Reversal of ethanol intoxication in humans: An assessment of the efficacy of propranolol

The effect of post-ethanol ingestion of a single dose of propranolol on acute intoxication was studied in 13 healthy male volunteers. A within subjects, double-blind, crossover design was employed. Each subject participated in two experimental sessions. In each session, subjects took a battery of tests under three conditions: Sober, Alcohol (0.8 g/kg) and Alcohol (1.1 g/kg) + Pill, in that order. The pill contained propranolol (40 mg) in one session and placebo in the other. Ethanol significantly reduced motor coordination, memory and divided attention performance and altered mood scores. Propranolol significantly increased ethanol's effects on divided attention, inebriation ratings and the electroencephalogram without significantly altering blood alcohol concentrations. There was no indication that propranolol antagonized any of ethanol's effects. These results agree with studies indicating that ethanol's effects are increased by a reduction in the functional capacity of central catecholamine systems. It is suggested that central catecholamine-stimulating drugs may reverse some of ethanol's effects.     

Decarboxylation of orally administered l-dopa in the human digestive tract

Summary Carboxyl labelled l-dopa was administered orally and intravenously to Parkinsonian patients and control subjects. Total radioactivity was measured in the expired air, urine and plasma. The activity in plasma was also measured before and after removal of carbon dioxide-dicarbonate. After intravenous administration about four times more radioactivity was recovered in the urine than after oral administration with a roughly corresponding decrease in the recovery from expired air, whereas a considerably smaller proportion of the total radioactivity in plasma was derived from carbon dioxide-bicarbonate. It is concluded that the major fraction of the orally administered l-dopa undergoes decarboxylation in the digestive tract before reaching the general circulation. No difference was observed between the Parkinsonian and the non-Parkinsonian group.     

The effect of l-dopa on young patients with simple schizophrenia,treated with neuroleptic drugs

Thirteen out of 18 young out-patients with simple schizophrenia under neuroleptic treatment completed a double-blind cross-over trial with Madopar® [l-Dopa + benserazid (a peripheral decarboxylase inhibitor)] and placebo. Nine patients were given 900 mg l-Dopa + 225 mg benserazid daily, 1 patient received 600 mg l-Dopa + 150 mg benserazid, and 3 patients, 300 mg l-Dopa + 75 mg benserazid. In these doses, l-Dopa was effective against emotional withdrawal, blunted affect, tendency to isolation and apathy, without inducing or aggravating productive, accessory symptoms. The activity score, according to the specific activity-withdrawal scale, was significantly increased (P<0.05), whereas the total BPRS score (Brief Psychiatric Rating Scale) was slightly, but significantly reduced (P<0.05). In cases where l-Dopa had to be limited to 600 and 300 mg daily, a tendency to anxiety, distortion of thinking, and a sense of unreality were observed, depending on the dose of l-Dopa. In no case were gastrointestinal, cardiovascular or neurological sideeffects observed.     

Striatal dopamine turnover and l-dopa treatment after short-term exposure of rats to manganese

The turnover rate of striatal dopamine (DA) and the effect of l-dopa treatment was investigated in rats after the daily oral administration of MnCl₂ · 4H₂O for a period of 30 days. The turnover rate of striatal DA, as determined by the administration of -methyl-p-tyrosine, increased significantly in manganese-exposed rats. l-Dopa administration resulted in a significant elevation in the levels of DA and its metabolite, homovanillic acid, in manganese-exposed rats, but these neurochemical changes could not be correlated with the concentration of manganese in the striatum. We therefore advise that l-dopa therapy should not be tried in early manganese intoxication, as it may aggravate manic symptoms due to marked increase in brain DA.     

Effects of d-amphetamine,maprotiline, l-dopa,and haloperidol on the components of the predatory behavior of the ferret,Putorius furo l.

Ferret predation on rats was examined in an arena. One hour before the test one of the following drugs was administered: d-Amphetamine (0.8 and 1.4 mg/kg IM), maprotiline (10 and 40 mg/kg orally), l-dopa (30 and 60 mg/kg orally), or haloperidol (0.14 and 0.6 mg/kg IM). Provided that capture was successful, the sequence of the behavioral components was not changed by these drugs. With the exceptions of paw movements and rolling over, which were not affected by the drugs, the components of predatory behavior were influenced differently. This leads to the assumption that a drug affects different mechanisms which control behavior. It is assumed that dopamine is involved in the control of capture elicitation as well as in the control of pursuit and biting. Capture elicitation was inhibited by d-amphetamine and l-dopa, but not by maprotiline, and was even facilitated by haloperidol. The orientation of pursuit movements and biting was impaired by l-dopa and improved by haloperidol, whereas maprotiline did not influence these components.     

The effects of l-Dopa,clonidine, and apomorphine on the acoustic startle reaction in rats

The present investigation provides evidence for noradrenergic involvement in the elaboration of the acoustic startle reaction.Within-subject experiments demonstrated that an amine-depleting dose of reserpine enhanced the level of the startle reaction and that this effect was reversed by the catecholamine precursor, l-Dopa. Chemical assays suggested a correlation between the accumulation of noradrenaline and reversal of reserpine effects. Administration of the noradrenaline receptor-stimulating agent, clonidine (0.125 or 0.250 mg/kg) produced marked reductions in startle amplitude reducing the response far below normal values in reserpinized subjects. By contrast, the dopamine receptor-stimulating agent, apomorphine (1.0 mg/kg) did not alter the response. None of the pharmacological agents used was found to alter the inhibition of the startle reaction which results from the presentation of neutral stimuli (prepulses) shortly before reflex elicitation.Taken together with an earlier report, the present data suggest that noradrenaline and serotonin have partially antagonistic control over the startle reaction.Submitted in partial fulfillment of the requirements for the Ph. D. degree from the University of Rochester. The thesis advisors, Dr. Carol Kellogg and Dr. James Ison, are warmly thanked for their advice, encouragement, guidance, and continuing support. The research was supported in part by NSF grant GB-14814, NIMH grant MH-10825, and ONR contact N00014-68-0091.     

Plasmatic renin activity in patients treated with l-dopa and inhibitor of dopa decarboxylase (IDC)

Plasmatic renin activity (PRA) was studied in patients receiving l-dopa, together with a decarboxylase inhibitor, at rest times and after periods of physical exertion. Although we can superimpose the results from untreated Parkinson's disease patients on those of the control group, the results are inversed in stabilized patients (lowered PRA) and dyskinetic patients (increased PRA). There is a definite correlation between the increase in PRA and intensity of the dyskinesia. Dosage is the only other factor differentiating the two groups of Parkinsonians treated. The figures relative to arterial pressure are studied in the various groups.     

Association l-Dopa,désipramine et inhibiteur de la décarboxylase dans le traitement de la dépression

The use of l-Dopa in the treatment of depressions has been suggested by pharmacological hypotheses and by observations made during the treatment of Parkinson's disease. The authors discuss the first results of their experiences using a combination of l-Dopa, a decarboxylase inhibitor, and desipramine. Some types of depression were rapidly relieved by such treatment, while those types associated with anxiety and agitation did not respond.

     

Formation of dopamine from 3-methoxytyrosine

Summary l-3-Methoxytyrosine-¹⁴C was given intravenously to mice, alone or following inhibitors of monoamine oxidase, catechol-O-methyl transferase or dopa decarboxylase. ¹⁴C-noradrenaline and ¹⁴C-dopamine in brain and heart were determined 2 h after the administration of the labelled compound. The results were very similar to those obtained in previous studies after a small dose of labelled dopa. Therefore, a careful paperchromatographic analysis of the l-3-methoxytyrosine-¹⁴C was made. It was found that 1.5% of the total radioactivity corresponded to dopa. Attempts to make a preparative separation of ¹⁴C-dopa from ¹⁴C-3-methoxytyrosine failed due to the appearance of another labelled impurity interfering with the determination of dopamine. Thus, the question whether dopamine can be formed from 4-methoxytyrosine in vivo could not be definitely answered. However, the serious interference of small amounts of radioactive impurities when working with labelled material in biological systems has been demonstrated once more.     

Propriétés différentielles d'un inhibiteur de la décarboxylase envers la l-Dopa et le l-5-HTP. Données polygraphiques et biochimiques

This study, comparing polygraphic data and biochemical dosages with a short term rabbit EEG recording technique, shows that Ro 4602 does not have the same quantitative (or even qualitative) effect whether combined with l-Dopa or l-5-HTP. Thus minimal and optimal doses of this inhibitor of the decarboxylase are not the same for the two precursors. Using equimolar doses, clinical effects on the whole appeared to be much more evident with the association Ro 4602-l-5-HTP than with Ro 4602-l-Dopa.

     

Nitric oxide synthesis,epileptic seizures and kindling

Nitric oxide (NO) has been implicated in synaptic changes underlying long-term potentiation and some forms of learning. It is unclear, however, whether NO contributes to long-term changes associated with the kindling of epileptic seizures. In the present study rats were treated, on the first 6 days of kindling, withl-arginine (l-Arg), the endogenous donor from which NO derives, or withl-nitro-arginine (l-No-Arg), a competitive inhibitor of NO synthesis, or with vehicle. Drugs were given in doses previously shown to affect learning or other behaviour.l-Arg (750 mg/kg IP) did not affect kindling or seizure severity.l-No-Arg (100 mg/kg) prolonged the duration of afterdischarges and convulsions on treatment days but did not advance kindling or affect seizures on subsequent days. A second experiment examined the possible rôle of NO in the development of resistance to seizures following prior seizures. Six or more stimuli were administered at 10-min intervals to fully-kindled rats after injection ofl-No-Arg or vehicle. Vehicle-treated rats became progressively more resistant to afterdischarges and convulsions with successive stimulations butl-No-Arg-treated rats failed to do so. Rats injected withl-No-Arg also showed an unexpected high mortality in the ensuing 24 h.l-No-Arg appeared to have no direct effect on the course of kindling but impaired the development of postictal resistance, and increased the duration and lethal after-effects of closely repeated seizures. The results do not support suggestions that antagonists of NO might prove clinically useful as anticonvulsants.     

Dizocilpine (MK-801), ketamine and phencyclidine: low doses affect brain field potentials in the freely moving rat in the same way as activation of dopaminergic transmission

The effects of dizocilpine (MK-801), (±)-5-methyl-10,11-dihydro-5Hdibenzo-[a,d]-cyclohepten-5,10-imine maleate, after IP injection into freely behaving rats, have been compared with the action of ketamine-chloride and phencyclidine (PCP). MK-801 produced strongly dose-dependent effects which could be followed quantitatively over a time of 4 h. During this time spectral analysis of the field potentials continuously recorded from frontal cortex, hippocampus, striatum, and reticular formation revealed a particular pattern of changes which was very stable over time, and, after low doses of 0.05 and 0.1 mg/kg, matched that produced by phencyclidine (2 and 4 mg/kg) or ketamine chloride (10 and 20 mg/kg). With higher doses of MK-801 a continuous change from power decreases to power increases was observed. These increases were accompanied by strong behavioral effects in terms of impaired locomotor control. All three non-competitive NMDA antagonists showed a high degree of similarity with respect to the changes of the frequency content of the field potentials over time. The same pattern of electrical changes could be observed after the application ofl-dopa (50 mg/kg) or amphetamine (0.2 mg/kg). This can be interpreted in the sense that the same population of cells within the recording area which is under dopaminergic control is at the same time under glutamate control. This leads to the hypothesis that it might be possible to bypass the missing dopaminergic control during parkinsonism by noncompetitive NMDA-receptor blocking drugs.     

Effect of monoamine precursors on the forced-swimming test in mice

The antidepressant properties of monoamine precursors were evaluated by the forced-swimming test for mice developed by Porsolt et al. DOPA but not 5-hydroxy-tryptophan (5HTP) shortened immobility at doses that did not increase locomotor activity. Although l-threo-dihydroxyphenylserine (DOPS), an artificial norepinephrine (NE) precursor, did not change immobility in intact mice, DOPS significantly reduced immobility in mice pretreated with the selective NE neurotoxin DSP4. These results suggest possible antidepressant properties of DOPA and DOPS, the latter of which may act as an antidepressant in a certain NE-depleting condition.     

Effects of l-tryptophan and ethanol on sleep parameters in the rat

Sleep parameters were monitored following (1) a single 2 g/kg oral dose of ethanol, (2) an oral dose of l-tryptophan (600 mg/kg), and (3) administration of both drugs simultaneously. Ethanol reduced REM and increased slow wave significantly. The effects of l-tryptophan were apparent only in the case of one parameter, REM latency. Administration of both drugs resulted in a significantly shorter REM latency than that observed for ethanol administered alone. Results are discussed in terms of possible changes in the biosynthesis of 5-HT.     

Inhibition of N-methyl-d-aspartate (NMDA) and l-glutamate-induced noradrenaline and acetylcholine release in the rat brain by ethanol

Summary The influence of ethanol on stimulation-evoked ³H-transmitter release was examined in slices of the rat brain cortex and corpus striatum preincubated with ³H-noradrenaline and ³H-choline, respectively. ³H-Transmitter release was stimulated by NMDA, l-glutamate, electrical impulses, reintroduction of Ca²⁺ ions (Ca²⁺-evoked release; after superfusion with Ca²⁺-free, K⁺-rich solution) or veratridine. In cortical slices preincubated with ³H-noradrenaline and superfused with Mg²⁺-free, otherwise physiologically composed salt solution, ethanol inhibited the NMDA- or l-glutamate-induced tritium overflow (IC₅₀ 45 and 37 mmol/l, respectively). In contrast, the tritium overflow in response to electrical stimulation, reintroduction of Ca²⁺ ions or veratridine was not affected by ethanol at concentrations up to 320 mmol/l; these experiments were carried out in cortical slices superfused with solution containing a physiological Mg²⁺ concentration. Ethanol also failed to inhibit Ca²⁺-evoked release in the absence of Mg2⁺ ions. In the presence of 1 mol/l veratridine, but not in its absence, NMDA induced tritium overflow even when cortical slices were superfused with salt solution containing a physiological Mg²⁺ concentration; again, ethanol inhibited this NMDA-evoked tritium overflow (IC₅₀ 73 mmol/l). In striatal slices preincubated with ³H-choline and superfused with Mg²⁺-free physiological salt solution, the NMDA-evoked tritium overflow was also, although at lower potency, inhibited by ethanol (IC₅₀ 192 mmol/l).In spite of the differences between the IC₅₀ values of ethanol determined for the inhibition of cortical noradrenaline and striatal acetylcholine release, it may be concluded that the NMDA receptor-ion channel complex is one of the sites of action underlying the ethanol-induced inhibition of neurotransmitter release. Since in the brain cortex the NMDA-induced ³H-noradrenaline release appears to be mediated by an excitatory interneurone activated by NMDA, this neuronal system may be involved in the cortical actions of ethanol.     

l-Dopa effects on motor and “central programming” deficits in Parkinsonism

A study was made to test the effects of treatment by l-Dopa on both motor and central programming deficits in Parkinsonism.Nine patients with Parkinsonism were tested on psychomotor tasks, involving both unimanual and bimanual performance, before and after treatment. Control data was obtained from 28 age-matched subjects. These were only tested on one occasion.As expected, there was a very significant improvement in motor performance of the Parkinsonism group after treatment by l-Dopa. The evidence of improvement in the central programming deficit was less conclusive, but seemed substantial enough to warrant further investigation.     

Demethylation of l-3-methoxytyrosine in vivo

Summary After administration of purified l-¹⁴C-3-methoxytyrosine (l-¹⁴C-3-MTO) to rats, the fractions of labelled amino acids, catecholamines and phenolcarboxylic acids of urine and brain have been separated by column chromatography. Prior to performing the quantitative determinations, the individual metabolites of each urinary fraction and of the cerebral catecholamine fraction were isolated by paper chromatography using different systems. Susbtantial amounts of ¹⁴C-3,4-dihydroxyphenylacetic acid (¹⁴C-DOPAC) as well as some ¹⁴C-3,4-dihydroxyphenylalanine (¹⁴C-DOPA) and traces of dopamine (DA) appeared in the urine. Furthermore, small amounts of ¹⁴C-DA and ¹⁴C-norepinephrine were found in the brain with two different chromatographic systems. The urinary excretion of ¹⁴C-DOPAC and ¹⁴C-DA was increased by pretreatment with dopacetamide, an inhibitor of catechol-3-O-methyl-transferase. A possible contamination of the l-¹⁴C-3-MTO with traces of l-¹⁴C-DOPA as a major source of the dihydroxylated metabolites has been ruled out. It is concluded that part of l-3-MTO undergoes demethylation in vivo and that the finding of DA in brain and urine after administration of l-3-MTO is not an artifact.     

Central effects of baclofen on thel-dopa induced hyperactive urinary bladder of the rat

Summary Cystometric recordings were performed in pentobarbitone anaesthetized rats and the effects of baclofen on urinary bladder function were evaluated as their influence on bladder hyperactivity induced by 1-dihydroxyphenylalanine (l-dopa) after peripheral decarboxylase inhibition. The bladder response was inhibited by intracerebroventricularly (i.c.v., 4th ventricle, 0.1 g) as well as by systemically administered (10 mg/kg i.v.) baclofen. Intravenous naloxone but not i.v. bicuculline i.c.v. substance P or i.c.v. glutamate antagonized the inhibitory actions of i.c.v. or/and i.v. baclofen.It is suggested that baclofen depresses the hyperactive bladder by a central action that is unrelated to bicuculline sensitive gamma aminobutyric acid mechanisms, substance P or glutamate neurotransmission but that is possibly related to interference with opioid mechanisms.     

Evidence for the role of nitric oxide in nicotine-induced locomotor sensitization in mice

Rationale Nitric oxide (NO) is implicated in both acute effects of addictive drugs and development of dependence to them. We investigated the role of NO in nicotine-induced locomotor sensitization.Objectives The effects of N-nitro-l-arginine methyl ester (l-NAME), a NO synthase inhibitor, and a combination of a NO precursor l-arginine and l-NAME on nicotine-induced locomotor sensitization were investigated in Swiss Webster mice.Methods Sensitization to psychomotor stimulating effect of nicotine was rendered by seven injections of nicotine (1 mg/kg) on every other day. To investigate their effect on the development of sensitization to nicotine, l-NAME (15–60 mg/kg) and l-arginine (1 g/kg) were given before nicotine administration during the first seven sessions. To investigate the effect of these compounds on the expression of nicotine sensitization, after a 4-day drug-free period another group of mice received a challenge injection of nicotine on day 18.Results Nicotine (1 mg/kg) produced a robust locomotor sensitization in mice. The doses of 30 mg/kg and 60 mg/kg of l-NAME blocked the development of sensitization to nicotine; and, l-arginine (1 g/kg) pretreatment reversed this effect of l-NAME. Likewise, the doses of 30 mg/kg and 60 mg/kg of l-NAME inhibited the expression of sensitization to nicotine on day 18; and, l-arginine (1 g/kg) pretreatment reversed this inhibitory effect of l-NAME.Conclusions Our results suggest that NO is implicated in the development and expression of nicotine-induced locomotor sensitization in mice.     

Possible involvement of l-arginine-nitric oxide pathway in modulating regional blood flow to brown adipose tissue of rats

To evaluate whether the l-arginine-nitric oxide (NO) pathway is involved in the regulation of regional blood flow to brown adipose tissue (BAT), the effects of two specific NO synthase inhibitors, N^G-nitro-l-arginine methyl ester (l-NAME) and N^G-monomethyl-l-arginine (l-NMMA), on the blood flow to interscapular brown adipose tissue (IBAT) were studied in urethane-anesthetized rats. Regional blood flow in MAT was measured with laser-Doppler flowmetry.An intravenous injection of l-NAME and l-NMMA, but not of either d-enantiomer, caused a transient and dose-dependent increase in IBAT blood flow. Dose-response curves for these NO synthase inhibitors showed that l-NAME was more potent than l-NMMA in increasing IBAT blood flow. We also observed a concomitant pressor effect accompanied by a slight decrease in heart rate following intravenous injection of l-NAME and l-NMMA. An elevation of IBAT blood flow and blood pressure induced by both l-NAME and l-NMMA was reversed by l-arginine in an enantiomerically specific manner. The increase in IBAT blood flow induced by NO synthase inhibitors was of shorter duration and less sensitive to l-arginine than the increase in blood pressure.Our results show that the WAY blood flow is increased by inhibition of NO synthase and that the response of IBAT vasculature to NO synthase inhibitors is different from that of the resistance vessels which regulate blood pressure. The involvement of l-arginine-NO pathways in modulating microcirculation in IBAT is suggested. Correspondence to: Y. Uchida at the above address