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A J Mandell

Publications and source records attributed to A J Mandell.

At least 19 recordsLinked to original sources
PubMed1979

Conformational influences on brain tryptophan hydroxylase by submicromolar calcium: opposite effects of equimolar lithium.

Tryptophan hydroxylase from rat midbrain, EGTA-pretreated and dialyzed, manifested allosteric properties with respect to its substrate tryptophan, cofactor tetrahydrobiopterin, and the calcium ion. Kinetic studies suggest two preferred enzyme conformations in the presence of low concentrations of the cosubstrates: a higher affinity form manifesting hyperbolic substrate kinetics, induced by submicromolar (0.4--0.8 microM) calcium in vitro and cocaine in vivo, and a lower affinity form exaggerating cooperativity with respect to substrate, induced by submicromolar (0.4 to 0.8 microM) lithium in vitro and lithium in vivo. Lithium's effect on serotonin biosynthesis may be due to its antagonism of the positive effector influence of calcium on tryptophan hydroxylase, either as a negative effector or by blocking the calcium site.

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PubMed1978

Fading: a new cytofluorimetric measure quantifying serotonin in the presence of catecholamines at the cellular level in brain.

A new histopharmacological approach to the study of serotonergic neurons is described. Using a computerized microspectrofluorimeter, we demonstrated that a measure of fluorescence fading reliably detects changes in serotonin even in the presence of catecholamines. This "fading measure" was validated with model droplets containing serotonin, norepinephrine or mixtures of the two, and with in vivo studies using pargyline to increase brain serotonin. After various doses of pargyline, a correlation of 0.927 was found between our intraperikaryal fading measure and a standard florimetric measure of serotonin in dissected samples of the raphe. Further experiments were designed to test the feasibility of the cytofluorimetric fading measure for quantifying differential changes in serotonin in intraperikaryal and extraperikaryal regions. Both LSD (75 and 150 microgram/kg) and a low dose of the monoamine oxidase inhibitor pargyline (25 mg/kg) increased intraperikaryal serotonin without affecting extraperikaryal fluorescence. Conversely, the serotonin reuptake inhibitor fluoxetine produced the opposite effect of selectively increasing extraperikaryal serotonin. Another inhibitor of serotonin reuptake, chlorimipramine, which also blocks reuptake of norepinephrine in vivo, markedly increased both intraperikaryal and extraperikaryal serotonin. These results confirm the utility of cytofluorimetric measures of serotonin within raphe cell bodies from untreated rats, and indicate that changes in the intracellular and extracellular concentrations of serotonin can be differentiated.

Animals↗
PubMed1978

Regional and subcellular distribution and some factors in the regulation of reduced pterins in rat brain.

We have studied the regional and subcellular distribution, functional role, and pharmacology of quinoid dihydropterin reductase (QDPR) and endogenous reduced pterins (PH4) subserving tyrosin hydroxylase (TOH) and tryptophan hydroxylase in the rat brain. There is a significant correlation between the regional distribution of PH4 and TOH but not between PH4 and tryptophan hydroxylase or between either TOH or tryptophan hydroxylase and QDPR. This suggests that a major portion of PH4 is associated with the biosynthetic activity of brain catecholaminergic systems. The regional and subcellular distribution of QDPR was inconsistent with a regulatory function for QDPR in monoamine synthesis. In vitro measures of PH4, TOH, and synaptosomal dopamine (DA) and serotonin synthesis in the striate cortex of untreated animals and animals subjected to neurotoxin or electrolytic lesions of the dorsal raphe or substantia nigra exhibit significant covariation of PH4 with synaptosomal DA but not serotonin synthesis and a significant partial correlation of PH4 with DA synthesis. The subcellular distribution of PH4 in the striatum demonstrates an association of PH4 with the biosynthetic function of dopaminergic nerve terminals. Reserpine and d-amphetamine in vivo elicited an increase and decrease, respectively, in striatal PH4 paralleling induced changes in synaptosomal DA synthesis. Other drugs altering central catecholaminergic function did not alter striatal PH4 levels significantly. The data suggest that 1) a major portion of total PH4 (as much as 90% in the striatum) is related to the function of catecholaminergic rather than serotonergic systems, 2) PH4 levels is a determinant of the velocity of DA synthesis and 3) PH4 levels are altered by some psychoactive drugs in association with changes in synaptosomal catecholamine biosynthetic rates.

Animals↗
PubMed1978

The effects of lysergic acid diethylamide and mescaline-derived hallucinogens on sensory-integrative function: tactile startle.

Tactile startle responding by male Sprague-Dawley rats given 60 presentations of air-puff stimuli (37.5 psi) was measured after the intraperitoneal administration of graded doses of hallucinogens and other psychoactive drugs. Among the drugs tested were the indoleamine-derived compounds, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine and psilocin, and the phenylethylamine-derived compounds, mescaline, 2,5-dimethoxy-4-methylamphetamine and a series of active and inactive congeners of 2,5-dimethoxy-4-methylamphetamine. All of the active phenylethylamines increased startle response magnitudes throughout the test session. This pattern of augmented startle suggests that these drugs increase reactivity. However, none of the indoleamine hallucinogens increased startle responding. Of the nonhallucinogenic drugs tested, only apomorphine increased startle responding, while clonidine significantly decreased it, and amphetamine, chlorimipramine, scopolamine and methysergide had no effect. In additional studies with LSD, it was found that LSD increased the response to only the first stimulus when more intense air-puffs were used (50 psi). Furthermore, when the number of stimuli was increased from 60 to 240 (1 hr) so that appreciable habituation was evident in controls, LSD impaired this habituation. Whereas the response magnitudes of the control group decreased by 70% across the session, the responses of LSD-treated rats decreased by only 32%. These results suggest that LSD and phenylethylamine-derived hallucinogens may differ in their effects on tactile startle responding.

Animals↗
PubMed1976

Histologic and enzymatic studies of the mesolimbic and mesostriatal serotonergic pathways.

Selective lesions of the dorsal (B7), median (B8), or lateral (B9) raphe nuclei were made stereotaxically in male rats 4 weeks before sacrifice. The extent of damage to each raphe nucleus was quantified histologically by means of a simplified formaldehyde histochemical method for visualization of serotonin in cryostat sections. A detailed mapping of the distribution of the yellow-fluorescent raphe perikarya provided the basis for quantification. Tryptophan hydroxylase activity was measured in 6 forebrain regions from each animal, and the results were correlated with the per cent damage to each raphe nucleus. Tyrosine hydroxylase was also assayed in 5 of these regions; it was not significantly affected by any of the raphe lesions. Dorsal raphe lesions reduced tryptophan hydroxylase activity in the striatum, thalamus, cortex, and hypothalamus, but not in the septal nuclei or hippocampus. Damage to B8 resulted in decrements in this serotonergic enzyme in the septal nuclei, hippocampus, cortex, and hypothalamus, but not in the striatum or thalamus. Lesions of the scattered B9 cells had no significant effect on enzyme activity in any region examined. These data suggest that the dorsal and median raphe nuclei provide two distinct though perhaps overlapping serotonergic systems innervating different parts of the forebrain: a mesostriatal pathway originating in B7 and a mesolimbic system derived from B8. Behavioral studies on the animals, which are presented in a companion paper, indicated that damage to the median nucleus is responsible for many of the behavioral effects previously reported after combined lesions of both major raphe nuclei.

Animals↗
PubMed1976

Behavioral studies following lesions of the mesolimbic and mesostriatal serotonergic pathways.

The behavior of rats with selective lesions of either the dorsal (B7), median (B8), or lateral (B9) raphe nuclei was compared to that of sham-lesioned controls in a variety of experimental situations. As described previously, the extent of damage to the midbrain raphe nuclei was determined by fluorescence histochemistry, and the tryptophan hydroxylase and tyrosine hydroxylase activities of 6 forebrain regions were measured for each rat. None of the lesions affected tyrosine hydroxylase activity. Lesions of B7, which reduced tryptophan hydroxylase in the striatum, thalamus, cortex, and hypothalamus, had no significant effect on any of the behavioral measures. Lesions of B9, although twice as large, neither reduced forebrain tryptophan hydroxylase significantly nor affected any of the behavioral variables. However, B8 lesions, which reduced hippocampal, septal, cortical, and hypothalamic tryptophan hydroxylase, had behavioral effects similar to those reported after combined raphe lesions parachlorophenylalanine. Median raphe-lesioned rats were hyperactive when placed in a novel environment and throughout the dark phase of the light/dark cycle. With respect to locomotor activity, B8-lesioned rats were also hyper-responsive to amphetamine. When placed in a stabilimeter and subjected to repeated air puff stimuli, rats with B8 lesions exhibited larger startle responses. Furthermore, only B8-lesioned animals perseverated when given two unreinforced trials in a Y-maze. All these histologic, biochemical, and behavioral variables were assessed individually for all 39 animals, and a multivariate correlational analysis incorporating the data of this and the preceding paper is presented here. These experiments suggest that the mesolimbic serotonergic pathway originating in B8 subserves some of the inhibition necessary to dampen behavioral responsivity.

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