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Biomedical subjects

M C Gerald

Publications and source records attributed to M C Gerald.

At least 37 records · Page 2Linked to original sources
PubMed1982

Cholinergic-independent effects of amphetamine on mammalian skeletal muscle contractions.

Studies were designed to investigated the cholinergic-independent mechanism(s) by which (+)-amphetamine produces a biphasic modification of directly stimulated contractions of skeletal muscle in the rat phrenic nerve-diaphragm preparation. In tissues pretreated with alpha-bungarotoxin, low concentrations of (+)-amphetamine (2.7-1.08 x 10(-4) M) enhanced muscle blockade. In other studies (Gerald, Meldrum and Skau, Res. Commun, chem. Path. Pharmac., 1982), high K+ concentrations or low Na+ concentrations antagonized amphetamine-enhancement of the twitch, while potentiating the blockade; in contrast K+-free media augmented amphetamine-induced enhancement of contractions. Low concentrations of amantadine, tetracaine, and tetrodotoxin increased the facilitatory response to (+)-amphetamine while the inhibitory effects of (+)-amphetamine were potentiated by higher concentrations of these antagonists; similar biphasic effects were observed with (-)-amphetamine and tetracaine. (+)-Amphetamine reserved the marked enhancement of the twitch produced by veratridine while, conversely, this neurotoxin failed to alter muscle contractions after (+)-amphetamine pretreatment. These findings suggest that amphetamine-induced enhancement and blockade of directly-stimulated skeletal muscle resulted from alterations in Na+ fluxes, possibly through interactions with membrane ionic channels.

Amantadine↗
PubMed1982

Biphasic amphetamine effects on skeletal muscle contractions: noncholinergic mechanisms.

Noncholinergic mechanisms underlying the biphasic effects of (+)-amphetamine on skeletal muscle contractions were studied in the directly-stimulated, cholinergically blocked, rat phrenic nerve-diaphragm preparation. Low (2.7-8.1 x 10(-4)M) and high (10.8-21.6 x 10(-4)M) levels of (+)-amphetamine produced concentration-dependent enhancement and blockade of muscle contractions, respectively, in tissues pretreated with alpha-bungarotoxin, beta-bungarotoxin, or (+)-tubocurarine. These biphasic effects were not modified by tyramine, phentolamine, or propranolol arguing against a mechanism involving a direct or indirect adrenoceptor interaction. Amphetamine did not modify (Na+-K+)-stimulated ATPase activity. Increased [K+] or decreased [Na+] antagonized (+)-amphetamine enhancement of contractions and potentiated blockade; similar effects were observed after high concentration amantadine or procaine pretreatment. K+-free media potentiated (+)-amphetamine facilitation of contractions as did low concentrations of amantadine or procaine. These results suggest that amphetamine may biphasically modify skeletal muscle contractions by interactions involving the movements of Na+ and K+ independent of (Na+-K+)-stimulated ATPase.

Amantadine↗
PubMed1981

The effect of 2-n-propyl-3-dimethylamino-5,6-methylenedioxyindene on caffeine-induced contractures of skeletal muscle.

It has been previously postulated that 2-n-propyl-3-dimethylamino-5,6-methylenedioxyindene (pr-MDI) exhibits calcium antagonistic properties with an intracellular site of action. The present investigation further substantiates this hypothesis by providing evidence that pr-MDI inhibits caffeine-induced contractures (which are mediated by intracellular calcium) of the isolated rat hemidiaphragm skeletal muscle both in the presence and in the absence of extracellular calcium.

Animals↗
PubMed1979

Tolerance to amphetamine-induced impairment of rotarod performance in rats.

Acute administration of d-amphetamine sulfate (30 mg/kg, i.p.) caused muscle weakness and 80% failure in rotarod performance in rats. The incidence of performance failure progressively decreased to 30% in animals receiving d-amphetamine and tested daily for 8 days. A similar progressive reduction in performance impairment was observed in animals receiving d-amphetamine for 3, 5, or 7 days (12.5%) and evaluated only once after the last dose. The tolerance is attributable to a physiological or biochemical rather than learning phenomenon.

Animals↗
PubMed1978

Brain and plasma concentrations of amphetamine isomers in mice.

Brain and plasma concentrations of (+)- and (-)-amphetamine were compared as a function of dose and time after administration to mice. Doses of an amphetamine isomer contained 12 muCi of [14C]-(+) or (-)-amphetamine. Thirty minutes after administration of 2.5, 5 or 10 mg/kg i.p., (+)-amphetamine/(-)-amphetamine concentration ratios in the brain were significantly greater than 1; this ratio was less than 1 for the 15 mg/kg dose. Plasma concentration ratios were significantly greater than 1 for all doses. The ratios of +/-isomers were consistently greater than 1 in brain and plasma when determined at various times (7.5--120 min) after 2.5 and 10 mg/kg i.p. By contrast, i.v. administration of these doses resulted in no isomeric differences in brain amphetamine, alhough plasma (+)-amphetamine/(-)-amphetamine ratios remained somewhat elevated. After SKF 525-A pretreatment, the i.p. and i.v. routes resulted in similar (+)-amphetamince/(-)-amphetamine concentration ratios. These results suggest that (-)-amphetamine has a higher apparent volume of distribution (Vd) than (+)-amphetamine [Vd for (+)- and (-)-amphetamine, 2.5 mg/kg i.v. = 3.35 and 4.61 liters/kg, respectively; Vd for (+)- and (-)-amphetamine 10 mg/kg i.v. = 2.36 and 4.61 liters/kg, respectively] and that the (-)-isomer may be extracted more efficiently by the liver [plasma clearance (V) for (+)- and (-)-amphetamine 2.5 mg/kg i.v. = 6.91 and 9.09 liters/hr/kg respectively; V for (+)- and (-)-amphetamine 10 mg/kg i.v. = 2.85 and 4.33 liters/hr/kg, respectively] resulting in lower plasma and brain concentrations after i.p. administration.

Amphetamine↗
PubMed1977

The effects of amphetamine isomers on rotarod performance.

The amphetamine isomers impair the rotarod performance of rats in a dose-related manner, with (+)-amphetamine approximately four-times as potent as its (-)-isomer. At a rotation speed of 4 rpm, 60 min after i.p. administration, the TD50 values (mg/kg) were: (+)-amphetamine, 24 (21.9-26.4) and (-)-amphetamine, 96 (76.3-118.4), with the curves not deviating from parallelism. Coadministration of the peripheral cholinesterase inhibitor neostigmine salicylate (0.005 mg/kg) attenuated (+)-amphetamine neurotoxicity [30 (26.4-34.1)]. These results, in conjunction with previously reported effects of the drug on isolated nerve-muscle preparations, suggest that the muscle weakness produced by high doses of amphetamine may result from inhibition of transmission at the neuromuscular junction.

Amphetamines↗
PubMed1977

The effects of chronic administration and withdrawal of (+)-amphetamine on seizure threshold and endogenous catecholamine concentrations and their rates of biosynthesis in mice.

The i.v. pentylenetetrazol seizure threshold was increased by 2.5 mg/kg and decreased by 15 mg/kg of a single (+)-amphetamine dose. After 7 consecutive days of amphetamine administration, tolerance developed to the decrease but not to the increase in seizure threshold. At 12--48 h after the last dose of 2.5 mg/kg seizure threshold was decreased, and at 36--48 h after the last dose of 15 mg/kg seizure threshold was increased. After acute and chronic administration of (+)-amphetamine (2.5 mg/kg) endogenous concentrations of whole brain dopamine (DA) were increased and returned to normal levels during the withdrawal period (12--48 h); endogenous norepinephrine (NE) levels were unchanged by acute and chronic drug treatment and during withdrawal. The rates of DA and NE synthesis were increased by chronic amphetamine administration at 24--48 h after drug withdrawal. An acute dose of (+)-amphetamine (15 mg/kg) decreased endogenous levels of DA and NE; normal levels of DA were detected with chronic drug treatment and during withdrawal, with NE remaining slightly depressed. The rates of synthesis of DA and NE were increased by acute and chronic amphetamine treatment and returned to normal 24--48 h after withdrawal. The rebound reversal in seizure threshold after (+)-amphetamine withdrawal suggests an abstinence syndrome that may be interpreted as evidence for the development of physical dependence to (+)-amphetamine after chronic drug administration.

Animals↗
PubMed1977

Catecholaminergic involvement in the effects of amphetamine isomers on seizure susceptibility.

The (+)-amphetamine (2.5 mg/kg) increase in pentylenetetrazol seizure was abolished by pretreatment with reserpine, alpha-methyltyrosine methyl ester (alpha-MT), FLA-63 or 6-hydroxydopa. All treatments except reserpine antagonized the increase in seizure threshold produced by (-)-amphetamine (4 mg/kg). Only reserpine +alpha-MT antagonized the decrease in seizure threshold produced by (+)-amphetamine (15 mg/kg). These results indicate that amphetamine alterations in PTZ seizure susceptibility are mediated indirectly via the release of newly synthetized and/or granular stores of catecholamines.

Amphetamine↗