Pairs of female rhesus monkeys were given either 0.5 mg radioactive pentazocine/kg intramuscularly or 1.5 mg radioactive pentazocine/kg orally and killed at intervals up to two hours. Plasma and cerebral tissue were analyzed for pentazocine and metabolites and other tissues for total radioactivity. Pentazocine was the only radioactive compound found in cerebral tissue from intramuscularly dosed animals and was always an order of magnitude higher in concentration than was plasma pentazocine. Cerebral and plasma pentazocine concentrations in orally dosed monkeys were one to two orders of magnitude lower than those in intramuscularly dosed monkeys. It is concluded that pentazocine is metabolized by the monkey as rapidly as it is absorbed.
Rat myocardial cells in vitro were irradiated with a laser microbeam in order to more fully define the nature of beating (“pacemaker”) and non-beating (“non-pacemaker”) cells. Cells were observed for several hours prior to their association into two-cell groups. Irradiation was performed on those two-cell groups where one of the two cells was a non-beater prior to association with a contracting cell. In 80% of the cases where the cell that was killed was the non-beater, the remaining cell (the beater) continued to contract normally. In 40% of the cases where the killed cell was the “beater” the non-beater continued to contract. These results suggest that cells classified as non-beaters prior to association with a beater, are capable of contracting on their own after the association with a beating cell is eliminated. It is concluded that the non-beating state is not immutable.
The brain possesses an independent, intrinsic renin-angiotensin system. A highly significant negative correlation between brain iso-renin and brain tissue water, sodium, potassium, calcium and magnesium has been found, suggesting that the locally formed angiotensin may be involved in cellular water and electrolyte balance, and possibly affects other metabolic activities, such as the metabolism of neurotransmitter substances.
The effect of acute and chronic lithium administration on the pressor response to norepinephrine and tyramine in anesthetized and conscious dogs was compared. In anesthetized dogs, acute lithium (50 mg/kg i.p.) administration caused a significant potentiation of the pressor response to norepinephrine but had no effect on tyramine-induced response. Following chronic administration of lithium (600 mg/day, 7–10 days) pressor response to both sympathomimetic agents was markedly decreased. In contrast, in conscious dogs, acute or chronic lithium administration failed to modify the pressor response to either agent. These latter results are at variance to those reported in man. Differences in species and methodology may account for this discrepancy. Results are discussed in light of known effects of lithium on biogenic amines. The serum lithium concentrations in both series of experiments were within the therapeutic range found to be beneficial in the treatment of affective disorders.
Aspirin has been tested intranasally and orally against nasal congestion produced in ferrets by infection with an influenza virus. When applied intranasally, concentrations as low as 0.001 percent showed decongestant activity. A single dose given after disease was well-established provided a significant effect for at least 7 hours. Intranasal administration to uninfected ferrets produced no change in nasal patency.
Water-deprived rats learned in one trial to avoid fluids whose tastes were paired with an intraperitoneal injection of a potent hashish extract. Aversions of similar strength were conditioned to different novel tastes on successive pairing sessions in the same animals, suggesting that the aversive effects of the drug are not a function solely of the novelty of the drugged state. Pretreatment with an inhibitor of drug-metabolizing hepatic enzyme systems greatly reduced the strength of hashish-induced learned taste aversions; thus the metabolites of cannabis underlie its noxious effects on the molecular level.
Plasma prolactin levels in the rat are elevated by reserpine treatment. This effect has generally been attributed to the inhibition of the monoaminergic component of regulation of secretion of prolactin inhibiting factor (PIF). In this study we report that ether stress which produces prolactin release in normal rats was equally effective in stimulating prolactin release in reserpine treated animals whose initial baseline prolactin levels were elevated. These results indicate that the ether stress induced release of prolactin is not due to inhibition of the secretion of PIF, and are compatible with the view that a prolactin releasing substance mediates this acute secretory response.
The quantitative histochemical distribution of GAD activity and GABA content in rat olfactory bulb is consistent with the hypothesis that granule cell inhibition is mediated by GABA. The data also indicate that GABA mediated inhibition should be considered in future investigations involving periglomerular cells.
High and low affinity uptake systems for GABA and glutamate are detectable in crude mitochondrial and synaptosomal fractions from adult rat brains, in 0.4 mm thick slices from newborn brains and in 0.1 × 0.1 × 2 mm prisms from adult brains. The high affinity system is not detectable in 0.4 mm thick slices from adult brains, being probably masked by the predominant uptake due to the low affinity transport system. It is suggested that the bulk of the low affinity uptake is due to non-synaptosomal structures and is destroyed during the preparation of 0.1 × 0.1 × 2 mm prisms and of subcellular fractions. The effects of the geometry of the slices in the determination of the results obtained is discussed.
Dibutyryl cyclic adenosine 3′,5′-monophosphate (DBcAMP), 25 mg/kg, administered intraperitoneally 25 minutes prior to testing produced a significant decrease in spontaneous locomotor activity (SLMA) to 58 percent of control and in exploratory behavior to 64 percent of control but failed to alter rotarod performance of mice. DBcAMP did not decrease activity when mice were pretreated with the nucleotide 24 hours prior to its subsequent administration. The results of time-response studies of DBcAMP and SLMA showed that the effects were present as early as 2 minutes after administration and persisted for approximately 90 minutes. Dose-response experiments showed a significant decrease in SLMA with 10 mg/kg and an 86 percent decrease with 75 mg/kg. The results suggest that DBcAMP acts centrally to alter several behavioral patterns in mice and that tolerance rapidly develops to its effects.
Pretreatment with desmethylimipramine (DMI), 2.5 mg/kg intravenously, abolished the hypotensive action of intravenous clonidine [2-(2,6 dichlorophenyl) amino-2-imidazoline hydrochloride] 30 μg/kg in unanaesthetised normotensive rabbits. The hypotensive action of intracisternal clonidine 1 μg/kg was reduced (mean arterial pressure fall 37.3 ± 2.39 mm Hg in controls; 10.2 ± 2.67 mm Hg after DMI). The magnitude of the acute pressor rise following intravenous noradrenaline was increased after DMI (dose ratio control: DMI pretreated 1:4.3). These results indicate that the hypotensive effect of both intravenous and intracisternal clonidine is reduced by a dose of DMI which inhibits neuronal uptake of noradrenaline.
Superfused helical strips of canine anterior mesenteric arteries relaxed in approximately 12% of the preparations when challenged with vasoconstrictor agents such as serotonin, norepinephrine, barium chloride and KCl. The muscle fibers in most of these preparations were longitudinally oriented.
The water content and its distribution, and the electrolyte content, were determined in the medulla oblongata of normal and renal hypertensive rats. The results showed that in renal hypertensive rats the water content, the intracellular water, the inulin and sucrose spaces, and the sodium content are increased without modifications in the potassium and chloride contents. Some explanations of these facts are discussed.
The uptake of [U-14C] glycine and unlabelled glycine into synaptosomes isolated from the telencephalon and spinal cord was studied. During the first 3 minutes, the rate of [U-14C] glycine (8 × 10−7M) taken up by synaptosome preparations (P2) from the spinal cord and telencephalon were estimated to be 0.100 and 0.0243 nmoles/mg protein/min, respectively. The addition of either 10−5M ouabain or 10−3M DNP significantly inhibited the accumulation of [U-14C] glycine. Approximately 85% of the radioactivity taken up by the incubated P2 fraction was found in the subfraction of P2 containing synaptosomes. A net accumulation of unlabelled glycine was observed when the crude synaptosomal fraction (P2) was incubated at 37°C in the presence of 0.0375, 0.075 and 0.15 mM glycine. In preparations from the telencephalon and spinal cord, this uptake of unlabelled glycine appeared to occur against a large concentration gradient. The rate of uptake was 2 to 6 times greater in preparations from the spinal cord than in similar preparations from the telencephalon.
Previous experiments have shown that lethal mechanical head injury decreases lung compliance in monkeys by 50% in the absence of any attendant gross lung pathology of edema; that this compliance decrease can be prevented by pretreatment with symphatholytic agents but not with the airway dilator isoproterenol or atropine; that these changes are absent from saline pressure-volume curve determinations and are associated with changes in the alveolar surfactants. The present experiments were carried out as a further investigation of the possible involvement of the sympathetics in the regulation of lung compliance. Stimulation of the pulmonary sympathetics by electrodes attached to the stellate ganglia in 10 cats pretreated with isoproterenol resulted in a statistically significant 28% decrease in the dynamic lung compliance without altering gross lung appearance or lung weight/body weight ratio from that of shamoperated controls.
The effects of sub-analgetic and analgetic doses of morphine (5–20 mg/kg) on the metabolism of intravenously administered [14C]-tyrosine (200 uCi/kg) in the mouse brain were investigated. A significantly increased conversion of [14C]-tyrosine to the [14C]-catecholamines was observed only at an analgetic dose of morphine. Furthermore, morphine increased the specific activity of brain [14C]-tyrosine and this effect was blocked by naloxone, a morphine antagonist.
The interactions of ouabain with noradrenaline, phentolamine, α-methylmetatyrosine and (+)-amphetamine indicate that the hypothermia produced by small doses of ouabain injected into the cerebral ventricles of the conscious mouse does not primarily involve an interference with noradrenergic systems within the brain. However, a direct action on thermoregulation, including a multiple interference with amine function, is possible.
2-Amino-7-hydroxytetralin has sleep effects in rats like mescaline and D-LSD, and it showed cross-tolerance with mescaline, as did D-LSD. These properties had been predicted by total valence electron calculations.
Two new adrenergic beta-receptor antagonists, H 93/26 and H 87/07, were compared with propranolol, alprenolol and practolol in some in vivo studies in the cat and guinea pig. H 93/26, H 87/07 and practolol inhibited the heart rate and contractile force responses to isoprenaline in considerably lower doses than were required to block the vasodilator and bronchodilator effects of isoprenaline. Propranolol or alprenolol, on the other hand, inhibited the studied responses to isoprenaline at about the same doses. In reserpinized cats H 87/07, practolol and alprenolol elicited a moderate increase of heart rate and contractile force due to beta-receptor stimulation. H 93/26 and propranolol were devoid of this property.
