustained increases in portal vein blood flow in animals fed ethanol for 10 days and withdrawn for 24 hr and in control animals. However, after chronic exposure to ethanol, the pattern of increase in blood flow in response to ethanol in the splanchnic organs was different between the ethanol-fed and control groups. Increases in portal vein flow in control groups were due to concomitant increases in small intestinal, colonic, and cecal blood flow while the increase in the ethanol-fed group was due to a rise in small intestinal and stomach blood flow. The increase in stomach blood flow that occurred in the animals treated chronically with ethanol may be viewed as a conditioned response to ethanol, since this was not found in the control group. These results, demonstrate that the pattern of increase in blood flow in the splanchnic organs produced by an acute dose of ethanol depends on the animal's previous exposure to ethanol.

The present investigation tested the hypothesis that multiple withdrawals from chronic ethanol treatment "kindles" seizure activity. Two animal models of kindled seizure activity--electrical stimulation of the inferior collicular cortex or the amygdala--were used to evaluate this hypothesis. Four withdrawals from a 12-day ethanol-liquid diet regimen facilitated the seizure kindling rate in the inferior collicular cortex, when the stimulation was initiated 7 days after the last withdrawal. In contrast, four withdrawals from this chronic ethanol regimen significantly attenuated the rate of amygdaloid kindling. When the withdrawals were increased to six or 10 using a 5-day chronic ethanol treatment schedule, the kindling rate in the inferior collicular cortex proved directly proportional to the withdrawal number. Continuous ethanol exposure over the same period as the 10 withdrawal group also facilitated the inferior collicular kindling rate, but not to the extent found in the 10 withdrawal group. A before, 10 withdrawals from the 5-day chronic ethanol liquid diet treatment attenuated the rate of amygdaloid kindling. Thus, this kindling action of repeated ethanol withdrawals appears specific to seizures originating from the inferior collicular cortex, not the limbic system. These findings support a previous hypothesis for a kindling etiology of alcoholism related seizures.

The authors explore the possible role of basal ganglia/limbic striatal and thalamocortical circuits in craving and loss of control in alcohol abuse and dependence. Alcoholics may suffer from a defect in the neuronal systems within basal ganglia/limbic striatal and thalamocortical neuronal circuits, especially within the striatoaccumbal-ventral pallidal portion of this circuit or its dopaminergic nigrotegmental modulation. Alcoholic craving may result from a neurophysiologically driven obsession resulting from overactivity within the fronto-thalamic neuronal loop, and loss of control of alcohol consumption may be a neurophysiologically driven compulsion resulting from further impairment of the basal ganglia/limbic striatal portion of this circuit caused by the acute dopaminergic effects of intoxication.

While the alcohol withdrawal syndrome (AWS) is frequently encountered in a number of medical settings, its clinical management is inconsistent. Appropriate management of the AWS can be enhanced by objectively quantifying principal symptoms. The modified or Milwaukee Selective Severity Assessment (MSSA) measures 10 symptoms of the AWS, providing clinicians with a quantitative indication of the syndrome's severity. The MSSA was administered to 487 successively admitted alcoholics entering an inpatient chemical dependency treatment center. The MSSA was used to evaluate the severity, monitor progression, and determine efficacy of treatment of the AWS. The MSSA aided clinicians in deciding which patients required pharmacologic intervention for their AWS. Two groups of patients are described: 435 whose AWS was not judged to be severe enough to require medication, and 52 whose AWS was sufficiently severe to warrant pharmacologic intervention. The MSSA allowed clinicians to accurately identify patients requiring pharmacologic intervention of the AWS: only 10.6% of 487 hospitalized alcoholics required pharmacotherapy. The MSSA is a convenient, effective, and efficient tool for monitoring the AWS.

Alcoholism and epileptic seizures frequently coincide. Two groups can be distinguished clinically and by EEG. In one group (group I), seizures occur only during a period of alcohol withdrawal or partial withdrawal and can only be explained because of alcoholism in the history of the patient. In the other group (group II), seizures occur spontaneously, as well as during alcohol withdrawal, and epileptogenic factors (residual brain damage, former epileptic seizures, and a family history of seizures) probably play an important role in the manifestation of the seizures. Paroxysms or focal abnormalities are rarely seen in group I; in group II, EEG abnormalities are seen approximately as frequently as in other epileptic conditions. Both groups were examined to determine the extent of their EEG abnormalities after 24 h of sleep deprivation. Before and after sleep deprivation, only 4% of 52 chronic alcoholic patients without epileptogenic risk factors had EEG foci. Of the 52, 2% before sleep deprivation and 8% after sleep deprivation had generalized paroxysms. Of 128 chronic alcoholic patients with additional epileptogenic factors, 19% before sleep deprivation and 24% after sleep deprivation had EEG foci, and 17% before and 28% after sleep deprivation had generalized paroxysms. The pathogenesis of epileptic seizures in both groups and the therapeutic consequences are discussed.

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.

Mice from five highly inbred strains were crossed in a complete diallel design. Five hundred and fifty-five offspring were given a liquid diet containing ethanol as their sole food source for 9 days in an attempt to induce dependence. At 6 hr postwithdrawal on day 10, the mice were given a battery of physiological and behavioral measures designed to assess the symptoms of withdrawal. Littermate data were aggregated separately by sex and the aggregate litter mean data was employed in a multivariate extension of Hayman's diallel analysis. Hypothesis sums of squares and cross-products were tested against pooled-within-cell sums of squares and cross-products using Wilk's lambda as a criterion. For each sex, a highly significant additive effect was found, with some evidence for dominance effects as well, suggesting the raw materials are present for successful genetic selection. There was some evidence for dominance effects as well, but no evidence for maternal and other reciprocal effects was found for the set of seven measures. Composites derived from the additive and general dominance hypotheses correlation matrices and error correlation matrix were compared with a composite index currently being used in a multivariate selection study of ethanol dependence. Total ethanol consumption during the exposure period was positively correlated with low dependence between strains, and negatively correlated with measures of low dependence within cells.

Dopamine content of blood, activity of adenylate- and guanylate cyclases in platelets and lymphocytes, catechol-O-methyltransferase in erythrocytes, dopamine-beta-hydroxylase in blood plasma, monoamine oxidase in platelets, cAMP and cGMP content of blood, and the intensity of 3H-DA uptake by platelets have been investigated in alcoholic patients at different clinical states. Most of these indices have been studied in the brain and blood of rats displaying different affinities to alcohol. The results indicate that, in addition to the previously described disturbances of DA turnover, changes occur in the functions of enzyme and receptor systems involved in the mechanism of catecholamine neuromediation. Rats preferring and avoiding alcohol exhibit different DA and cyclic nucleotide concentrations in the blood and a trend towards different activity of some enzymes in the brain. It is suggested that: (1) the disturbances in the regulation of catecholamine neuromediation are involved in the mechanism of development of alcohol dependence; (2) the genetically-determined abnormalities of catecholamine neuromediation may contribute to an individual's attitude to alcohol.

This article reviews the similarities and differences of alcoholism and drug abuse from a biopsychosocial perspective. Special emphasis is given to newer developments. In biology, the role of endorphins and isoquinolines is considered against the more traditionally recognized clinical differences between alcohol and drug disorders. Consideration is given to psychological themes such as the utility of the addictive personality concept, the impact of more sophisticated prevention strategies, and the combined treatment of alcoholics and drug abusers. Reports from social fields include a cross-cultural view of chemical dependence and an appraisal of legal and political trends which influence chemical use and the civil rights of chemical users. Recent developments in the biologic, psychologic and social sciences have solidified the impression that the chemical dependencies, for all their differences, share a number of important characteristics. The etiology of alcoholism and drug abuse has been attributed to biopsychosocial causes, currently a widely accepted hypothesis. From one perspective, this theory could be seen as a grab bag approach, since no specific universal cause has been discovered while many have been postulated. From another aspect, the hypothesis is a rational synthesis of present knowledge which finds no one etiological factor to be either preeminent or ubiquitous. This article presents in succession an overview of the biology, psychology and sociology of chemical dependence with emphasis on integrating newer developments with familiar knowledge.

Ejaculates from 30 patients with alcohol toxic delirium have been tested. We found a decreased number of hypospermia (n = 8) and a reduced sperm density of 18 mill.spermatozoa/ml. Judging sperm density, morphology and motility, 29 sperm-counts are severe pathological. The disturbance of spermiogeneses is most pronounced (2 = 0.01), when increased FSH-values (n = 10) and acute alcohol toxical hepatitis (n = 4) were found, but is less dependent on the drinking habits according to Jellinek or on increased oestradiol values (n = 6) or increased CK-values. The sperm parameters in chronic alcoholics show no better values when fertility has been proved before (n = 10).

Clinically, patients with Delirium Tremens (DT) and acute alcohol hallucinosis (impending DT) appear excited with vivid false perception. Cerebral blood flow and eeg correspondingly point to hyperexcitability in the CNS during these conditions. Clinical trials with barbital treatment in alcohol withdrawal shows that the amount of drug and the drug plasma concentration is the same no matter whether the physical signs of withdrawal are accompanied by hallucinations and clouding of consciousness. The psychotic signs in DT and acute alcoholic hallucinosis develops after many years of alcoholism as does seizures. We hypothesize that physical withdrawal is determined by the degree of physical dependence developed during the most recent drinking period whereas the psychotic signs and seizures are due to a cumulated CNS hyperactivity developed over many years of repeated alcohol intoxication and withdrawal. Changes of electrolyte concentrations in plasma or CSF do not play an important role in the pathogenesis of DT and related clinical states except that changes in calcium and inorganic phosphate metabolism indirectly point to changes in membrane excitability. A new model for a study of rapidly repeated intoxication and withdrawal episodes in rats has shown that repetition of episodes augments the convulsive component of withdrawal whereas the non-convulsive signs are dependent on the most recent episode only. The augmentation of the convulsive component correlates with regional differences in brain glucose consumption. Furthermore, synaptic proteins and acidic phospholipids may be involved in the development of CNS hyperexcitability during alcohol withdrawal. In conclusion both clinical and experimental studies indicate that severe alcohol withdrawal reactions may consist of two components: 1) Physical withdrawal signs determined by recent physical dependence. 2) A long term cumulated CNS hyperexcitability relating to seizures and psychotic signs during withdrawal. This state is elicited by alcohol withdrawal but it represents a cumulated and permanent or long lasting CNS dysfunction in alcoholics. The precise biochemical/pathophysiological mechanisms for the development of the two-component dysfunction still remain to be clarified in detail.

The regional cerebral blood flow of 12 patients with severe alcohol withdrawal reactions (delirium tremens or impending delirium tremens) was measured during the acute state before treatment and after recovery. Greater cerebral blood flow was significantly correlated with visual hallucinations and agitation during the acute withdrawal reaction. The results suggest that delirium tremens and related clinical states represent a type of acute brain syndrome mainly characterized by CNS hyperexcitability.

Delirium tremens frequently ends with behaviorally deep sleep after which the patient has usually recovered from the withdrawal state. This sleep has been called "terminal sleep" or "critical sleep". In the present study terminal sleep was investigated in 14 chronic alcoholics. Polysomnographic recordings were undertaken during terminal sleep and the patients' behavior was observed after the patients awoke from terminal sleep. A marked decrease in stages 3 and 4 sleep was found in all the patients. Sleep cycles were regularly observed in 10 patients, while in the remaining four patients sleep cycles were not observed in terminal sleep. The patients who exhibited regular sleep cycles had fully recovered from delirium tremens after they awoke from terminal sleep, and they never relapsed into delirium tremens afterwards. In contrast, the patients who demonstrated terminal sleep in which sleep cycles were not observed revealed inactive and sometimes disoriented behavior suggesting slight disturbances of consciousness. These patients developed delirium tremens repeatedly thereafter. Therefore, terminal sleep can be divided into two different types. One is recovery sleep from sleep deprivation induced by delirium tremens, in which sleep cycles are observed. The other is not sleep, but a state which is indicative of disturbances of consciousness.