In the present series of experiments we have studied the effects of the dihydropyridine calcium channel antagonist nifedipine on ethanol-induced changes in behavior and dopamine (DA) release and metabolism. The locomotor-stimulatory effect of low doses of ethanol (2.5 g/kg) was antagonized by nifedipine, whereas ethanol-induced sedation observed after higher doses (4.5 g/kg) was potentiated. Biochemical studies indicated that ethanol enhanced the metabolism and release of DA in the striatum and the DA-rich limbic regions measured by post mortem analyses of DA-metabolites by HPLC with electrochemical detection and by in vivo voltammetry in anaesthetized rats, respectively. Pretreatment with nifedipine antagonized the stimulatory effects of ethanol on the DA-system. Nifedipine reduced the preference for ethanol, estimated by the relative intake of ethanol (6% v/v) and water in a free-choice situation, suggesting an influence of nifedipine not only on the stimulatory but also on the positive reinforcing effects of ethanol. The present results suggest that the locomotor-stimulatory and positive reinforcing effects of ethanol as well as its enhancing effect on dopaminergic activity may involve an enhancement of calcium mediated mechanisms.

SUMMARY1. Antidiuretic hormone (ADH) was infused into normal male rats at a rate of 60 flu./min. 100 g body wt., to maintain an effectively constant maximal circulating level. Four groups of rats were used; they were waterloaded by receiving together with the ADH, i.v. infusions of hypotonic dextrose (2.5 g/100 ml.) at different rates (1.0, 4-5, 9-0 and 12 ml./hr, respectively), over an infusion period of 4 hr.2. Urine flow rate increased in all groups, the rate and extent of the increase being related to the volume rate of infusion. The differences in urine flow rates between the four groups were due almost entirely to increases in free water clearance, with no consistent differences in osmolal clearance between the groups. At the end of the 4 hr infusion period, osmolal clearances were closely similar in the four groups.3. Papillary and medullary tissue solute concentrations were progressively reduced at the higher rates of infusion. The changes were due to small increases in the water content, together with a profound decrease in urea concentration and a smaller decrease in sodium concentration. However, papillary osmolality was consistently higher than urine osmolality at the three highest rates of dextrose infusion.4. As urine flow rate increased, there was a progressive reduction in the degree of osmotic equilibration between the final urine and the papillary tip. For urea, however, the degree of equilibration remained high.5. It is concluded that, in the rat, the rate of flow per se, along the collecting duct, is an important determinant of final urine concentration; even if there is an osmotic driving force for water re-absorption in the renal medulla, and the collecting duct walls are permeable to water, osmotic equilibration is restricted by tubular flow rate.

Blocks of tissue from the hypothalamus, olfactory bulb, or striatum of rats were incubated in vitro to study the basal and potassium-stimulated release of endogenous catecholamines. When ethanol (100-250 mM) was added to these preparations in vitro no changes in release were observed. When ethanol (3.0 g X kg-1) was injected intraperitoneally in vivo, however, and 3,4-dihydroxyphenylethylamine (DA, dopamine) release was measured in vitro at various times after drug administration, significant increases in the basal release and decreases in the potassium-stimulated release were observed in striatum and olfactory bulb. In striatum, these changes showed a more rapid onset and a longer duration than in olfactory bulb. In both brain regions, DA release did not differ from controls at 4-6 h after the ethanol injection, although blood ethanol concentrations remained elevated. This may imply the tissue's acquisition of acute functional tolerance to the drug. Similar increases and decreases in the basal and the potassium-induced release of DA from striatal tissues were also found at 1 h after injection of a lower dose of ethanol (1.0 g X kg-1). In terms of behavior, this lower dose of ethanol produced only mild intoxication and ataxia, in contrast to the loss of righting reflex following the higher dose.

1-Methyl-4-phenylpyridinium ion (MPP+) was shown to accumulate concentration-dependently in slices from rat striatum. At 10 microM, MPP+, the tissue concentration was found to be 118 +/- 9 microM following 75 min of incubation. The accumulation of MPP+ was reduced in the presence of 10 microM of the selective dopamine uptake inhibitor GBR 12909 (-50%) or by destruction of the dopaminergic terminals by complete hemisection of the forebrain 4 days before the experiments (-75%). Accumulation of MPP+ in the catecholamine-poor occipital cortex and cerebellum was only 25% of that obtained in striatum. Reserpine pretreatment of the rats in-vivo did not modify the accumulation of MPP+ in the striatal slices. MPP+ (1-10 microM) increased the net efflux of dopamine and reduced the efflux of the dopamine metabolite DOPAC from the striatal slices. The effect on dopamine was readily diminished if MPP+, after a 15 min incubation, was then omitted from the medium. In contrast, the DOPAC efflux was reduced for 75 min even though MPP+ was present in the incubation medium only for the first 15 min. In the presence of the monoamine oxidase inhibitor, pargyline (350 microM), MPP+ also produced an increase in dopamine efflux. In normal medium, the presence of the dopamine uptake inhibitor GBR 12909 (10 microM), or the absence of calcium, failed to modify the MPP+-induced increase in dopamine efflux. MPP+ also increased dopamine efflux from slices from reserpinized rats.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Acute ethanol administration causes a biphasic change in rat liver tyrosine aminotransferase activity. 2. The initial decrease is significant with a 200 mg/kg dose of ethanol, is prevented by adrenoceptor-blocking agnets and by reserpine, but not by inhibitors of ethanol metabolism, and exhibits many of the characteristics of the inhibition caused by noradrenaline. 3. The subsequent enhancement of the enzyme activity by ethanol is not associated with stabilization of the enzyme, but is sensitive to actinomycin D and cycloheximide. 4. It is suggested that the initial decrease in aminotransferase activity is caused by the release of catecholamines, whereas the subsequent enhancement may be related to the release of glucocorticoids.