Indole(ethyl)amine N-methyltransferase in the brain.

An enzyme which N-methylates various indole(ethyl)amine substrates was isolated from brain, separated from the pituitary and the pineal glands. It appeared localized in the supernatant and synaptosomal areas after discontinuous sucrose-gradient ultracentrifugation. This is the first demonstration of the enzyme in brain.

Narcotic drugs: effects on the serotonin biosynthetic systems of the brain.

The effects of short- and long-term administration of morphine on the activity of two measurable forms of rat brain tryptophan hydroxylase were studied. Morphine administration produced an immediate decrease and a longterm increase in the nerve ending (particulate) enzyme activity but did not change the cell body (soluble) enzyme activity. Cocaine administration demnonstrated a short-term decrcease in measurable nerve eniding enzyme activity that was due to the inhibition of the high affinity uptake (the Michaelis constant, K(m) is 10-(5) molar) of trytophan, the serotonin precursor. Cocaine did not aflect the low affinity uptake K(m) = 10-(5) molar) of tryptophan. Both the uptake of the precursor and the enizymiie activity appeared to be drug-sensitive regullatory processes in the biosynthlesis of serotonin.

Short- and long-term lithium administration: effects on the brain's serotonergic biosynthetic systems.

Short-term treatment with lithium chloride stimulates the uptake of tryptophan and its conversion to serotonin by striate synaptosomes. Preincubation of striate synaptosomes with L-tryptophan and in vivo administration of L-tryptophan appear to act in a similar manner. Midbrain tryptophan hydroxylase activity is reduced in temporal continuity with the lithium-induced activation of tryptophan uptake and conversion. By 10 days, conversion of tryptophan to serotonin in nerve endings becomes a joint function of the maintained increased uptake of tryptophan and a decreased level of tryptophan hydroxylase activity in nerve endings. The occurrence of this delayed alteration corresponds in time to the previously described axoplasmic flow rate for tryptophan hydroxylase.

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.

Corticosteroid responses to limbic stimulation in man: localization of stimulus sites.

Corticosteroids in human plasma and urine increase after amygdala stimulation, and plasma corticosteroids decrease after hippocampus stimulation. Five subjects underwent unilateral temporal lobectomy, and histopathologic localization of electrode sites was attempted. Localization was successful for six sites: three in basolateral amygdala and three in hippocampus.

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.

Dreaming sleep in man: changes in urine volume and osmolality.

Epochs of dreaming sleep, as measured by rapid eye movements, consistently correlated with biphasic change in urine volume and osmolality in catheterized human subjects. Marked decrease in volumne and increase in oslnolality were followed by a hypotonic diuresis.

Ultra-slow frequency bands reflecting potential coherence between neocortical brain regions.

Recent studies of electromagnetic ultra-slow waves (⩽0.1Hz) have suggested that they play a role in the integration of otherwise disassociated brain regions supporting vital functions (Ackermann and Borbely, 1997; Picchioni et al., 2010; Knyazev, 2012; Le Bon et al., 2012). We emphasize this spectral domain in probing sensor coherence issues raised by these studies using Hilbert phase coherences in the human MEG. In addition, we ask: will temporal-spatial phase coherence in regional brain oscillations obtained from the ultraslow spectral bands of multi-channel magnetoencephalograms (MEG) differentiate resting, "task-free" MEG records of normal control and schizophrenic subjects? The goal of the study is a comparison of the relative persistence of intra-regional phase locking values (PLVs), among 10, region-defined, sensors in examined in the resting multichannel, MEG records as a function of spectral frequency bands and diagnostic category. The following comparison of Hilbert-transform-engendered relative phases of each designated spectral band was made using their pair-wise PLVs. This indicated the proportion of shared cycle time in which the phase relations between the index location and reference leads were maintained. Leave one out, bootstrapping of the PLVs via a support vector machine (SVM), classified clinical status with 97.3% accuracy. It was generally the case that spectral bands ⩽1.0Hz generated the highest values of the PLVs and discriminated best between control and patient populations. We conclude that PLV analysis of the oscillatory patterns of MEG recordings in the ultraslow frequency bands suggest their functional significance in intra-regional signal coherence and provide a higher rate of classification of patients and normal subjects than the other spectral domains examined.

Fibroblast growth factor stabilizes ribonucleic acid and regulates differentiated functions in a multipeptide-secreting neuroendocrine cell line.

A clonal cell line (44-2C) which synthesizes and secretes somatostatin, neurotensin, calcitonin (CT), and CT gene-related peptide and transiently expresses c-fos was used to characterize the mechanism of action of basic fibroblast growth factor (bFGF). bFGF had two modes of action: 1) short term incubation of 44-2C cells with bFGF increased the cellular content of neurotensin, somatostatin, and CT; and 2) bFGF enhanced the response of the cells to rat hypothalamic GRF-mediated cAMP efflux. The long term action of bFGF was manifested by the permissive effect of the molecule. bFGF had a sustained effect on RNA synthesis, and pretreatment with bFGF for 24 h altered the time course of response of the cells to rat GRF. In this cell line the cellular action of bFGF was not mediated via protein kinase-C action. bFGF was not mitogenic in 44-2C cells. bFGF stimulated uridine incorporation without affecting thymidine incorporation. Results obtained with actinomycin-D and alpha-amanitin suggest that the above effects of bFGF can be correlated with increased RNA stability produced by bFGF.

Induction of c-fos, calcitonin gene expression, and acidic fibroblast growth factor production in a multipeptide-secreting neuroendocrine cell line.

The multipeptide-secreting 44-2C cell line maintains differentiated function when grown in a serum-free, growth factor- and hormone-deprived milieu. The cells continue to synthesize and secrete calcitonin (CT), CT gene-related peptide, neurotensin, and somatostatin and respond to cellular secretagogues such as GRF and acidic and basic fibroblast growth factor. We designed experiments to ascertain the functional role(s) of cellular factors involved in the maintenance of the differentiated state in 44-2C cells. We report here the phenotypic transformation that occurs in these cells in the course of adjustment to the serum-free state. We also show the differential increase in CT-specific mRNA, the transient induction of c-fos, and the characterization of biologically active acidic fibroblast growth factor.

Dynamical entropy is conserved during cocaine-induced changes in fetal rat motor patterns.

Our previous studies demonstrated that the intra-cisternal (IC) administration of cocaine to fetal rats increased motor activity and decreased responsiveness to perioral stimulation. One explanation for these observations comes from the behavioral pharmacology of stimulant drugs: increased motor activity is often associated with a decrease in its variety. Previous power spectral transformation of this data suggests an alternative explanation: cocaine-induced hyperactivity fixates a new behavioral pattern with complexity equal to that of saline controls. We explore these possibilities using statistical techniques derived from studies of nonlinear dynamical systems, examining patterns of the total motor activity of the individual fetus as counts per 5 s interval on either gestational day E20 or E21 for 20 min following IC injections of saline, 2.5 or 10 mg/kg of cocaine. The results are consistent with a state in which increased spontaneous activity is associated with the emergence of a new dynamical pattern which conserves entropy and provides experimental support for a fundamental conservation-variational relation, hT approximately equal to lambda 1 x DR, that has been proven for abstract models of chaotic dynamical systems. A multivariate analysis of variance (MANOVA) followed by appropriate analyses of variance (ANOVAs) and pairwise comparisons revealed that, whereas cocaine induced increases in the total amount of motor activity, the rate of increase in the variety of new sequences in activity counts over time did not change with treatment and age conditions. This invariant is quantified by an absence of change in topological entropy, delta hT = 0. The analyses also showed that, in order to maintain hT values, compensatory changes took place in the leading Lyapounov characteristic exponent, lambda 1 (the distance between sequential values 'stretched' along the increasing amplitudes of the variations) such that delta lambda 1 > 0, and the correlation dimension, DR (the hierarchical range of possible values, 'complicated clustering') was reduced, so that delta DR < 0. Our findings are consistent with the idea that the association between cocaine-induced increases in activity and decreases in adaptive response are not due to the dynamical entropy loss of decreased behavioral variety, but are rather the result of competitive interference by a drug-induced, equally complex, new pattern of spontaneous behavior.

Sonication, calcium, and peptides have systematic effects on the nonlinear dynamics of tyrosine hydroxylase activity.

Sonication, dialysis, calcium, and peptides have systematic effects on the nonlinear dynamics of tyrosine hydroxylase (TOH). Under standard assay conditions TOH shows a high amplitude fluctuation in catalytic output across time that is eliminated either by sonication or by dialysis. This coherent dynamic is restored with the addition to the dialyzed preparation of either calcium in micromolar concentrations or certain peptides (SOM, MSH), but not others (CCK, TRH).

Effects of amphetamine on hemispheric asymmetry and regional distribution of tetrahydrobiopterin in rat brain.

Hemispheric asymmetry and regional distributions of tetrahydrobiopterin under the influence of d-amphetamine has been examined using the high performance liquid chromatography method with fluorescence detection. The results indicate that there is a natural imbalance of tetrahydrobiopterin concentration between the two striata in normal rats and amphetamine has a depressing effect on this asymmetry. In addition to confirming the previous finding based on a double-enzyme assay method that amphetamine decreased striatal tetrahydrobiopterin level, the present results suggest that amphetamine influences tetrahydrobiopterin in central serotonergic, dopaminergic as well as noradrenergic systems in a consistent way.

TRH influences the pterin cofactor- and time-dependent instabilities of rat raphe tryptophan hydroxylase activity assessed under far-from-equilibrium conditions.

Systematic effects on the dynamics of rat raphé tryptophan hydroxylase were observed in the presence of thyrotropin-releasing hormone under the far-from-equilibrium conditions of a kinetic scattering paradigm. The peptide reduced the amplitude of velocity fluctuations across fine-grained increases in cofactor or time and induced rare, high-amplitude irregularities suggesting phase transitions at relatively long wavelengths. Respectively, these two effects of the neuropeptide resemble the statistical changes observed in the same enzyme system in the presence of the lithium ion and the tricyclic antidepressant chlorimipramine under comparable assay conditions. Neither the subtleties of control dynamics nor their responses to the peptide were demonstrable under the saturating conditions of Michaelis-Menten or allosteric kinetics. These findings have possible implications for neurotransmitter regulation in view of the most current information about dynamical interactions among proteins, peptides, and ion ligands in aqueous environment.

The influence of neuropeptides on amine synthesis: Cholecystokinin-8 and neurotensin reduce striatal tyrosine hydroxylase activity.

Cholecystokinin-8 and neurotensin, neuropeptides found in relatively high concentrations in some catcholaminergic neurons and/or terminal or cell body areas, reduced native and polyanion-activated rat striatal tyrosine hydroxylase activity, but not that of the enzyme activated by phosphorylating conditions. Substance P, ?(3)-melanocyte-stimulating hormone, [d-ala(2), d-leu(5)]-enkephalin, or thyrotropin-releasing hormone had no effect on the native enzyme or on either activated form. Cholecystokinin-8 and neurotensin may interact with polyanion-activated or membrane bound-activated tyrosine hydroxylase to modulate its activity.

A kinetic scattering approach to the non-linear instabilities of rat brain tyrosine hydroxylase preparations at several levels of tetrahydrobiopterin cofactor demonstrates evolutionary behavior characteristic of global dynamical systems.

Statistical patterns from the time-dependent fluctuations in kinetic scattering of a complex rat brain tyrosine hydroxylating system reveal near periodic, quasi-periodic, and chaotic regimes that alternate in a non-linear manner across linear changes in tetrahydrobiopterin cofactor concentrations, a phenomenon characteristic of the initial condition- and parameter-sensitive evolutionary behavior of global dynamical systems.

Aromatic alkylamine N-acetyltransferase in regional tissues in developing rat brain.

The specific activities of N-acetyltransferase (EC 2.3.1.5) were examined in several regions of rat brain of both sexes at various times after birth. The enzyme activity increased with development in whole brain, hippocampus, midbrain, cerebellum and the remainder of brain, peaking around 36 days of age. Lineweaver-Burk plots indicated linear kinetics for N-acetyltransferase in dialyzed supernatant and ammonium sulfate precipitates from the newborn rat brain, whereas enzyme preparation further purified by Bio Gel yielded biphasic kinetics. These data remain consistent with the possibility that there are two forms of N-acetyltransferase in rat brain even from birth.