Kathleen A. Grant

Ethanol withdrawal seizures and the NMDA receptor complex

Prior biochemical and electrophysiological studies have shown that low doses of ethanol inhibited calcium influx through the N-methyl-D-aspartate (NMDA) receptor/ionophore. The present data show that chronic ethanol treatment results in an increase in the number of NMDA receptor/ionophore complexes in the hippocampus, a brain area known to be associated with ethanol withdrawal seizure activity. Treatment during withdrawal with NMDA-exacerbated handling induced withdrawal seizures in the ethanol-dependent mice, while administration of the NMDA receptor-associated calcium channel antagonist MK-801 decreased the occurrence and severity of the withdrawal seizures in a dose-dependent manner. The results are consistent with the hypothesis that the up-regulation of the NMDA receptor systems following chronic ethanol treatment may mediate the seizures associated with ethanol withdrawal in dependent animals.

Brain regional specificity and time-course of changes in the NMDA receptor-ionophore complex during ethanol withdrawal

Previous work, using membrane receptor binding techniques, demonstrated an increase in hippocampal MK-801 binding sites in mice after chronic ethanol ingestion. The current studies, using quantitative autoradiography, demonstrate that chronic ethanol ingestion also produces increases in MK-801 binding in cerebral cortex, striatum and thalamus, as well as in hippocampus. The persistence of changes in MK-801 binding paralleled the time-course for ethanol withdrawal seizure susceptibility. These results support the hypothesis that an increase in the number of NMDA receptor/channel complexes in hippocampus, and possibly other brain regions, plays a role in the generation or expression of ethanol withdrawal seizures.

Ethanol and the NMDA receptor

The actions of glutamate, the major excitatory amino acid in the CNS, are mediated by three receptor subtypes: kainate, quisqualate and N-methyl-D-aspartate (NMDA) receptors. Ethanol, in vitro, is a potent and selective inhibitor of the actions of agonists at the NMDA receptor. Following chronic ethanol ingestion, the number of NMDA receptor-ion channel complexes in certain brain areas is increased. This increase may contribute to the generation of ethanol withdrawal seizures, since administration of an NMDA receptor antagonist can reduce these seizures. The results suggest that certain acute behavioral effects of ethanol, such as effects on memory, as well as certain aspects of ethanol withdrawal, may involve the NMDA receptor.

Blockade of the discriminative stimulus effects of ethanol with 5-HT3 receptor antagonists.

The ability of selective 5-HT3 receptor antagonists to block the discriminative stimulus effects of ethanol was investigated in pigeons trained with food reinforcement to discriminate ethanol (1.5 g/kg; IG) from water. The 5-HT3 receptor antagonists that are substituted tropines, ICS 205-930 (0.1–0.56 mg/kg) and MDL 72222 (3.0–17.0 mg/kg), blocked ethanol-appropriate responding, in a dose-dependent manner, suggesting that some of the discriminative stimulus effects of ethanol are mediated via the 5-HT3 receptor. The blockade the discriminative stimulus effects of ethanol occurred in the presence of approximately 25–40 mM blood ethanol levels. Furthermore, the ethanol dose-effect function was shifted to the right by increasing doses of MDL 72222, suggesting a surmountable antagonism of the discriminative stimulus effects of ethanol. However, the benzamide zacopride (0.56–1.7 mg/kg), which is also a 5-HT3 receptor antagonist, did not block the discriminative stimulus effects of ethanol. In addition, the dopaminergic antagonist haloperidol and the 5-HT2 receptor antagonist ketanserin also failed to block the ethanol discrimination. The results suggest that 5-HT3 mediated neurotransmission is an important component of ethanols discriminative stimulus effects, but that the structural characteristics of the selective 5-HT3 receptor antagonists influence their ability to block this action of ethanol. Furthermore, these findings implicate a significant role of 5-HT3 activity in the behavioral effects of ethanol that may provide a pharmacological means for therapeutic intervention of alcohol abuse.

NMDA Receptors: Role in Ethanol Withdrawal Seizures

Physical dependence on ethanol is defined by the presence of an ethanol withdrawal syndrome that becomes apparent following cessation of ethanol intake and elimination of ethanol from the individual. This withdrawal syndrome has been wellcharacterized in humans as well as in animal models, and consists of several symp toms that have been classified as early (tremor, diaphoresis, hallucinations, convulsions) and later (delirium tremens, increased autonomic activity and prohse sweating, profound disorientation) .2 Many neurochemical alterations have been described during ethanol withdrad,3.4 and it is likely that changes in the activity of certain neuronal systems contribute to specific withdrawal symptoms. In particular, recent studies have begun to elucidate the neurochemistry of ethanol withdrawal seizures. These seizures have certain characteristics of grand mal seizures, and are more likely to occur in individuals with a history of ethanol withdrad or epileptic seizures. In fact, it has been postulated that ethanol withdrawal may be likened to kindlingY5 in that repeated episodes of ethanol withdrawal result in more rapid development of physical dependence and a more severe withdrawal syndrome.5.6 Therehre, the mechanisms that have been proposed to underlie the development of kindling may serve as a framework for studying the neurochemical basis for ethanol withdrawal seizures. Two neuronal systems that have been found to be very sensitive to modulation by ethanol (see below) have also been implicated in long-term synaptic potentiation (LTP), a model for neuroadaptation, as well as in kindling processes. These are the 7-amino-

HIGH-GRADE NON-HODGKIN'S LYMPHOMA IN PATIENTS WITH AIDSa

n An apparent excess of high grade non-Hodgkins lymphoma has been reported among those at risk for acquired immunodeficiency syndrome (AIDS), especially homosexual men. Common to these cases are pre-existing lymphadenopathy, concomitant opportunistic infections or Kaposis sarcoma, and an extremely poor prognosis. The Cancer Registry for the San Francisco Bay Area was reviewed to obtain data on the incidence of undifferentiated non-Hodgkins lymphoma among single men ages 20-50 years in 2 periods: 1975-78 and 1979-82. The Registry recoreded no such cases in the earlier period and 9 cases (6 Burkitts and 3 non-Burkitts) in 1979-82. In addition, descriptive data were obtained from area oncologists on non-Hodgkins lymphomas that developed in 18 single men 20-60 years of age in 1979-83. 17 of these men were homosexual, and the median age was 36 years. Prodromal manifestations associated with AIDS were present in various combinations in all homosexual patients. All 10 patients treated with chemotherapy had complete responses, but relapse occurred quickly in all but 2 patients (including the 1 heterosexual). Only 3 men in this series remain alive, but have other diagnostic criteria for AIDS. The 1-year survival rate for the Bay Area cases was 13%, compared with 48% in heterosexual controls with undifferentiated lymphomas treated at the National Cancer Institute. 3 major differences were noted between the California cases and NCI controls: 1) all homosexual men had prodromal manifestations of either generalized lymphadenopathy or Kaposis sarcoma or opportunistic infections compared to none of the controls: 2) Most Bay Area men had stage D (widespread or central nervous system) lymphoma on presentation; 3) the response to chemotherapy was poorer among cases than controls. Because of these differences, it is argued that malignant lymphomas that occur in members of AIDS risk groups should be a diagnostic criterion for AIDS.n

The Role of Arginine Vasopressin in Alcohol Tolerance

Administration of the neuropeptide, arginine vasopressin, to animals that have acquired functional tolerance to ethanol will maintain such tolerance, even in the absence of further ethanol ingestion by the animals. In mice, this action of the peptide is mediated by central nervous system V1 receptors and requires intact brain noradrenergic systems. Autoradiographic studies have shown that some V1 receptors are localized presynaptically on catecholaminergic neuronal terminals in the mouse lateral septum, suggesting that vasopressin may act via modulation of catecholamine release. In addition, vasopressin has been found to increase mRNA levels for the proto-oncogene, c-fos, in septum and hippocampus, possibly by an action at postsynaptic receptors. Expression of c-fos, which has been hypothesized to play a role in central nervous system neuroadaptation, could transform short-term actions of vasopressin into long-term effects on ethanol tolerance. Studies with vasopressin antagonists indicate that the endogenous peptide influences tolerance, and therefore the effect of chronic ethanol ingestion on vasopressin synthesis and release was studied. In mice and rats, hypothalamic vasopressin mRNA is decreased by chronic ethanol exposure, although effects on plasma vasopressin levels differ in the two species. The effect of ethanol on extrahypothalamic vasopressin synthesis in brain is under investigation. The results suggest mechanisms by which vasopressin can produce long-term changes in central nervous system function, and provide evidence for a disturbance of vasopressin regulation during chronic ethanol ingestion.

Decreased performance in a delayed alternation task by rats genetically deficient in vasopressin

Acquisition and retention of a delayed alternation task by rats genetically deficient in vasopressin (AVP) due to the homozygous occurrence of the Brattleboro diabetes insipidus (DI) gene (M520/DI) were compared to the response of rats that were heterozygous (M520/HZ) or normal (M520/N) with respect to the DI gene. No significant difference in the adaptation to the apparatus was observed between the groups. However, the rate at which the M520/DI rats acquired the alternation task was significantly slower than the acquisition rates of M520/HZ and M520/N rats. In addition, the maximum intertrial interval reached by the M520/DI rats was significantly shorter than the intertrial intervals reached by the M520/HZ and M520/N rats, indicating the ability to retain information was impaired in the M520/DI rats. These results are consistent with the hypothesis that AVP modulates the acquisition and retention of information for normal memory processes.

Some implications of animal alcohol self-administration studies for human alcohol problems

A partir des donnees en experimentation animale sur la mise en place du processus de dependance alcoolique (ethanol), les auteurs tirent quelques implications sur ce meme processus chez letre humain

Ethanol and the NMDA Receptor: Insights into Ethanol Pharmacology

The relationship between lipid solubility and the pharmacological actions of ethanol and other alcohols was demonstrated many years ago (Meyer and Gottlieb, 1926). Since then it has been shown that alcohols can partition into cell membranes and perturb the structure of the bulk membrane lipids (Chin and Goldstein, 1977), and that the intoxicating potency of alcohols is positively correlated with their lipid-perturbing capacity (Lyon et al., 1981). These results led to the hypothesis that the pharmacological actions of ethanol stem from its nonspecific effects on membrane lipid “fluidity” and subsequently a perturbation of the activities of membrane-bound proteins (e.g., receptors, enzymes). However, relatively high concentrations of ethanol are necessary to produce significant increases in membrane lipid fluidity (Chin and Goldstein, 1977; Lyon et al., 1981), and inspection of the literature reveals that the function of few membrane-bound proteins is significantly affected by concentrations of ethanol that are relevant in vivo. There are some exceptions to this observation, including the effects of low concentrations of ethanol on the stimulatory guanine nucleotide binding protein, Gs (Saito et al., 1985; Valverius et al., 1987), and the GABA receptor-coupled chloride channel (Allan and Harris, 1987; Suzdak et al., 1986), which is the major inhibitory neurotransmitter system in the brain.