Ethanol administration potentiates cocaine-induced dopamine levels in the rat nucleus accumbens.

Ethanol and cocaine are frequently co-abused, and the drug combination has been reported to produce an increased and prolonged subjective euphoria as compared to when either drug is administered alone. Acute administration of ethanol or cocaine increases the extracellular dopamine (DA) concentration in the nucleus accumbens (NAcc), a terminal region of the mesolimbic dopaminergic pathway. In the present study, the effects of separate and concurrent administration of cocaine and ethanol on DA concentrations in the NAcc were studied in rats pretreated with ethanol. Four groups of rats received either ethanol (2 g/kg, i.p.) or saline twice daily for 6 consecutive days. Thereafter, rats were given injections of saline or cocaine for another 2 days (i.e. treatment days 7 and 8) using a 'binge' administration pattern (three i.p. injections of 15 mg/kg each with 1-h interval starting 40 min after the first of the two daily doses of ethanol/saline). Stereotypic behavior was scored after each 'binge' of cocaine or saline on days 7 and 8. The DA and DA metabolite concentrations were measured using microdialysis on day 8. Ethanol enhanced the effect of cocaine on DA concentration in the NAcc as compared to a single administration of cocaine. The DA levels increased and reached their maximum values within 20-40 min after the cocaine administration, then gradually declined until the next injection 1-h later. Cocaine-induced stereotypic behavior was significantly increased in both saline and ethanol pretreated groups, though there was no significant difference between the two groups. The results of this study suggest that the enhanced DA transmission may be related to the experience produced by concurrent abuse of ethanol and cocaine in humans.

Cerebrospinal fluid of newborn infants contains a deglycosylated form of the intermediate filament nestin.

Nestin is an intermediate filament protein found in CNS progenitor cells. Nestin reappears in CNS tumor cells and reactive astrocytes after CNS injury. In this study we investigated whether nestin could be detected in the cerebrospinal fluid (CSF) of newborn infants and whether expression levels change with gestational age (GA) and/or brain injury. Using Western blot analysis, we examined the expression of nestin in the CSF of newborn infants (GA 25-42 wk) with asphyxia (n = 14), periventricular leukomalacia and peri(intra)ventricular hemorrhage (n = 7), and in a control group (n = 11). Protein extract from the periventricular brain tissue of a 1-wk-old infant was also analyzed. Nestin was detected in all the CSF samples and in the protein extract from the periventricular brain tissue. Although the CSF levels of nestin expression did not change with increasing GA, the asphyxia group had significantly lower levels of nestin in the CSF. An unexpected finding was that brain-derived nestin had an apparent molecular mass of approximately 240 kD, whereas all analyzed CSF samples contained two nestin-immunoreactive proteins at 200 and 220 kD. Experimental deglycosylation of the 240-kD form reduced the molecular mass to 220 kD, indicating that nestin undergoes a specific deglycosylation upon release into the CSF.

Monoamine neurotransmitters and metabolites in the cerebrospinal fluid following perinatal asphyxia.

While the release of neurotransmitters is involved in the pathophysiology of brain damage following birth asphyxia, it also plays a role in endogenous defense against such damage. Levels of monoamines and the main cerebral monoamine metabolites in the cerebrospinal fluid (CSF) were measured in asphyxiated and control infants within 24 h after birth. The results indicate an increased turnover of noradrenaline (NA) and dopamine following asphyxia. Furthermore, the NA stores in the brain seem to be exhausted in some cases. We conclude that this increase in catecholamine turnover to some extent explains the clinical symptoms of hypoxic-ischemic encephalopathy and that it may reflect an intrinsic adaptive capacity to perinatal distress.

Fetal anaemia and its relation with increased concentrations of adenosine.

Adenosine concentrations were measured in umbilical venous blood obtained by cordocentesis from 14 fetuses of 19-34 weeks' gestation. The concentration did not change significantly with gestational age, but anaemic fetuses showed significantly increased concentrations of adenosine and there was a positive association with blood oxygen tension. These findings suggest that the fetus responds to tissue hypoxia by increasing blood adenosine concentrations from at least 19 weeks' gestation.

Neuropeptide Y and catecholamine release in the piglet during hypoxia: enhancement by theophylline.

Sympathoadrenal activity was studied in 13 young piglets during hypoxia. The piglets were anaesthetized with chloralose/urethane, tracheostomized, paralyzed with gallamine and artificially ventilated. A femoral artery catheter was inserted and used for blood sampling. The piglets were challenged with 6 min of 6% CO2, 10 min of 12% O2 and 6 min of 6% O2 before and after theophylline (an adenosine receptor antagonist) treatment 20 mg/kg (n = 9) or saline (n = 4). Plasma samples were obtained before, during and after each hypercapnic or hypoxic period and analysed for their content of noradrenaline, adrenaline and neuropeptide Y. Hypercapnia with 6% CO2 and moderate hypoxia with 12% O2 did not lead to any significant increase of either noradrenaline (NA), adrenaline (A) or neuropeptide Y (NPY). However, severe hypoxia with 6% O2 increased the NA level from 30 to 66 nmol/l; the A level from 1 to 28 nmol/l and NPY from 140 to 213 pmol/l. After treatment with theophylline the baseline NA increased from 27 to 40 nmol/l, A rom 1.5 to 4.0 and NPY concentration from 65 to 171 pmol/l. Theophylline moderately enhanced the release of NPY, NA and A during the 12% O2 challenge. However, during the severe hypoxia (6%), the increase of NA (from 49 to 333 nmol/l), A (from 8 to 214 nmol/l) and NPY (from 184 to 385 pmol/l) showed considerably enhancement after the theophylline treatment. The results obtained before and after saline were similar showing that the duration of the experiments per se did not change the baseline levels or the effect of the challenges on NA, A or NPY levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypocapnia and cerebral ischaemia in hypotensive newborn piglets.

This study tested the hypothesis that hypocapnia superimposed upon hypotension produces a further reduction in cerebral blood flow velocity (CBFV). In 12 newborn piglets, CBFV was measured continuously by Doppler ultrasound through an artificial fontanelle. Hypotension was induced by removing 30 ml/kg of blood. Increasing the ventilator rate reduced the average arterial carbon dioxide tension from 5.5 to 2.0 kPa. When mean arterial pressure (MAP) was held steady at 45 mm Hg or above, hypocapnia produced a substantial drop in CBFV but, in all the piglets with MAP below 38 mm Hg, hypocapnia failed to change CBFV by 10%. Hypocapnia produced an increase in lactate in sagittal sinus blood but cerebral venous hypoxanthine concentrations were not affected by hypocapnia. Hyperventilation (without haemorrhage) produced a significant drop in MAP, preventable by infusing colloid. Hypocapnia itself does not further reduce CBFV in the hypotensive piglet. However, the pressure effect of hyperventilation may significantly impair the cerebral circulation.

Adenosine concentration in umbilical cord blood of newborn infants after vaginal delivery and cesarean section.

Umbilical blood was collected immediately at birth (less than 30 s) in full-term infants after vaginal deliveries (n = 33) and elective cesarean sections (n = 11). Blood gases, plasma adenosine, hypoxanthine, and catecholamine concentrations were determined. In vaginally born infants the median arterial adenosine concentration was found to be 0.46 microM (range 0.13-2.06) and the venous 0.48 microM (0.09-1.62). These levels were significantly higher (p less than 0.01) than in infants delivered by elective cesarean section; 0.16 microM (0.04-0.42) in the artery and 0.17 microM (0.02-0.56) in the vein. Vaginally born infants showed about a 4-fold higher level of umbilical arterial catecholamines than infants born by elective cesarean section. There was a strong inverse correlation between arterial hypoxanthine concentration and pH (r = -0.81, p less than 0.01). It is suggested that increased adenosine release at vaginal delivery modulates the stress response elicited by the strong catecholamine surge and may furthermore exert protective effects in perinatal asphyxia.

Respiratory and neuroendocrine responses of piglets to hypoxia during postnatal development.

Breathing response to 12% and 6% O2 in N2 (at isocapnia) was measured in anaesthetized piglets, 1-5 and 19-25 days old, before and after 3 mg kg-1 i.v. naltrexone. The degree of interaction between the anaesthetic and naltrexone was assessed. At the end of each hypoxic trial, arterial blood was sampled for measurements of pH and gas tensions, (Met)enkephalin-Arg6-Phe7, adenosine, noradrenaline and adrenalin. Whereas respiration in older animals was stimulated by hypoxia, young piglets had a biphasic response with a pronounced ventilatory decrease in response to severe hypoxia (6% O2/N2). In young animals there was a greater ventilatory response with naltrexone than without the drug, and the biphasic hypoxic response was ameliorated or reversed by naltrexone. Levels of adrenalin increased and those of encephalin, adenosine and noradrenaline tended to increase during hypoxia in the younger age group. Levels of adenosine showed significant increase when data from both age groups and levels of hypoxia were pooled. Combined with previously reported physiological evidence regarding adenosine in hypoxic depression, we conclude that the present results are compatible with a role of opioid peptides and adenosine in the early postnatal response to hypoxia.

Plasma catecholamine levels in preterm infants. Effect of birth asphyxia and Apgar score.

Catecholamine levels were measured in cord arterial blood from preterm infants. Relatively lower catecholamine levels were found in the preterm infants than in term infants, although no significant correlation was found between noradrenaline and adrenaline levels and either gestational age or birthweight. Significantly higher catecholamine levels were found after labour. Preterm females had significantly higher catecholamine levels than boys after asphyxia and tended also to have higher catecholamine levels without asphyxia, although not significant. Catecholamine levels were also significantly elevated in those infants with a low Apgar score (less than 7 at 5 min) and those who were acidotic (cord arterial pH less than 7.25). A good correlation was found between a low Apgar score and the presence of acidosis.

Fetal catecholamines and the Apgar score.

The association between Apgar score, pH and catecholamine levels was investigated in 181 newborn infants with a gestational age between 29 and 43 completed weeks. Umbilical arterial blood was obtained before the first breath with the double clamp technique and pH was measured. Plasma adrenaline and noradrenaline were analyzed by high performance liquid chromatography. The Apgar score at 1 minute was above or equal to seven in 167 infants. Forty-four per cent of these infants had pH below 7.25. A negative correlation between log noradrenaline and pH (r = 0.52, p less than 0.001) and between log adrenaline and pH (r = 0.40, p less than 0.001) was found. In 14 infants the Apgar score was below seven. The median pH was 7.21 (range 7.02-7.32). Also in this group a negative correlation between log noradrenaline and pH (r = 0.60, p less than 0.05) and between log adrenaline and pH (r = 0.77, p less than 0.01) was noted. We concluded that the Apgar score is an insufficient measure of fetal asphyxia defined as fetal acidosis but rather reflects the vitality of the newborn.

Reduced uptake of noradrenaline into storage vesicles from the pregnant uterus.

A noradrenaline (NA) storage vesicle fraction was isolated from the uteri of virgin as well as pregnant guinea-pigs. The uptake of 3H-NA into respective vesicle fractions was compared. Total uptake of 3H-NA in the presence of Mg2+ (2.5mM) and ATP (2.5 mM) at 30 degrees C after 20 min was 6.0 +/- 1.4 pmol . mg-1 in uterus fractions from virgin guinea-pigs as compared to 1.87 +/- 0.41 pmol . mg-1 in uterus fractions from pregnant animals. When desipramine (5mM) was added in order to block neuronal uptake the corresponding figures were 4.75 +/- 0.92 and 0.51 +/- 0.18 pmol . mg-1, respectively. Thus in the presence of desipramine (5mM) uptake was reduced by 21.4% in fractions from virgin uteri but by 72.7% in fractions from pregnant uteri. Reserpine (0.1 microM) inhibited uptake of 3H-NA by 34% in fractions from virgin uteri and by 46% in fractions from pregnant uteri. Our results indicate a decreased amount of functional storage vesicles in uteri of guinea-pigs at term pregnancy and are consistent with the proposed degeneration of adrenergic nerves during pregnancy.