Preclinical voluntary drinking models for alcohol abstinence-induced affective disturbances in mice.

Negative reinforcement is widely thought to play an important role in chronic alcohol-use disorders (AUDs), and high comorbidity between AUDs and affective disorders highlights the importance of investigating this relationship. Prominent models posit that repeated cycles of alcohol (ethanol, EtOH) exposure and withdrawal produce circuit adaptations in the central nervous system that drive a transition from positive- to negative reinforcement-based alcohol seeking. Evidence supporting this theory has accumulated in large part using forced EtOH administration models, such as chronic intragastric gavage and chronic vapor inhalation. However, recent studies utilizing simple voluntary EtOH delivery systems show that forced abstinence from EtOH intake administered by the animal itself can produce evolving and significant affective disturbances, particularly in female C57BL/6J mice. Here, we highlight these recent studies to support the idea that voluntary EtOH administration in mouse models, as well as a protracted abstinence period and less commonly used behavioral tasks, could unveil affective disturbances during abstinence that have remained elusive using high dosage forced EtOH administration paradigms.

Alcohol use and mismatch negativity in young patients with psychotic disorder.

Mismatch negativity (MMN) is a neurophysiological indicator of the brain's ability to extract relevant information from an irrelevant background. MMN has been described as a reliable biomarker of schizophrenia and more recently it has found to be impaired in the early stages of psychosis. In addition, drugs (including alcohol) that block glutamate's N-methyl-D-aspartate receptor have been shown to reduce MMN. This study aims to determine whether risky alcohol consumption in young patients with psychotic disorder further impacts or changes their MMN response. Patients with high-alcohol use were found to show reduced temporal MMN amplitudes compared with patients with low-alcohol use and controls. In contrast, early psychosis patients with low-alcohol use showed reduced fronto-central MMN amplitudes compared with controls; whereas patients with high-alcohol use showed an intermediate response at these sites. Correlational analysis revealed distinct patterns of association between MMN and alcohol use in patients with early psychosis compared with controls. This study shows that early psychosis outpatients who engaged in risky drinking have decreased temporal MMN amplitudes, compared with their peers. This may reflect an additive effect of N-methyl-D-aspartate receptor hypofunction and high-alcohol consumption.

Endothelial dysfunction during acute alcohol withdrawal syndrome.

BACKGROUND: Endothelial dysfunction (EF) is a central phenomenon in a variety of conditions associated with increased cardiovascular morbidity. Here, we investigated EF during acute alcohol withdrawal syndrome before and 24h after medication. We aimed to analyze microcirculation, applying the post-occlusive reactive hyperemia (PORH) test and spectral analysis of skin vasomotion as markers of EF. Additionally, we explored whether segmentation of spectral analysis data may disclose more detailed information on dynamic blood flow behavior. METHODS: We investigated 30 unmedicated patients during acute alcohol withdrawal syndrome and matched controls. Patients were reinvestigated after 24h when half of them had been treated with clomethiazole. Capillary blood flow was assessed on the right forearm after compression of the brachial artery. Parameters of PORH such as time to peak (TP), slope and PORH indices were calculated. Spectral analysis was performed in order to study five different frequency bands. Withdrawal symptoms were quantified by means of the alcohol withdrawal scale (AW scale). RESULTS: We observed a blunted hyperemic response in patients after occlusion of the brachial artery indicated by significantly increased TP and decreased PORH indices. In contrast, vasomotion as investigated by spectral analysis was not altered. Segmentation analysis revealed some alterations in the cardiac band at rest, and indicated differences between treated and untreated patients after 24h. CONCLUSION: Our results suggest peripheral endothelial dysfunction in patients during acute alcohol withdrawal. No major influence of treatment was observed. Future studies need to address the relation of EF to cardiac morbidity during alcohol withdrawal.

[Alcohol-induced hallucinosis. Clinical aspects, pathophysiology and therapy]. / Die Alkoholhalluzinose. Klinik, Pathophysiologie und Therapie.

In recent years, little research has been focused on alcohol hallucinosis. The psychopathology of alcohol hallucinosis (vivid acoustic hallucinations, paranoid symptoms and fear) resembles paranoid schizophrenia, but other organic mental disorders have to be excluded too. Prognosis is usually good, but in 10-20% of cases alcohol hallucinosis tends to become chronic. Possible pathophysiological mechanisms involved in the development of the syndrome are changes in dopaminergic transmission or other neurotransmitter systems and neuronal membranes, elevated levels of betacarbolines and an impaired auditory system. For treatment, highly potent neuroleptics (haloperidol) are the drugs of first choice. In the case of alcohol abstinence the prognosis is good, but otherwise the risk of a recurrence is high.

The neurology of alcoholic denial: implications for assessment and treatment.

Alcohol has neurotoxic effects that frequently result in significant sensorimotor and cognitive deficits. These cognitive deficits may have profound implications for the behaviour and treatment of patients who abuse alcohol. In particular, the deficits in executive cognition that are typical of alcoholic dementia result in difficulties with planning, insight and impulse control. These deficits are frequently misinterpreted as alcoholic denial and are therefore assumed to have a psychodynamic basis. This paper reviews the neurological substrates for insight and self-monitoring and discusses a possible pathophysiology for a subgroup of alcoholic patients who exhibit alcoholic denial. Implications of this model for the evaluation and treatment of alcoholic patients are discussed.

[The neurobiology of alcoholism. Neuropathology and CT/NMR findings]. / Zur Neurobiologie der Alkoholabhängigkeit. Neuropathologie und CT/NMR-Befunde.

The authors deal with the heuristic value of the "neurobiological model of alcohol dependence". It allows the study of the influence of a defined noxe on different brain structures. Additionally, it enables the quantification of regeneration and restitution processes in abstinence. Because of this, the alcoholism model goes beyond dementia, the model which has dominated brain research so far. Neuropathological studies in humans and animals found a reduction in the volume of white matter and a partial degeneration, or even loss of specific neurons. According to animal data, this could to a certain extent be genetically determined. Alcohol exerts a distinct influence on different neurotransmitter systems. This research will deepen our understanding of the neurotoxic and psychotropic properties of alcohol, and of the development of dependence. Little is known about the role of astrocytes in the reaction of the brain to alcohol. Here again, the neurobiological model of alcohol dependence could be of value in learning more about their interactions with neurons. Using Magnetic Resonance Imaging and CAT-scans, the decrease in volume of white and grey matter was demonstrated in vivo. The degree and the time course of brain damage seems to be influenced less by drinking history than by age and gender. There is evidence that female alcoholics develop brain damage more readily than men. When abstinent, an increase in the volume of white and grey matter can be observed. This is not due to the rehydration of brain tissue alone. Future research will need to deal with the question of whether the central nervous system is capable of partial regeneration. For the study of neuroplasticity, the neurobiological model of alcohol dependence seems to be particularly well suited.

The glutamatergic basis of human alcoholism.

OBJECTIVE: Although alcoholism is one of the most common psychiatric diagnoses, understanding of its pathophysiology remains poor. Accumulating evidence suggests that neurophysiological and pathological effects of ethanol are mediated to a considerable extent through the glutamatergic system. This article reviews the evidence of ethanol's effects on glutamatergic transmission and proposes a glutamatergic basis for alcoholism. METHOD: The information was derived from original research. The authors located more than 100 articles from psychiatry and neuroscience journals that related ethanol to glutamatergic transmission. They critically reviewed the neurobiology of the glutamatergic system in alcoholism and synthesized a unifying glutamatergic theory. RESULTS: Acute effects of ethanol disrupt glutamatergic neurotransmission by inhibiting the response of the N-methyl-D-aspartate (NMDA) receptor. Prolonged inhibition of the NMDA receptor by ethanol results in development of supersensitivity; acute removal of ethanol causes marked augmentation of activity of postsynaptic neurons, such as those in the noradrenergic system, and, in the extreme, glutamate-induced excitotoxicity. Neurobiological effects of alcoholism, such as intoxication, withdrawal seizures, delirium tremens, Wernicke-Korsakoff syndrome, and fetal alcohol syndrome, can be understood as a spectrum of consequences of ethanol's effect on the glutamatergic system. CONCLUSIONS: A host of findings support the hypothesis that the unifying mechanism of action of ethanol in interference with glutamatergic neurotransmission, especially through the NMDA receptor. Alcoholism may be considered another member of the expanding family of glutamate-related neuropsychiatric disorders. These insights should increase understanding of the biologic vulnerabilities leading to ethanol abuse and dependence and aid development of more effective pharmacologic interventions.

Zinc deficiency and corticosteroids in the pathogenesis of alcoholic brain dysfunction--a review.

Chronic alcoholism is associated with hypercortisolemia and low serum zinc (Zn). Hypercortisolemia could be responsible for alcoholic cerebral atrophy and is also associated with enhanced NMDA neurotoxicity. It is hypothesized that low brain Zn, noted in chronic alcoholics, enhances NMDA excitotoxicity and ethanol withdrawal seizure susceptibility. Also, Zn deficiency can produce neuronal damage through increased free radical formation. Clinically, Zn replacement therapy may be a rational approach to the treatment of alcohol withdrawal seizures and alcohol-related brain dysfunction.

Alcoholic dementia.

At least four distinct cerebral diseases--Wernicke-Korsakoff, Marchiafava-Bignami, pellagrous encephalopathy, and acquired hepatocerebral degeneration--have a close association with chronic alcoholism. Each is characterized by a distinctive pathologic change and a reasonably well-established pathogenesis; in each the role of alcohol in the causation is secondary. The question posed in this review is whether there is, in addition to the established types of dementia associated with alcoholism, a persistent dementia attributable to the direct toxic effects of alcohol on the brain--i.e., a primary alcoholic dementia. The clinical, psychologic, radiologic, and pathologic evidence bearing on this question is critically reviewed. None of the evidence permits the clear delineation of such an entity. The most serious flaw in the argument for a primary alcoholic dementia is that it lacks a distinctive, well-defined pathology, and it must remain ambiguous until such time as its morphologic basis is established.

[Subacute encephalopathy with seizures in chronic alcoholism]. / Subakute Enzephalopathie mit Anfällen bei chronischem Alkoholismus.

We report a case of subacute encephalopathy with seizures in chronic alcoholism (age 34 years). This syndrome clearly differs from the known neurological complications of chronic alcoholism. One of the authors has observed (and reported) such cases in the Baltimore area. Subacute encephalopathy is characterized by lethargy, confusion and neurological deficits such as hemiparesis, homonymous hemianopsia and aphasia. Epileptic seizures (generalized tonic-clonic, focal) are obligatory. The EEG shows very prominent slowing and periodic lateralized paroxysmal discharges (PLEDs). The condition is complicated by a variety of internal-medical complications. Structural neuroradiological tests are either normal or irrelevant. The cause and pathogenesis remain obscure. The subacute course ends with gradual resolution.

[Main involvement of the central nervous system in alcoholism]. / Principales atteintes du système nerveux central dans l'alcoolisme.

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 value of brainstem auditory evoked potentials in early diagnosis of Wernicke's encephalopathy.

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.

[Use of cranio-cerebral hypothermia among the complex resuscitation measures in mental disorders]. / Primenenie kraniotserebral'noi gipotermii v komplekse reanimatsionnykh meropriiatii pri psikhicheskikh zabolevaniiakh.

Craniocerebral hypothermia was employed in multimodality treatment of 10 patients with hypertoxic schizophrenia and 60 patients with intoxication psychoses, the clinical picture of which was characterized by increasing hypoxia and edema-swelling of the brain. Hypothermia was made to a cerebral temperature of 28-30 degrees C for 4-6 hours in the presence of the neurovegetative blockade. The data obtained attest to a high therapeutic efficacy of craniocerebral hypothermia.

[A psychophysiological analysis of the cognitive tempo by means of evoked potentials]. / Psikhofiziologicheskii analiz kognitivnogo tempa metodom vyzvannykh potentsialov.

A new approach to measure the speed of cognitive behaviour is introduced. The decomposition of reaction time allows to identify different stages: perception, comparison steps and motoric organization. For this reason the additive factor method and the analysis of event-related potentials is used. The results show specific decelerations in elderly subjects and alcoholics. The application of the method in clinical psychodiagnostic and psychopharmacology is discussed.

Multiple withdrawals from chronic ethanol "kindles" inferior collicular seizure activity: evidence for kindling of seizures associated with alcoholism.

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.

Positron emission tomography as a technique for studying the chronic effects of alcohol on the human brain.

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.