S03
NEUROPHYSIOLOGY OF ACETALDEHYDE: FROM CHANNELS TO BEHAVIOR
S03.1
ACETALDEHYDE AND ETHANOL INTERACTIONS ON CALCIUM-ACTIVATED POTASSIUM (BK) CHANNELS IN PITUITARY (GH3/GH4) CELLS
- A. Handlechner,
- T. M. Weiger,
- V. Kainz and
- A. Hermann
+ Author Affiliations
Abstract
The importance of acetaldehyde (ACA), the primary metabolite of ethanol (EtOH) oxidation, in the central effects of EtOH has been a controversial issue. Since accumulation of ACA by the EtOH oxidative enzyme catalase within the central nervous system has been established, evidence suggests that ACA is responsible for at least some of the effects on the brain that so far have been attributed to EtOH. Calcium-activated potassium (BK) ion channels exhibit various functions like action potential repolarization, regulation of blood pressure, hormones secretion or transmitter release. BK channels represent a prominent cellular target for EtOH, which is well documented to increase BK channel activity in a dose-dependent manner. The simultaneous presence of ACA and EtOH reflects the physiological situation in the brain after drinking and may result in synergistic as well as antagonistic actions. BK single channel activity was recorded both from outside out and inside out patches. According to requirements, EtOH and ACA were applied separately, simultaneously or successively and at various levels of free internal calcium. The effect of a 30% hypotonic solution was also tested. BK channel amplitude, open probability and mean channel open time were analyzed and statistically evaluated. Extracellular application of EtOH enhanced BK channel activity. This increase was blocked by intracellular ACA in a concentration-dependent manner. BK channel amplitudes were not affected, but mean channel open time was reduced significantly. Furthermore, the EtOH-induced activation was repeatable after wash out, but not following an intermediate application of ACA. Our results suggest an inhibitory impact of ACA on BK activation by EtOH. ACA interacts specifically with EtOH at BK channels since intracellular ACA had no effect relating to hypotonicity. Moreover, our study implies that ACA interferes with BK activity and that ACA has to be considered carefully in the context of EtOH actions.
- © The Author 2011. Published by Oxford University Press on behalf of the Medical Council on Alcohol. All rights reserved
S03.2
ETHANOL, ACETALDEHYDE AND DOPAMINE NEURONS
- M. Diana,
- M. Mereu,
- D. Sirca,
- G. Muggironi and
- A. Peana
+ Author Affiliations
Abstract
There has been a great deal of activity in recent years in the study of the direct effects of ethanol on the dopamine reward system originating in the ventral tegmental area (VTA). In addition, recent evidence suggests that acetaldehyde formed in the brain or periphery may be a crucial factor in the central effects of ethanol. This paper examines the actions of ethanol and acetaldehyde on neurons of the ventral tegmental area in vivo and in vitro. Ethanol has specific effects on dopamine neurons and there is recent evidence that some of the in vivo and in vitro effects of ethanol are mediated by acetaldehyde. Taken together, the evidence suggests that acetaldehyde is essential in the activating effects of ethanol on dopamine VTA neurons. The link between acetaldehyde and ethanol actions on brain reward pathways may provide a new avenue for development of agents to reduce alcohol craving.
S03.3
BRAIN MAPPING OF CFOS IMMUNOREACTIVITY AFTER CENTRAL AND PERIPHERAL ADMINISTRATION OF ETHANOL AND ACETALDEHYDE IN RATS
- M. Correa1,
- N.K. Segovia2,
- R. Vontel2,
- L. Lopez-Cruz1,
- M. Pardo1 and
- J.D. Salamone2
+ Author Affiliations
Abstract
The ethanol metabolite acetaldehyde has been shown to be biologically active and to have characteristic effects on behavior, some of which are different from its parent compound, ethanol. In general, peripheral administration of acetaldehyde requires much lower doses than the doses used for ethanol to reach similar effects. However, when centrally administered, either in the ventricles or in discrete brain nuclei, acetaldehyde has demonstrated to be only slightly more potent than ethanol at regulating behavioral output. Thus, different patterns between ethanol and acetaldehyde emerge depending on the dose and the route of administration. Ethanol administered through different routes induces early-gene protein expression in several brain regions, and such expression reflects specific activation of brain pathways. In the present work, we assessed the pattern of c-Fos expression in male Sprague–Dawley rats over a broad range of brain areas, after peripheral (intraperitoneal, i.p.) or central (intraventricular i.c.v.) ethanol and acetaldehyde administration. Ethanol and acetaldehyde were compared using behaviorally relevant doses for both substances, but higher doses also were used in order to compare potency and efficacy. Acetaldehyde i.p. was more potent than ethanol at activating early gene expression in many brain areas. Induction of c-Fos promoted by i.c.v. administration at doses that induced locomotion was very similar for both drugs, consistent with previous behavioral data, although acetaldehyde was in general also more efficacious. Nucleus accumbens, in particular the core subdivision, which has been demonstrated to regulate behavioral activation, was one of the areas most affected by both drugs after both routes of administration, and also was the area at which the differences between both substances were stronger. These results suggest that ethanol and acetaldehyde share common mechanisms of action when acting directly in the brain, especially in motor and motivation control areas. However, their effects after peripheral administration can be related to independent mechanisms. [This research was supported by Fundació Bancaixa-UJI (P1B152007), Plan Nacional de Drogas. Ministerio de Política Social y Consumo (2010I024) Spain and by NIH/NIMH (MH078023-01A1) USA.]
S03.4
OVERVIEW OF THE BEHAVIORAL EFFECTS OF ACETALDEHYDE
- E. Quertemont
+ Author Affiliations
Abstract
Acetaldehyde has long been suggested to be involved in the development of alcoholism. In agreement with this idea, recent studies reported multiple behavioral effects of acetaldehyde. These studies provided direct evidence through the administration of acetaldehyde and indirect evidence through experimental manipulations of ethanol metabolism. In rodents, acetaldehyde was shown to induce stimulant and reinforcing effects at low doses, especially when injected directly into brain. Further evidence of the role of acetaldehyde in the reinforcing and stimulant effects of acetaldehyde is based on brain catalase inhibition and on acetaldehyde sequestration. Conversely, acetaldehyde at higher doses produces sedation and aversive effects. Other effects of acetaldehyde include ataxia, amnesia and hypothermia. However, in humans, the possible reinforcing and stimulant effects of acetaldehyde are almost entirely supported by casual observations. Together, these studies show that acetaldehyde has a behavioral profile very similar to ethanol, further suggesting its involvement in the behavioral effects of alcohol consumption. However, the brain concentrations of acetaldehyde after alcohol consumption remain a controversial issue. In most of the studies on the behavioral effects of acetaldehyde, and especially in the indirect studies relying on ethanol metabolism manipulations, there was no attempt to directly measure brain acetaldehyde concentrations. While the role of acetaldehyde in the development of alcoholism is not yet definitively demonstrated, all these recent studies show that this hypothesis about the role of acetaldehyde has a sound basis.
