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The role of the dopamine D1 receptor subtype in alcohol-seeking behaviors was studied in mice genetically deficient in dopamine D1 receptors (D1 -/-). In two-tube free choice limited (1-5 h) and continuous (24 h) access paradigms, mice were exposed to water and increasing concentrations of ethanol (3%, 6% and 12% w/v). Voluntary ethanol consumption and preference over water were markedly reduced in D1 -/- mice as compared to heterozygous (D1 +/-) and wild-type (D1 +/+) controls, whereas overall fluid consumption was comparable. When offered a single drinking tube containing alcohol as their only source of fluid for 24 h, D1 -/- mice continued to drink significantly less alcohol than D1 +/+ and D1 +/- mice. Dopamine D2 receptor blockade with sulpiride caused a small but significant reduction in alcohol intake and preference in D1 +/+ mice and attenuated residual alcohol drinking in D1 -/- mice. Dopamine D1 receptor blockade with SCH-23390 very effectively reduced alcohol intake in D1 +/+ and D1 +/- mice to the level seen in untreated D1 -/- mice. These findings suggest involvement of both dopamine D1 and D2 receptor mechanisms in alcohol-seeking behavior in mice; however, these implicate D1 receptors as having a more important role in the motivation for alcohol consumption.

Rats were treated with ethanol for 11-15 days, after which the brain neurotransmitter receptors for dopamine, acetylcholine, serotonin and noradrenaline were measured. The rats were intubated at 12 h intervals with 4 g/kg ethanol, and sacrificed 10 h after the last intubation. After ethanol treatment, the specific binding of 3H-haloperidol to dopamine receptors was significantly decreased in the mesolimbic areas by 20 +/- 6%, but was unchanged in the striatum. Specific binding of 3H-serotonin was increased by 63 +/- 29% in the striatum and by 32 +/- 9% in the brainstem, but decreased by 20 +/- 7% in the hippocampus. The specific binding of 3H-quinuclidinyl benzilate to muscarinic acetylcholine receptors increased by 7 +/- 2% in the striatum, but decreased by 5 +/- 2% in the cerebral cortex. The specific binding of 3H-WB-4101 to alpha-adrenergic receptors was unchanged in all brain areas assayed, namely the striatum, mesolimbic areas, hippocampus, hypothalamus, brainstem and cerebral cortex. These changes may be related to some aspects of tolerance to, and dependence on, ethanol.

Hypothermia and motor impairment (tilt-plane test) were used to assess whether N-methyl-D-aspartate (NMDA) receptors play a role in the development of rapid tolerance to ethanol, i.e., tolerance to a second dose of ethanol given 24 h after the effect of the first dose of ethanol had disappeared. Results showed that (+)-MK-801 and ketamine blocked the development of rapid tolerance to ethanol on both tests. Since these drugs did not modify blood or brain alcohol levels in any of the groups, the blockade of ethanol rapid tolerance cannot be attributed to changes in pharmacokinetics of ethanol. These data suggest that the role of NMDA receptors in ethanol tolerance may be similar to their role in memory and learning, involving a facilitation of transmission in certain synapses.

The effects of catecholamines (CA) and ethanol (EtOH), singly and in combination, on the kinetics of rat brain (Na+ + K+)-ATPase were studied. Addition of 0.05 M EtOH alone did not change Vmax or Km for K+, Na+, Mg2+ and ATP. Addition of 0.1 mM dopamine (DA) or noradrenaline (NA) alone stimulated the enzyme activity in presence of vanadium-containing ATP as substrate, but not with vanadium-free ATP except in the presence of high Mg2+ : ATP ratios. CA alone decreased the Km slightly for K+ and by about 50% for ATP, increased it for Mg2+ and did not change it for Na+. However, the combination of DA or NA + EtOH produced a marked inhibition which was competitive for K+, and uncompetitive or mixed for Mg2+, Na+ and ATP. The inhibitory effect of NA + EtOH was abolished in 20 mM K+. These findings suggest that NA sensitizes the enzyme to EtOH inhibition at physiological K+ concentrations, by conformational change away from the outwardly facing K+-binding E2P for to the inwardly facing Na+-binding E1P form.

The objective of the present studies was to investigate the effect of voluntary ethanol consumption for 21 days on the brain beta-endorphin system of C57BL/6 (alcohol-preferring) and DBA/2 (alcohol-avoiding) strains of mice. As expected, C57BL/6 mice consumed a significantly higher quantity of the 10% ethanol solution than the DBA/2 mice. Under basal conditions the content of beta-endorphin like peptides differed only in the nucleus accumbens, higher levels being found in the DBA/2 mice. Voluntary ethanol consumption induced an increase in the hypothalamic content of mRNA coding for proopiomelanocortin, associated with a significant increase in the tissue content of beta-endorphin-like peptides in the arcuate nucleus and septum of the C57BL/6 mice, but did not alter the activity of the brain beta-endorphin system of the DBA/2 mice. Since voluntary ethanol consumption was not associated with nutritional deficits and stress, the ethanol-induced enhanced activity of the brain beta-endorphin system of the C57BL/6 mice must be a direct effect of ethanol and may be important in controlling the voluntary ethanol consumption by this strain of mice.

Modulation of gamma-aminobutyric acidA (GABAA) receptor function by drugs such as ethanol may depend on the genetic heterogeneity of GABAA receptor subunits, which vary across species and cell types. For this reason, the effects of ethanol on gamma-aminobutyric acid receptor-activated chloride currents (IGABA) were examined using whole-cell voltage-clamp recordings in primary cultures of neurons obtained from different species (chick, mouse and rat) and from different brain regions (cerebral cortex, hippocampus, cerebellum and spinal cord), and in acutely dissociated neurons from rat neocortical slices. Low concentrations (1-50 mM) of ethanol produced an enhancement of IGABA in some cells from each brain region examined. In cells obtained from the rat and chick cerebral cortex, 40-58% of cells exhibited an ethanol-sensitive IGABA. Moreover, a statistically significant variation in the response to ethanol was found in rat cortical neurons obtained from different litters. In mouse hippocampal neurons, potentiation of IGABA was obtained with ethanol concentrations (1-10 mM) well below those needed to inhibit neuronal responses to N-methyl-D-aspartic acid (30-50 mM), suggesting a differential sensitivity of these two receptor mechanisms to ethanol. Potentiation of IGABA by ethanol was reversed by the benzodiazepine receptor partial inverse agonist RO15-4513 (ethyl 8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine - 3-carboxylate), but was not affected by chelation of intracellular calcium. Furthermore, high concentrations of GABA attenuated the ability of ethanol to enhance IGABA. These results are consistent with the hypothesis that ethanol facilitates coupling between receptor binding and chloride channel activation.

Sham and electrolytic lesions of the dorsal, median, and dorsal + median raphe nuclei were made in different groups of rats. One week later, daily oral treatment with ethanol (5 g/kg p.o. for 25 days) was started. This treatment produced tolerance to the hypothermic and motor impairing (moving belt test) effects of ethanol. On day 26, ethanol was stopped and subcutaneous injection of either 10 micrograms of des-Gly9-[Arg8]vasopressin (DGAVP) in saline or saline alone was started. The retention of tolerance to ethanol was measured at 3-day intervals for both hypothermia and motor-impairment. In sham-saline groups, disappearance of tolerance took 3 days for the hypothermic effect, and 9 days for the motor-impairment effect. Tolerance to both effects, however, was still observed after 9 days in DGAVP-treated rats with either sham or dorsal raphe lesions. Peptide treatment, on the other hand, failed to maintain tolerance in rats with median or median + dorsal raphe lesions. These results suggest that an intact mesolimbic serotonin pathway is necessary for the action of DGAVP on the retention of ethanol tolerance.

Tolerance to the hypnotic effect of ethanol in mice is prolonged by once daily intraventricular injections of arginine vasopressin. This action is similar to that reported previously when vasopressin was administered subcutaneously. The results indicate that maintenance of ethanol tolerance by vasopressin is a centrally mediated action of the peptide, and is not due to possible aversive properties of peripherally administered vasopressin.

In a dose of 0.1 mg/kg, PIA had marked behavioural effects in long-sleep mice (which show a high sensitivity to ethanol, while no significant effect was observed in short sleep mice (low sensitivity to ethanol). The number of [3H]PIA binding sites in cortex and subcortical brain regions was significantly higher in long-sleep than in short-sleep mice. The KD value was higher in cortex and cerebellum in the short-sleep mice, but there were no differences in the number of hippocampal beta-adrenoceptors or in the adenosine analogue-induced increase in cyclic AMP accumulation in slices of mouse hippocampus.