Biomedical subjects

M Asencio

Publications and source records attributed to M Asencio.

8 recordsLinked to original sources

PubMed1999

Biochemical and behavioral effects of boldine and glaucine on dopamine systems.

The aporphine alkaloids boldine and glaucine have been reported to show "neuroleptic-like" actions in mice, suggesting that they may act as dopamine antagonists. We have found that in vitro boldine displaces specific striatal [3H]-SCH 23390 binding with IC50 = 0.4 microM and [3H]-raclopride binding with IC50 = 0.5 microM, while the affinities of glaucine at the same sites are an order of magnitude lower. In vivo, however, 40 mg/kg boldine (i.p.) did not modify specific striatal [3H]-raclopride binding and only decreased [3H]-SCH 23390 binding by 25%. On the other hand, 40 mg/kg glaucine (i.p.) displaced both radioligands by about 50%. Behaviors (climbing, sniffing, grooming) elicited in mice by apomorphine (0.75 mg/kg s.c.) were not modified by boldine at doses up to 40 mg/kg (i.p.) but were almost completely abolished by 40 mg/kg glaucine (i.p.). In the apomorphine-induced (0.1 mg/kg s.c.) rat yawning and penile erection model, boldine and glaucine appeared to be similarly effective, inhibiting both behaviors by more than 50% at 40 mg/kg (i.p.). Boldine and glaucine, injected i.p. at doses up to 40 mg/kg, were poor modifiers of dopamine metabolism in mouse and rat striatum. These data suggest that boldine does not display effective central dopaminergic antagonist activities in vivo in spite of its good binding affinity at D1- and D2-like receptors, and that glaucine, although less effective in vitro, does appear to exhibit some antidopaminergic properties in vivo.

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PubMed1999

Dopaminergic pharmacology and antioxidant properties of pukateine, a natural product lead for the design of agents increasing dopamine neurotransmission.

The dopaminergic and antioxidant properties of pukateine [(R)-11-hydroxy-1,2-methylenedioxyaporphine, PUK], a natural aporphine derivative, were analyzed in the rat central nervous system. At dopamine (DA) D1 ([3H]-SCH 23390) and D2 ([3H]-raclopride) binding sites, PUK showed IC50 values in the submicromolar range (0.4 and 0.6 microM, respectively). When the uptake of tritiated dopamine was assayed by using a synaptosomal preparation, PUK showed an IC50 = 46 microM. In 6-hydroxydopamine unilaterally denervated rats, PUK (8 mg/kg but not 4 mg/kg) elicited a significant contralateral circling, a behavior classically associated with a dopaminergic agonist action. When perfused through a microdialysis probe inserted into the striatum, PUK (340 microM) induced a significant increase in dopamine levels. In vitro experiments with a crude rat brain mitochondrial suspension showed that PUK did not affect monoamine oxidase activities, at concentrations as high as 100 microM. PUK potently (IC50 = 15 microM) and dose-dependently inhibited the basal lipid peroxidation of a rat brain membrane preparation. As a whole, PUK showed a unique profile of action, comprising an increase in extracellular DA, an agonist-like interaction with DA receptors, and antioxidant activity. Thus, PUK may be taken as a lead compound for the development of novel therapeutic strategies for Parkinson disease.

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PubMed1995

Structure-antioxidative activity relationships in benzylisoquinoline alkaloids.

The antioxidative properties of the aporphines boldine, glaucine and apomorphine, and of the benzyltetrahydroisoquinolines (+/-)-coclaurine and (+/-)-norarmepavine were compared in the brain homogenate autoxidation model. The IC50 values found lay in the 16-20 microM range for the aporphines and were 131.7 microM, and 79.3 microM for coclaurine and norarmepavine, respectively. These results indicate that the antioxidative capacity (AC) of these compounds is related to the presence of the biphenyl system rather than phenol groups. The non-phenolic glaucine inhibited the 2,2'-azobis-(2-amidinopropane)(AAP)-induced inactivation of lysozyme with an IC50 value of 12 microM, while the corresponding values for the phenolic coclaurine and norarmepavine were 10 and 20 microM, respectively. N-Methylation of glaucine to its quaternary ammonium reduced its protective effect by two-thirds. This result suggests that a benzylic hydrogen neighbouring a nitrogen lone electron pair may be the key to the protective effect of non-phenolic aporphines.

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PubMed1990

Intravenous cocaine self-administration in rats is reduced by dietary L-tryptophan.

Rats were trained to self-administer intravenously-delivered cocaine. Four lever-press responses resulted in a cocaine infusion (0.2 mg/kg) during daily 24-h sessions. The rats were also trained to obtain water from tongue-operated solenoid-driven drinking spouts. Ground food and water from a standard drinking bottle were also available. When cocaine injections reached stable levels, L-tryptophan was mixed with the rats' food for 5 days. Three concentrations of L-tryptophan (2, 4, and 8%) were tested in different groups of five rats each. Three other groups of five rats each received the same L-tryptophan treatments; however, in these rats saline was substituted for cocaine and a sweet drinking solution consisting of glucose and saccharin (G + S) replaced water in the automatic drinking device. Two other groups consisting of five rats each self-administered a higher (0.4 mg/kg) or lower (0.1 mg/kg) unit dose of cocaine and food adulterated with 4% tryptophan. At the two higher concentrations L-tryptophan reduced cocaine infusions by at least 50% during the 5 days of treatment, and cocaine infusions returned to baseline levels within 48 h after the regular diet was restored. Responding reinforced by the G + S solution was not altered by any of the L-tryptophan concentrations. Food intake was substantially lowered by the 8% L-tryptophan concentration; however, water intake, responding on an inactive lever, and the number of saline infusions were not affected by addition of L-tryptophan to the food. L-Tryptophan had the same magnitude of effect on self-administration of the 0.1 and 0.2 mg/kg unit doses of cocaine, but behavior maintained by the highest cocaine dose (0.4 mg/kg) was resistant to the effect of L-tryptophan. The results of this experiment indicate that L-tryptophan reduces behavior reinforced by IV cocaine infusions.

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PubMed1990

Effects of carbamazepine on self-administration of intravenously delivered cocaine in rats.

Carbamazepine (Tegretol) is widely used therapeutically as an anticonvulsant. Based on an hypothesis that links electrical kindling in the limbic system (leading to seizures) to reverse tolerance or sensitivity to cocaine's effects, carbamazepine is being tested as a treatment for human cocaine users. The purpose of this experiment was to examine the effects of carbamazepine on intravenous cocaine self-administration in rats. Rats self-administered intravenously delivered cocaine (0.2 mg/kg) under a fixed-ratio 4 schedule. When cocaine injections reached stable levels, carbamazepine was mixed with the rats' food for 8 days. Three doses of carbamazepine were tested (80, 120, and 160 mg/kg) in different groups of 5 rats each. The rats were later separated into groups with a high (greater than 750 infusions) and a low (500-750 infusions) cocaine baseline. Two control groups of 5 rats each received carbamazepine treatments (120 or 160 mg/kg) and self-administered an orally delivered solution of glucose and saccharin (G + S). At the highest carbamazepine dose in the high cocaine baseline group, carbamazepine reduced cocaine infusions by at least 50 percent and food intake by approximately 25 percent during the 8 days of treatment. Cocaine infusions returned to baseline within 24 hr after the regular diet was restored. Carbamazepine had a minimal effect in groups of rats with lower cocaine baselines. Responding reinforced by the G + S solution was reduced by both the 120 and 160 mg/kg carbamazepine doses. Water intake was not systematically affected by the addition of carbamazepine to the food; however, activity measures were significantly lower in some groups at the higher carbamazepine doses.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1990

Fluoxetine reduces intravenous cocaine self-administration in rats.

Rats self-administered intravenously delivered cocaine (0.2 mg/kg) under a fixed-ratio (FR) 4 schedule during 24-hr sessions. Water was freely available from both a drinkometer and a standard water bottle. After behavior had stabilized, the rats were injected with fluoxetine HCl at 10:00 a.m. and 4:00 p.m. for 5 consecutive days. Three groups of 5 rats each received a different dose of fluoxetine (2.5, 5 or 10 mg/kg) via the IV cannula. In three other groups of rats a glucose and saccharin solution (G + S) was substituted for water in the automatic drinking device and saline was substituted for cocaine. These three groups of rats received the same fluoxetine doses as the cocaine self-injecting groups. In two additional groups of 5 rats each, the cocaine dose was changed to 0.1 or 0.4 mg/kg, and 5 mg/kg fluoxetine injections were given. The two higher doses of fluoxetine (5 and 10 mg/kg) reduced cocaine infusions (0.2 mg/kg) by at least 50 percent on all 5 days of treatment, and cocaine infusions returned to baseline levels within 48 hr after fluoxetine treatments were terminated. Behavior maintained by the G + S solution was also reduced by the two higher fluoxetine doses; however, this reduction did not reliably occur until the last two days of fluoxetine administration. The G + S intakes returned to baseline levels within 24 hr after fluoxetine treatment. Fluoxetine also reduced cocaine infusions in the group of rats that received the lower unit dose of cocaine (0.1 mg/kg); however, it had almost no effect on behavior maintained by a higher cocaine dose (0.4 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1989

Nicotine dependence in rats.

Health hazards associated with nicotine and tobacco use are well known. A contributing factor, the dependence producing potential of this drug, has become widely accepted. However, there are only a few human and animal studies that provide objective measures of the behavioral consequences of nicotine abstinence. The purpose of the present experiment was to use sensitive measures to examine behavioral disruptions that resulted when nicotine administration was terminated. Six rats were administered 96 daily intravenous infusions of nicotine (0.125 mg/kg/infusion) for at least 10 days. They were trained to respond on a tongue-operated solenoid-driven drinking device that delivered 0.005 ml of a glucose and saccharin solution (G + S) per lick. When nicotine access was terminated for six days, there was a marked suppression in behavior reinforced by the sweetened solution, and this disruption was immediately reversed when nicotine was reinstated. In contrast, nicotine removal also resulted in a decrease in food intake on the first day, but on subsequent days food intake was significantly higher than when nicotine was administered. When cotinine (0.25 mg/kg/infusion), a metabolite of nicotine was substituted for nicotine for six days, similar disruptions resulted in responding maintained by G + S, but food intake was not significantly decreased on the first day of nicotine abstinence. These findings illustrate the utility of sensitive behavioral tests to reveal effects of nicotine abstinence.

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PubMed1988

Behavioral dependence on caffeine and phencyclidine in rhesus monkeys: interactive effects.

Five rhesus monkeys were trained to self-administer orally-delivered phencyclidine (PCP) and water under concurrent fixed-ratio (FR) 8 schedules. Liquid deliveries were contingent upon lip-contact responses on solenoid-operated drinking spouts, and food pellet delivery was contingent upon responses on a centrally-located lever. Food was available during three 1-hr periods each day under an FR 64 or FR 80 schedule. The liquids were available during three 6.5-hr periods after each food component. In the first experiment caffeine (4 or 8 mg) was added to each 6-g food pellet, and after responding stabilized, noncaffeinated pellets were substituted for the caffeinated pellets for eight days. There were no differences in food-, water- or PCP-maintained behavior due to caffeine concentration (4 vs. 8 mg/pellet) although the monkeys consumed twice as much caffeine at the higher concentration. Food-maintained responding was reliably reduced by 25-50 percent the first day of caffeine removal, and there was a recovery of responding characterized by intermittent cycles of low response rates over the next 7 days. Water and PCP intake were not systematically disrupted when caffeine access was terminated. In the second experiment the monkeys were tested with caffeinated (6 mg/pellet) and noncaffeinated pellets under conditions of PCP removal (water substitution) and reinstatement. Under both food conditions, when PCP access was terminated, pellet deliveries decreased by about 50 percent and gradually recovered over the 8-day water substitution phase. However, behavioral disruptions were more severe under conditions in which monkeys received caffeinated pellets, suggesting an interactive effect due to termination of PCP access and decreased caffeine intake. These results indicate that disruptions in operant baselines are sensitive indicators of the effects of discontinuing caffeine access; however, the severity and time course of behavioral disruptions due to caffeine removal are considerably less than after termination of PCP access.

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