Effects of long-term reserpine treatment on brain tyrosine hydroxylase and behavioral activity

Treatment of rats with reserpine (for 8 or 9 days) produced a temporally related increase in behavioral activity and in tyrosine hydroxylase activity in the midbrain. Weight loss resulting from such treatment was not sufficient, by itself, to account for either the behavioral or enzymatic changes. The results support the role of catecholamines in behavioral arousal.     

Thyroid state: effects on pre- and postsynaptic central noradrenergic mechanisms

For hypothyroid rats, spontaneous motor activity was less than that in matched normal controls, and the specific activity of tyrosine hydroxylase in the midbrain was significantly greater than that in controls. Rats made hyperthyroid with thyroxine became hyperactive and showed increased sensitivity to the behaviorally activating effects of norepinephrine administered intraventricularly. In hyperthyroid rats, the specific activity of tyrosine hydroxylase in the midbrain remained within the normal range. These results are consonant with studies that suggested both receptor "tuning" and feedback regulation of activity of enzymes involved in biosynthesis of presynaptic neurotransmitter as methods of regulation of the central catecholamine synapse. These results may also help explain the reported potentiation by thyroid hormone of the antidepressant effects of imipramine.     

Neural systems responding to degrees of uncertainty in human decision-making

Much is known about how people make decisions under varying levels of probability (risk). Less is known about the neural basis of decision-making when probabilities are uncertain because of missing information (ambiguity). In decision theory, ambiguity about probabilities should not affect choices. Using functional brain imaging, we show that the level of ambiguity in choices correlates positively with activation in the amygdala and orbitofrontal cortex, and negatively with a striatal system. Moreover, striatal activity correlates positively with expected reward. Neurological subjects with orbitofrontal lesions were insensitive to the level of ambiguity and risk in behavioral choices. These data suggest a general neural circuit responding to degrees of uncertainty, contrary to decision theory.     

Cyclic adenosine monophosphate: selective increase in caudate nucleus after administration of L-dopa

Treatment with the dopamine precursor L-dopa produced a significant accumulation of adenosine 3',5'-monophosphate (cyclic AMP) in the caudate nucleus of the rat. In contrast, there was no change in the amount of cyclic AMP in the cerebellum. Accumulation of cyclic AMP in the caudate nucleus after administration of L-dopa was prevented by prior treatment with the decarboxylase inhibitor RO 4-4602. These observations and those in other laboratories support the assumption that dopamine formed from L-dopa selectively activates striatal adenylate cyclase. The in vivo activation of adenylate cyclase after treatment with L-dopa may be a useful model for studying neurological and psychiatric disorders that are thought to involve the dopaminergic system of the brain.     

Lysergic acid diethylamide: sensitive neuronal units in the midbrain raphe

Units in areas of the midbrain rich in neurons containing serotonin respond to parenteral injections of d-lysergic acid diethylamide by a reversible cessation of spontaneous activity. The dose required is at or below threshold for gross behavioral effects. An inhibition of neurons containing serotonin after administration of d-lysergic acid diethylamide could account for the decreased metabolism of serotonin produced by this drug.     

Regulation of phosphodiesterase synthesis: requirement for cyclic adenosine monophosphate-dependent protein kinase

Endogenous cyclic adenosine monophosphate (AMP) and its dibutyryl derivative increase cyclic AMP phosphodiesterase activity in cultured lymphoma cells. This effect is prevented by cycloheximide. A variant population of cells deficient in cyclic AMP-dependent protein kinase contains lower basal phosphodiesterase activity, which cannot be induced by cyclic AMP.     

Involvement of adenosine 3',5'-monophosphate in the activation of tyrosine hydroxylase elicited by drugs

Immediately after the injection of reserpine (16 micromoles per kilogram, intraperitoneally), aminophylline (200 micromoles per kilogram, intraperitoneally), and carbamylcholine (8.2 micromoles per kilogram, intraperitoneally), the concentration of adenosine 3',5'-monophosphate in adrenal medulla of rats is increased severalfold. The three drugs also cause a delayed increase of medullary tyrosine hydroxylase activity. Our results are consistent with the view that an increase of medullary adenosine 3',5'-monophosphate concentration is involved in the drug-induced increase of tyrosine hydroxylase activity in adrenal medulla. Experiments with tyramine (130 micromoles per kilogram, intraperitoneally) suggest that the increase of tyrosine hydroxylase activity and of adenosine 3',5'-monophosphate concentrations is independent of an increase in adrenal catecholamine turnover rate.     

Cyclic nucleotide phosphodiesterase: high activity in a mammalian photoreceptor

Purified outer segments of bovine rods exhibit phosphodiesterase activity against adenosine and guanosine cyclic 3',5'-monophosphates (cyclic AMP and cyclic GMP). The enzyme hydrolyzed cyclic GMP more rapidly than cyclic AMP at low substrate concentrations. The presence of high phosphodiesterase activity in this highly specialized organelle suggests that this enzyme may function in control of cyclic nucleotide concentration during visual excitation or adaptation.     

Protein kinase translocation as an early event in the hormonal control of uterine contraction

beta-Adrenergic stimulation with isoproterenol inhibits contractility, increases cyclic adenosine monophosphate (AMP) concentration, decreases the concentration of unsaturated cyclic AMP receptor sites, and increases cyclic AMP-independent kinase in the uterus of ovariectomized rats. The total soluble kinase activity is reduced. The protein kinase activity lost from the cytosol was translocated to the microsomal fraction mostly in a cyclic AMP-independent form, suggesting a particulate substrate for the activated enzyme.     

Corticosterone regulation of tryptophan hydroxylase in midbrain of the rat

The tryptophan hydroxylase activity in the rat midbrain decreases after adrenalectomy and is restored by treatment with corticosterone. Cycloheximide, adminiistered intracisternally, prevents the restoration of the enzyme activity by corticosterone. Cycloheximide administration to adrenalectomized rats resutlts in a further decrease in the enzyme activity. an indication that the enzyme has a rapid turnover even in the absence of corticosterone.     

Substance P and somatostatin regulate sympathetic noradrenergic function

Peptidergic-noradrenergic interactions were examined in explants of rat sympathetic superior cervical ganglia and in cultures of dissociated cells. The putative peptide transmitters substance P and somatostatin each increased the activity of the catecholamine-synthesizing enzyme tyrosine hydroxylase after 1 week of exposure in culture. Maximal increases occurred at 10(-7) molar for each peptide, and either increasing or decreasing the concentration reduced the effects. Similar increases in tyrosine hydroxylase were produced by a metabolically stable agonist of substance P, while a substance P antagonist prevented the effects of the agonist. The data suggest that the increased tyrosine hydroxylase activity was mediated by peptide interaction with specific substance P receptors and that peptides may modulate sympathetic catecholaminergic function.     

Multiple daily amphetamine administration: behavioral and neurochemical alterations

In rats, multiple daily amphetamine injections (2.5 milligrams per kilogram of body weight, injected subcutaneously every 4 hours for 5 days) resulted in a progressive augmentation in response, characterized by a more rapid onset and an increased magnitude of stereotypy. By contrast, offset times of both the stereotypy and the poststereotypy hyperactivity periods were markedly shortened. When the animals were retested with the same dose of amphetamine 8 days after the long-term treatment was discontinued, the time of offset of the stereotypy and hyperactivity phases had recovered to values found with short-term amphetamine treatment, whereas the more rapid onset of stereotypy persisted. Brain monoamine and amphetamine concentrations and tyrosine hydroxylase activity were determined in comparably treated rats at times corresponding to the behavioral observations. The behavioral data indicate that enhanced responsiveness to amphetamine following its repeated administration may contribute to the development of amphetamine psychosis.     

Catecholamine and dibutyryl cyclic AMP effects on myosin adenosine triphosphatase in cultured rat heart cells

Catecholamines and dibutyryl adenosine 3', 5'-monophosphate (dibutyryl cyclic AMP) increase the activity of myosin adenosine triphosphatase in cultured rat heart cells. Dichloroisoproterenol, an inhibitor of the beta receptor of the catecholamines, inhibits the action of the catecholamines but not of cyclic AMP.     

Septal tryptophan-5-hydroxylase: divergent response to raphe lesions and parachlorophenylalanine

A soluble form of tryptophan-5-hydroxylase activity was found to be present in areas rich in serotonergic terminals (colliculi, hippocampus, septal area, and remaining telencephalon) as well as in brainstem, an area rich in cell bodies. The enzymatic activity in all brain regions, except the septal area, was inhibited to varying degrees following administration of parachlorophenylalanine. Destruction of the raphe nuclei in the midbrain led to a large and comparable decrease in both serotonin content and tryptophan hydroxylase activity of the hippocampus. In contrast, these lesions did not significantly affect the enzymatic activity of the septal area although the serotonin content was decreased by 72 percent. These findings suggest that the major portion of the tryptophan hydroxylase activity of the septal area is uniquely different from that found in other telencephalic areas in that it is not localized in serotonergic nerve terminals nor is it inhibited by parachlorophenylalanine.     

Adenosine 3',5'-monophosphate waves in Dictyostelium discoideum: a demonstration by isotope dilution--fluorography

The distribution of adenosine 3',5'-monophosphate (cyclic AMP) in fields of aggregating amoebae of Dictyostelium discoideum was examined by a novel isotope dilution-fluorographic technique. Cellular cyclic AMP was visualized by its competition with exogenous 3H-labeled cyclic AMP for high-affinity binding sites on protein kinase immobilized on a Millipore filter used to blot the monolayer. The cyclic AMP was distributed in spiral or concentric circular wave patterns which centered on the foci of the aggregations. These patterns were correlated with those of cell shape change that propagate through the monolayers: cells in regions of high concentrations of cyclic AMP were elongated (presumably moving up a cyclic AMP gradient), whereas those in regions of low cyclic AMP concentrations were randomly directed. The highest cyclic AMP concentrations were about 10(-6)M. The widths of the regions of elevated cyclic AMP were about 0.3 to 1 millimeter which, assuming a wave velocity of 300 micrometers per minute, suggests that a cell signals for about 1 to 3 minutes. These observations support the hypothesis that the aggregation process in Dictyostelium is mediated by the periodic relay of cyclic AMP signals and suggest a simple scheme for the dynamics of the aggregation process.     

Adenosine 3'5'-monophosphate: inhibition of complement-mediated cell lysis

An increase in adenosine 3',5'-monophosphate (cyclic AMP) in rat mast cells, achieved by stimulating the cells with prostaglandin E(1), by preventing cyclic AMP breakdown with aminophylline, or by adding exogenous dibutyryl cyclic AMP, prevented complement-mediated cytolysis as assessed by both histamine release and vital dye exclusion. Dibutyryl cyclic AMP also suppressed water-induced osmotic lysis.     

Oscillation of cyclic adenosine monophosphate concentration during the myocardial contraction cycle

The concentration of adenosine 3',5'-monophosphate (cyclic AMP) rises and falls during each myocardial contraction cycle. Peak concentrations of cyclic AMP precede peak development of systolic tension. Epinephrine alters the normal oscillation in myocardial cyclic AMP and increases both diastolic and systolic concentrations of the cyclic nucleotide. These transient changes in myocardial cyclic AMP indicate a potential role for cyclic AMP as a beat-to-beat regulator of myocardial contractility.     

Adrenal tyrosine hydroxylase: compensatory increase in activity after chemical sympathectomy

Destruction of peripheral sympathetic nerve endings with 6-hydroxydopamine causes a disappearance of cardiac tyrosine hydroxylase, accompanied by a twofold increase in adrenal tyrosine hydroxylase and a small increase in phenyl-ethanolanine-N-methyl transferase. No change in adrenal catecholamine content occurs under these conditions.     

Growth inhibition by adenosine 3',5-monophosphate derivatives does not require 3',5' phosphodiester linkage

Analogs of adenosine 3',5'-monophosphate (cyclic AMP) inhibit the growth of cultured cell lines. The effects of 8-bromo- and N6-butyryl-substituted analogs of cyclic and noncyclic AMP on six cell lines were examined and were equally inhibitory. Variant cell lines with altered cyclic AMP-dependent protein kinase were more resistant to both cyclic and noncyclic nucleotides. We conclude that growth inhibition by analogs of cyclic AMP (i) does not require a 3',5' phosphodiester bond and (ii) may be mediated by a pathway involving endogenous cyclic AMP.     

Growth arrest and morphological change of human breast cancer cells by dibutyryl cyclic AMP and L-arginine

The growth in vitro of human breast cancer cells, line MCF-7, was inhibited by a daily supplement of L-arginine (1 milligram per milliliter). Arginine acted synergistically with dibutyryl adenosine 3',5'-monophosphate (cyclic AMP) (10(-6) molar) to enhance the growth inhibitory effect: the cell replication ceased completely within 2 days after treatment. The growth arrest accompanied a change in cell morphology and was preceded by increases in the cellular concentration of cyclic AMP, adenylate cyclase, and type II cyclic AMP-dependent protein kinase activities as well as a decrease of estrogen binding activity. The results suggest that growth of human breast cancer cells is subject to cyclic AMP-mediated regulation and that arginine may play a specific role in this process.