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M H Aprison

Publications and source records attributed to M H Aprison.

At least 37 records · Page 2Linked to original sources
PubMed1985

Choline acetyltransferase and glutamate uptake in the nucleus tractus solitarius and dorsal motor nucleus of the vagus: effect of nodose ganglionectomy.

Unilateral removal of the nodose ganglion resulted in a significant decrease in choline acetyltransferase activity in the ipsilateral dorsal motor nucleus of the vagus but was without effect on enzyme activity in the nucleus of the solitary tract. High affinity glutamate uptake in the dorsal motor nucleus of the vagus and along the rostrocaudal extent of the nucleus of the solitary tract was not affected by nodose ganglionectomy.

Animals↗
PubMed1985

Blockade of a 5-hydroxytryptophan-induced animal model of depression with a potent and selective 5-HT2 receptor antagonist (LY53857).

To test the hypothesis that a new potent and selective 5-HT2 receptor antagonist would be an excellent blocker of D,L-5-hydroxytryptophan (5-HTP)-induced response suppression in an animal model of depression, we administered LY53857 60 min prior to 5-HTP injections into rats working on an operant schedule for milk reinforcement. As predicted, LY53857 pretreatment significantly blocked 5-HTP depression (90%) in doses as low as 0.1 mg/kg ip. When the dose of LY58357 was further reduced to 0.025 mg/kg, blockade of 5-HTP-induced depression was still greater than 30%. In doses as high as 5.0 mg/kg, LY53857 alone had no effect on the baseline performance of rats working a VI 1 schedule. Pretreatment with desipramine (2.5 mg/kg), an antidepressant characterized as having major noradrenergic effects, did not significantly block the 5-HTP-induced depression. These data suggest that the 5-HTP-induced depression is mediated by serotonergic mechanisms involving 5-HT2 receptors, as LY53857 is a selective antagonist of these receptors. These data also support the suggestion, based on other published data from this laboratory, that some antidepressants are antagonizing 5-HT2 receptors in our animal model of depression and may also act in a similar manner in depressed patients. Thus, this new drug could be of interest as a possible antidepressant agent of the general type that was proposed earlier by Aprison and Hingtgen (1981).

5-Hydroxytryptophan↗
PubMed1985

Neurochemical studies of the nucleus of the solitary tract, dorsal motor nucleus of the vagus and the hypoglossal nucleus in rat: topographical distribution of glutamate uptake, GABA uptake and glutamic acid decarboxylase activity.

The topographical distribution of glutamate uptake, GABA uptake, and GAD activity was studied in caudal, intermediate and rostral areas of the nucleus of the solitary tract (NTS), dorsal motor nucleus of the vagus (DMN) and the of the solitary tract (NTS), dorsal motor nucleus of the vagus (DMN) and the hypoglossal nucleus (n.XII). Within the NTS and n.XII, all three neurochemical parameters exhibited increasing activity from caudal to rostral regions. The distribution pattern for glutamate uptake within the DMN was qualitatively similar to the other nuclei studied, whereas GABA uptake and GAD activity were found to be homogeneously distributed within the DMN. The NTS also exhibited a medial-lateral heterogeneity for glutamate and GABA uptake, with the medial aspect of this nucleus containing significantly higher uptake than the lateral aspect.

Afferent Pathways↗
PubMed1984

Postsynaptic serotonergic blockade following chronic antidepressive treatment with trazodone in an animal model of depression.

Acute pretreatment with clinically equivalent doses of antidepressive drugs has been observed to block D,L-5-hydroxytryptophan (5-HTP) induced behavioral depression in rats working on a food-reinforced operant schedule. Data from studies designed to distinguish presynaptic from postsynaptic events, indicated that the antidepressants were acting in part as blockers of postsynaptic serotonergic receptors. Using the same 5-HTP model of depression, we studied both the chronic and acute effects of a recently introduced antidepressant, triazolopyridine compound. Rats working for milk reinforcement and exhibiting behavioral depression following administration of 50 mg/kg 5-HTP were pretreated (one hr before 5-HTP) with 1, 2, or 4 mg/kg trazodone with resulting blockade of 5-HTP induced depression of 35, 62 and 70% respectively. Chronic administration of trazodone (2 mg/kg trazodone/day) also resulted in a significant blockade of the 5-HTP effect (75%). Neither 2 mg/kg or 4 mg/kg trazodone was found to potentiate the shorter period of depression following 25 mg/kg 5-HTP. Chronic treatment with the antidepressant drugs, amitriptyline or mianserin also blocked 5-HTP depression. Thus, as in our earlier studies, these data suggest an important postsynaptic mechanism associated with chronic administration of trazodone, amitriptyline and mianserin which could be implicated in the therapeutic effectiveness of these drugs. The potency of trazodone in relation to other antidepressant drugs in our behavioral model of depression paralleled their potency in displacing radioligand binding to 5-HT receptors, and gives additional support for the new hypersensitive postsynaptic serotonin receptor theory of depression.

5-Hydroxytryptophan↗
PubMed1983

Loss of Purkinje cell-associated benzodiazepine receptors spares a high affinity subpopulation: a study with pcd mutant mice.

In order to identify the relative number of benzodiazepine (BZ) receptors in Purkinje and granule cells, the Purkinje cell degeneration (pcd) mutant mouse was used at different ages. In these mice, Purkinje cells have degenerated almost completely by 45-50 days of age. Granule cell loss occurs only later, and is most severe between 180 and 300 days. [3H]Flunitrazepam (FNZ) and [3H]ethyl-carboline-3-carboxylate (beta-CC) were used as ligands. In the 45-50-day-old pcd mice, it was found that there is approximately a 50% decrease in the number of receptors as labeled by [3H]beta-CC or [3H]FNZ, when the binding is expressed as fmol/cerebellum. The binding decreased by approximately 80% in 300-day-old pcd mice (fmol/cerebellum). [3H]FNZ was not displaced by 1 microM RO5-4864, ruling out binding to glial cells. Nonlinear regression analysis of FNZ saturation data provided evidence for two populations of receptors (high and low affinity sites). Only the low-affinity sites were reduced in number at 45 days. [3H]beta-CC saturation data showed, however, only one population of receptors. The total number of receptors (Bmax) was significantly lower for beta-CC than for FNZ in the control mice. It appears that 50% of the total BZ receptors is associated with Purkinje cells. In addition, our data on 300-day-old pcd mutants strongly suggest the existence of granule cell-associated BZ receptors.

Animals↗
PubMed1983

Specific binding of the muscarinic antagonist [3H]quinuclidinyl benzilate is not associated with preganglionic motor neurons in the dorsal motor nucleus of the vagus.

The present study evaluates the binding of [3H]quinuclidinyl benzilate, [3H]QNB, as a measure of cholinergic muscarinic binding in six areas of the rat medulla oblongata associated with the cranial nerves. In an experimental group, the right vagus nerve was severed in the neck in order to determine whether the specific muscarinic binding sites might be located on cells that contribute efferent fibers to the vagus nerve. The level of activity of choline acetyltransferase (ChAT) also was determined in the same six areas. Additional experiments utilizing the retrograde transport of toxic ricin, a 60,000 dalton agglutinin that acts as a potent ribosomal toxin, was carried out to further evaluate localization of specific muscarinic binding in the DMN after destruction of the preganglionic efferent cells. These results support the conclusion that specific binding of the muscarinic antagonist [3H]QNB observed in the DMN of the vagus of the rat is not associated with the large cells that contribute efferent fibers into the vagus nerve. We suggest that the specific cholinergic muscarinic binding is located on interneuronal cell surfaces, on afferent terminals of local circuit neurons, or on afferent terminals of long projection axons which arise from neurons in the brainstem, hypothalamus, or forebrain.

Acetylcholinesterase↗
PubMed1983

Serotonergic changes in specific areas of rat brain associated with activity--stress gastric lesions.

To study serotonergic involvement in the development of gastric lesions following activity wheel stress, three groups of rats (gastric lesions, no gastric lesions, and home--cage controls) were killed following exposure to the experimental procedures. The brains were dissected into eight specific areas and subjected to analyses for serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) using high performance liquid chromatography with EC detection. Lower levels of 5-HT were found in the midbrain, cortex, and hippocampus of rats with gastric lesions compared to either the no lesion group, subjected to shorter periods of activity--stress, or the home--cage control group. Levels of 5-HT and 5-HIAA were elevated in the pons/medulla oblongata of both the lesion and the no lesion groups compared to the home--cage controls. Corticosterone levels in blood were also significantly elevated in the lesion group. These data on serotonin changes in the CNS suggest a possible role for this neurotransmitter in stress-induced gastric pathology.

Animals↗
PubMed1982

Distribution and uptake of glycine, glutamate and gamma-aminobutyric acid in the vagal nuclei and eight other regions of the rat medulla oblongata.

In order to study the central neurochemical control of the vagus nerve, the contents of glycine, GABA, glutamate and five other amino acids have been measured in ten anatomically distinct regions of the rat medulla oblongata. Additionally, the high affinity uptake of glycine, GABA, glutamate, and leucine were measured in the same ten medullary regions. The data support published evidence for glutamatergic and GABAergic transmission in the nucleus of the tractus solitarius (NTS), and glycinergic inhibition in the hypoglossal nucleus. The data also lead to the suggestion that GABA and glutamate may be taken up into glial cells which exist along fiber tracts.

Afferent Pathways↗
PubMed1981

Viscerotopic localization of preganglionic parasympathetic cell bodies of origin of the anterior and posterior subdiaphragmatic vagus nerves.

Utilizing the retrograde HRP transport method, fibers from anterior and posterior subdiaphragmatic branches of the vagus nerve in the rat were traced to their cells of origin in the brainstem. Efferents to the gut supplied by the subdiaphragmatic vagus nerves derive from cell bodies organized in a viscerotopic, spindle-shaped longitudinal cell column throughout the longitudinal extent of the classically described dorsal nucleus of the vagus (DNV) and in regions of nucleus commissuralis (NC), caudal to the DNV. This entire longitudinal group of cells is called the DNV cell column. In the caudal one third of the DNV cell column, the cell bodies were found in the midline and paramedian posterior portion of the NC, and in the anterior portion of the caudal DNV, in a horizontally oriented cluster of cells when viewed in cross section. In the middle one third of the DNV cell column, the cell bodies moved laterally, but still maintained their anterior position in the nucleus. In the rostral one third of the cell column, the cell bodies were located at the lateral margin of the DNV. A few scattered cell bodies extended caudally from the DNV cell column into the dorsal region of lamina X of spinal cord, and reached as far caudal as the C5-C6 segments. The anterior subdiaphragmatic branch of the vagus contained axons whose cell bodies were mainly but not exclusively located in the ipsilateral (left) side of the medulla, while the posterior subdiaphragmatic branch of the vagus contained axons whose cell bodies were found bilaterally in the medulla, with a majority (approx. 60%) located on the ipsilateral (right) side, and approximately 40% located on the contralateral (left) side.

Afferent Pathways↗
PubMed1981

Distribution of choline acetyltransferase, acetylcholinesterase, muscarinic receptor binding, and choline uptake in discrete areas of the rat medulla oblongata.

Quantitative measurements were made of choline acetyltransferase (CAT) activity, acetylcholinesterase (AChE) activity and cholinergic muscarinic receptor binding ([3H]QNB) in eight areas of a cross-section of the rat medulla oblongata. A fourth cholinergic parameter, high-affinity choline uptake, was measured in three groups of these areas. CAT, AChE and [3H]QNB binding were found to be highest in the hypoglossal nucleus and the dorsal motor nucleus of the vagus; the lowest value was in the area which contains the inferior olive and the corticospinal tract. The distribution of AChE and CAT activities varied approximately 7- to 10-fold among the eight regions examined, whereas that of the muscarinic receptor varied only about 4-fold. The Na+-dependent high-affinity choline uptake varied approximately 20-fold from the region with the lowest activity (inferior olivary nucleus and corticospinal tract) to that with the highest activity (tissue areas containing the dorsal motor nucleus, hypoglossal nucleus of the solitary tract and nucleus cuneatus). The four cholinergic parameters are statistically correlated throughout all the areas of the medulla which were studied.

Acetylcholinesterase↗
PubMed1981

Postsynaptic action by four antidepressive drugs in an animal model of depression.

To further test the new hypersensitive postsynaptic serotonin (5-HT) receptor theory of depression bases on or animal model, it was necessary to demonstrate that some of the currently used antidepressive drugs can block D,L-5-hydroxytryptophan (5-HTP) induced depression acting through postsynaptic rather than presynaptic mechanisms. Rats working for milk reinforcement and exhibiting behavioral depression following administration of 5-HTP (IP) were pretreated (1 hour before the 5-HTP injection) with fluoxetine (5 mg/kg IP) or methysergide (5 mg/kg IP) to establish a behavioral basis for distinguishing between pre- and postsynaptic events, respectively. Fluoxetine, a known specific uptake blocker of 5-HT, potentiated the depressive effect of 12.5 mg/kg 5-HTP by 200%. Methysergide, a postsynaptic blocker of 5-HT, almost completely (93%) abolished the depressive effect of 50 mg/kg 5-HTP. Since acute pretreatment with comparable clinical doses of the antidepressive drugs, mianserin, amitriptyline, imipramine, or iprindole, resulted in blockade of the 5-HTP induced depression by 70, 50, 40, and 20% respectively, these drugs can act as antagonists of 5-HT at the postsynaptic serotonin receptor. When these results are viewed in terms of recent data reported from CNS binding studies, the therapeutic effects of some antidepressants may be explained by their postsynaptic rather than presynaptic effects at central serotonergic receptors.

5-Hydroxytryptophan↗
PubMed1981

Redefinition of the location of the dorsal (motor) nucleus of the vagus in the rat.

The rostrocaudal extent of the preganglionic parasympathetics of the vagus nerve (DNV, the dorsal nucleus of the vagus, also called the dorsal motor nucleus of the vagus) was traced using the retrograde horseradish peroxidase (HRP) transport method. Labeled cells were found within, and both rostral and caudal to, the classically-defined DNV. Cell bodies of origin of the preganglionic parasympathetics of the vagus formed a continuous longitudinal, spindle-shaped column extending from an area rostral to the rostralmost border of the inferior olivary nucleus caudally through the nucleus commissuralis (NC) of the lower medulla, and continuing in an attenuated fashion in the dorsal commissural gray (CG) of the cervical spinal cord. The rostral quarter of this cell column consisted of only a few cells lateral to the fourth ventricle in the mid-medulla. The middle one-half of the DNV cell column included the classically-defined dorsal nucleus of the vagus, located dorsolateral to the hypoglossal nucleus and lateral to the fourth ventricle rostrally, and located dorsolateral to the hypoglossal nucleus and the central canal caudally. In the caudal medulla, the caudal quarter of the cell column consisted of cell bodies in the NC. Scattered labeled cell bodies were found in the CG of the spinal cord, extending caudally to the C3--C6 level.

Animals↗
PubMed1981

Determination of the equilibrium dissociation constants and number of glycine binding sites in several areas of the rat central nervous system, using a sodium-independent system.

Parameters affecting the binding of [3H]glycine to membrane fractions isolated from the cerebral cortex, midbrain, cerebellum, medulla oblongata, and spinal cord of the rat were investigated in a Na+-free medium. A [3H]glycine binding assay was established in which the binding was specific, saturable, pH-sensitive, and reversible. Conditions were chosen in an effort to minimize binding to glycine uptake sites. From data on specific [3H]glycine binding Scatchard plots were prepared and the KD and Bmax values were calculated. Two glycine binding sites (high and low affinity) were identified only in the medulla (KD: 44, 211 nM; Bmax: 361, 1076 fmol/mg protein) and spinal cord (KD: 19, 104 nM; Bmax: 105, 486 fmol/mg protein). The ranges of the KD and Bmax values for the other three areas studied were 59 to 144 nM and 882 to 3401 fmol/mg protein, respectively. When the glycine content of each area, expressed as fmol/neuron, was plotted against the respective KD (high affinity), a negative correlation was found (r = --0.90; p less than 0.05). A similar negative correlation was found between the glycine content and Bmax (r = --0.88; p less than 0.05). Hill plots indicated a slope of essentially 1.0 for all areas. GABA, taurine, strychnine, diazepam, bicuculline, and imipramine had little or no effect on [3H]glycine binding.

Amino Acids↗
PubMed1980

Pre- and postsynaptic serotonergic manipulations in an animal model of depression.

Rats working on a food-reinforced operant schedule and exhibiting behavioral depression following administration of D,L-5-hydroxytryptophan (5-HTP) were pretreated with one of three drugs: methysergide, fluoxetine, or amitriptyline. The former two drugs were used to establish a basis for distinguishing between pre- and postsynaptic events. We found that methysergide, a known postsynaptic blocker of serotonin, almost completely abolished the depressive effect of 5-HTP, whereas fluoxetine, a known specific uptake blocker of serotonin, potentiated the depressive effect of the 5-hydroxytryptamine (5-HT) precursor. Amitriptyline, one of the commonly prescribed antidepressive drugs, reduced the behavioral depression following 5-HTP by approximately 50%. These data indicate that amitriptyline can act as an antagonist of 5-HT at the postsynaptic receptor. The results of this study, as well as those recently reported from CNS membrane binding studies, suggest that the therapeutic effects of some antidepressive drugs may be explained by their postsynaptic rather than presynaptic properties at central serotonergic receptors. Thus, these studies support the hypothesis that some types of human depression may be primarily due to an excess of free 5-HT acting at postsynaptic receptors.

5-Hydroxytryptophan↗