Walter A. Hunt

Role of acetaldehyde in the actions of ethanol on the brain — A review

Over the last 30 years, acetaldehyde has been postulated to mediate various actions of ethanol on the brain. Experiments have studied ethanol consumption after acetaldehyde infusions into the brain, in rodents with high or low activities of hepatic and brain ethanol-metabolizing enzymes, and after treatment with drugs that alter the metabolism of acetaldehyde after ethanol ingestion. Evidence that acetaldehyde is involved in the actions of ethanol has been inconsistent because of the lack of knowledge of the brain acetaldehyde concentrations required to exert their effects, the lack of correlation between the activities of ethanol-metabolizing enzymes across strains of rodents and ethanol consumption, and the lack of specificity of drugs altering acetaldehyde metabolism. The formation of significant amounts of acetaldehyde the brain in vivo after ethanol ingestion and by what mechanism has not been clearly established, although catalase is a promising candidate. Future research needs to directly demonstrate in brain the formation of acetaldehyde in vivo, determine the concentrations in brain areas involved in ethanol consumption, and evaluate the possible actions of drugs other than an ability to block acetaldehyde metabolism.

Are binge drinkers more at risk of developing brain damage

Alcoholism is often associated with brain damage and cognitive deficits. Because drinking patterns can include periods of alcohol consumption followed by abstinence, binge drinking may enhance the possibility of brain damage. Chronic administration of ethanol leads to upregulation of N-methyl-D-aspartate (NMDA) and calcium receptors and increased release of glucocorticoids. NMDA-mediated mechanisms and glucocorticoid actions on the hippocampus are associated with brain damage. Thus, ethanol withdrawal may make the brain more vulnerable to damage from these mechanisms, especially with binge drinking. Therapeutic adjuncts for treating ethanol withdrawal, including NMDA, calcium, and glucocorticoid antagonists, may eventually prove useful in preventing further brain damage in alcoholism.

Craving research: future directions

Many prospective clinical studies have concluded that craving does not reliably predict relapse and that the concept is of little or no clinical utility. Contrary to earlier more simplistic clinical models of addiction, more recent models do not require that craving be present for relapse to occur. New approaches to study human craving may enhance its predictive validity and yield more knowledge of its nature, course, behavioural sequelae and regulatory function in alcohol/drug consumption. These approaches include empirical research that focuses on: (1) the elucidation of the domains of craving (i.e. subjective experience, physiological responses, behavioural sequelae and their inter-relationships); (2) the temporal dynamics of craving (i.e. its course over minutes or days, as well as its natural history over the course of a drinking career); (3) the factors that may mediate/moderate/determine the development and resolution of craving; (4) studies of the predictive validity of craving measures; and (5) the development of valid methods of measuring the different domains of craving. The conclusions are that future craving research should: (1) incorporate more sophisticated general theories of behaviour (conditioning, cognitive social learning, neurobiological, and genetic); (2) apply more sophisticated and standardized measurement methods and experimental paradigms, including studies in which alcohol is made available to human subjects; and (3) effective development of new pharmacological and behavioural therapies for relapse prevention depend on greater understanding of the nature and measurement of craving.

Attenuation of radiation- and drug-induced conditioned taste aversions following area postrema lesions in the rat

The effects of lesions of the area postrema on the acquisition of radiation- and drug-induced (histamine and lithium chloride) conditioned taste aversions were investigated. The results indicated that area postrema lesions caused a significant attenuation of the aversion produced by pairing a novel sucrose solution with radiation (100 rad) or drug injection. Further, the area postrema lesions produced a similar level of attenuation of the taste aversion in all three treatment conditions. The results are discussed in terms of the implications of this finding for defining the mechanisms by which exposure to ionizing radiation can lead to the acquisition of a conditioned taste aversion.

A role for behavioral sensitization in uncontrolled ethanol intake

The processes that underlie the transition from controlled to uncontrolled consumption of ethanol are unknown. Behavioral sensitization is proposed as one of these processes and occurs with repeated administration of psychomotor stimulants whereby both behavioral and neurochemical responses to the drugs are progressively enhanced. Because ethanol shares some actions in common with these drugs, chronic exposure to ethanol may intensify its reinforcing properties. The effect of ethanol on several behavioral models suggests that behavioral sensitization may develop especially in the presence of environmental cues. Thus, a research opportunity exists to study factors that contribute to an increasing probability of progressively higher ethanol consumption. Knowledge of these factors will lead to a better understanding of why some people drink uncontrollably.

Deficits in the Sensitivity of Striatal Muscarinic Receptors Induced by 56Fe Heavy-Particle Irradiation: Further 'Age-Radiation' Parallels

We had previously shown that there was a loss of sensitivity of muscarinic receptors (mAChR) to stimulation by cholinergic agonists (as assessed by examining oxotremorine enhancement of K(+)-evoked release of dopamine from neostriatal slices) in animals that had been exposed to energetic particles (56Fe, 600 MeV/n), an important component of cosmic rays. This loss of mAChR sensitivity was postulated to be the result of radiation-induced alterations in phosphoinositide-mediated signal transduction. The present experiments were undertaken as a first step toward determining the locus of these radiation-induced deficits in signal transduction by examining K+ enhancement of release of dopamine in 56Fe-exposed animals (0, 0.1, and 1.0 Gy) with agents [A23187, a potent Ca2+ ionophore, or 1,4,5-inositol trisphosphate (IP3)] that bypass the mAChR-G protein interface and by comparing the response to oxotremorine-enhanced K(+)-evoked release of dopamine. Results showed that although oxotremorine-enhanced K(+)-evoked release of dopamine was reduced significantly in the radiation groups, no radiation effects were seen when A23187 or IP3 was used to enhance K(+)-evoked release of dopamine. Since similar findings have been observed in aging, the results are discussed in terms of the parallels between aging and radiation effects in signal transduction that might exist in the neostriatum.

An assessment of the behavioral toxicity of high-energy iron particles compared to other qualities of radiation

Conditioned taste aversion was used to evaluate the behavioral toxicity of exposure to high-energy iron particles (56Fe, 600 MeV/amu) in comparison to that of gamma photons (60Co), high-energy electrons, or fission neutrons. Exposure to high-energy iron particles (5-500 cGy) produced a dose-dependent taste aversion with a maximal effect achieved with a dose of 30 cGy. Gamma photons and electrons were the least effective stimuli for producing a conditioned taste aversion, with a maximal aversion obtained only after exposure to 500 cGy, while the effectiveness of fission neutrons was intermediate to that of photons and iron particles, and a maximal aversion was obtained with a dose of 100 cGy. In the second experiment, rats with lesions of the area postrema were exposed to iron particles (30 cGy), but failed to acquire a taste aversion. The results indicate that (1) high-energy iron particles are more toxic than other qualities of radiation and (2) similar mechanisms mediate the behavioral toxicity of gamma photons and high-energy iron particles.

Studies of neurotransmitter interactions after acute and chronic ethanol administration

Evidence is accumulating suggesting that ethanol has a biphasic effect on several neurotransmitters in the brain and that interactions between two or more transmitters may contribute to the behavioral response obtained after ethanol administration. In the nigrostriatal complex where the most data have been derived, dopaminergic activity responds in a biphasic manner to ethanol treatment. At low doses, dopaminergic activity is elevated, while at high doses, activity is reduced. After chronic ethanol treatment, pre- and postsynaptic dopaminergic activity is hypoactive. Pharmacological data have suggested the possible involvement of acetylcholine (ACh) and gamma-aminobutyric acid (GABA) in the actions of ethanol on the striatal dopaminergic system. In support of this postulate, striatal high-affinity choline uptake, an index of ACh release, is elevated after high doses of ethanol and after ethanol withdrawal. GABA turnover exhibits a biphasic response to ethanol treatment. At low doses of ethanol, GABA turnover is reduced, while at high doses, turnover is unaffected. These latter effects correlate with known interrelationships of these transmitters in the nigrostriatal complex. The data suggest that an action of ethanol on one transmitter may influence the response of another transmitter to ethanol. To further address the interrelationship of transmitters, a high-performance liquid chromatographic method has been developed to study the activity of several transmitters simultaneously. This approach promises to shed more light on this important area.

Transient Alterations in Neurotransmitter Activity in the Caudate Nucleus of Rat Brain after a High Dose of Ionizing Radiation

A single 10,000-rad dose of high-energy electrons induced an increase in dopaminergic and cholinergic activity in the caudate nucleus of the rat brain as assessed by K+-stimulated dopamine release in vitro and high-affinity choline uptake. These alterations occur during early transient incapacitation (ETI) and dissipate as the animal recovers behaviorally, in about 30 min after irradiation. Although the responses observed resemble those that result from blockade of dopamine receptors, no radiation-induced changes were found in dopamine-sensitive adenylate cyclase activity and [3H]haloperidol binding, two indices of dopaminergic receptor function. The data suggest that changes in dopaminergic and cholinergic activity are associated with the development of ETI and may play a role in the behavioral decrement observed under this condition.

Relationship between Linear Energy Transfer and Behavioral Toxicity in Rats Following Exposure to Protons and Heavy Particles

Rats were exposed to protons (155 MeV) or to helium (165 MeV/amu), neon (522 MeV/amu) or argon (670 MeV/amu) particles to evaluate the behavioral toxicity of these types of radiations. Behavioral toxicity was assessed using the conditioned taste aversion paradigm. Exposure to all types of radiation produced dose-dependent increases in the intensity of the acquired taste aversion. However, the intensity of the aversions, measured as the dose that produced a 50% decrease in the intake of the sucrose-conditioned stimulus, did not show significant variation as a function of the linear energy transfer (LET) of the radiation. The results are discussed in terms of the relationship between LET and behavioral toxicity.