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M H Aprison

Publications and source records attributed to M H Aprison.

At least 19 recordsLinked to original sources
PubMed1992

Muscimol and N,N-dimethylmuscimol: from a GABA agonist to a glycine antagonist.

By using molecular modeling methods, a molecular mechanism was identified which can explain how the incorporation of two methyl groups in place of two hydrogen atoms on the terminal nitrogen atom of muscimol can not only convert this potent agonist at GABAnergic receptors to an inactive molecule at these receptors, but also can convert this new derivative to an antagonist of glycine at glycinergic receptors. This insight into the molecular mechanism operative in the conversion of physiological function provides a basis for understanding how a single molecule may be able to act at both the GABA- and glycine-inhibitory receptors.

Chemical Phenomena↗
PubMed1991

Molecular modeling of the weak glycine antagonist iso-THAO.

When compared to strychnine, a potent glycine antagonist, iso-THAO, a bicyclic 5-isoxazolol zwitterion, has been reported to be a weak glycine antagonist. Since there are so few glycine antagonists, and there is a striking lack of similarity between the structures of these two antagonists, iso-THAO was studied using current molecular modeling techniques and quantum mechanical calculations in order to compare the structural features and charge distributions of iso-THAO with glycine. The results of this study confirm our earlier hypothesis that an antagonist to inhibitory neurotransmitters like glycine and GABA has at least three binding sites to the natural receptor that are very similar to three such binding sites in the transmitter and its agonists, and each antagonist has an additional negative binding site. We speculate that the latter negative binding site can attach to the top of the chloride channel within the receptor complex. The diminished inhibitory activity of iso-THAO is attributed to its poor structural congruence with the three atom attachment sites used by glycine at its natural recognition site.

Azepines↗
PubMed1991

Differential effect of 5-hydroxytryptophan on approach and avoidance behavior in rats.

The current hypersensitive postsynaptic serotonin receptor theory of depression developed and expanded by Aprison and Hingtgen was based on an animal model of behavior in which food-reinforced approach behavior was suppressed following 5-hydroxytryptophan (5-HTP) administration. In this paper, data are presented to show that when the same animal is taught to emit, alternatingly, approach and avoidance behavior, and the serotonin precursor, 5-HTP, is administered, only the approach behavior is affected. Adult, male Wistar rats were trained on Sidman avoidance (RS20:SS10) and food-reinforced approach (VI 1) schedules. During the first part of this study, rats received separately 50-min sessions for approach and avoidance responding. For the second part, both schedules were given in the same experimental chamber. In the third part, 10-min alternating approach and avoidance components were combined in the same 50-min sessions. Significant behavioral suppression of approach responding was observed following administration of L-5-HTP (50 mg/kg IP), as well as after D,L-5-HTP (25 and 50 mg/kg IP) in a dose-dependent relationship, whereas no significant effect was seen for Sidman avoidance responding during this type of session. These results support the role of serotonin in food-reinforced approach behavior and suggest that suppression of Sidman avoidance behavior may be mediated by other neurotransmitter systems.

5-Hydroxytryptophan↗
PubMed1989

On the GABAA receptor: a molecular modeling approach.

Bicuculline methobromide, a complex alkaloid, antagonizes in some unknown manner the action of GABA, an important inhibitory transmitter in the CNS. To help understand the mechanism of this antagonism we have employed molecular modeling techniques to assess the similarity and difference between this antagonist and GABA plus four direct GABA agonists. Topological and electronic charge congruence between these five molecules was examined in great detail. It was found that each of the five molecules has three clearly defined atoms that serve as attachment points at the GABAA receptor site. It is hypothesized that an additional negatively charged atom on bicuculline serves as an additional point of attachment that blocks the nearby chloride ion channel. The model presented offers an explanation of why muscimol acts as a better agonist than GABA as well as rationalizing why (+)-bicuculline acts as an antagonist but (-)-bicuculline does not.

Bicuculline↗
PubMed1989

Activity-wheel stress and serotonergic hypersensitivity in rats.

Adult male Wistar rats were subjected to activity wheel stress: unlimited access to an activity wheel for up to twelve days and food for 30 to 60 min each day. Each treated rat was paired with a control, the latter being housed in home cages and given sufficient food to maintain a weight similar to the stressed partner. All rats were previously trained on a variable interval schedule for milk reinforcement. When the activity of the stressed rat increased rapidly then decreased suddenly, the pair was decapitated for biochemical analysis. Levels of the serotonin metabolite, 5-hydroxyindoleacetic acid, decreased by 50%, and the Bmax for ketanserin binding increased by 19% in frontal cortical homogenates from the stressed rats when compared to controls. These data support the concept that stress increases the sensitivity of central serotonin receptors.

Animals↗
PubMed1989

Tetrahydroaminoacridine (THA) as a pharmacological probe in Alzheimer's disease (AD) and other neurodegenerative disorders.

Unlike other potent enhancers of cholinergic function in the central nervous system (CNS), THA appears to sustain improved function in many moderately impaired AD patients when the Summers procedure is followed. THA has a complex pharmacology. In addition to its enhancement of cholinergic transmission a hydroxylated metabolite might chelate aluminum (A1), thereby removing multiple toxicological constraints on CNS function. This mobilized THA metabolite-A1 complex might either be re-distributed to less sensitive sites or removed from the CNS across the blood-brain barrier (BBB). Since the known presence of A1 in AD brain is not necessarily causal, a positivistic approach to research and treatment with THA and its metabolites might serve to clarify this difficult and challenging problem.

Aluminum↗
PubMed1988

Response suppression in rats after bilateral microinjection of 5-hydroxytryptophan in lateral hypothalamus.

Studies using the 5-hydroxytryptophan (5-HTP) animal model of depression have led to the development of the hypersensitive postsynaptic serotonin receptor theory of depression. To demonstrate more clearly that the 5-HTP-induced suppression is a centrally mediated phenomenon, rats were implanted with bilateral cannulae in the lateral hypothalamus and received microinjections of D,L-5-HTP (100-500 ng) 15 min after the start of a VI operant session (milk reinforcement). Significant decreases in responding were observed that were comparable to those obtained after a systemic injection of 50 mg/kg D,L-5-HTP. Rats receiving a microinjection of 5-HTP in the posterior hypothalamus did not exhibit a behavioral effect. Rats working on shock-avoidance schedules did not demonstrate response suppression following microinjection of 5-HTP into the lateral hypothalamus, which is the same result as that following systemic 5-HTP administration. These data support the important role previously assigned to central 5-HT mechanisms in the 5-HTP animal model of depression.

5-Hydroxytryptophan↗
PubMed1987

Identification of a glycine-like fragment on the strychnine molecule.

Strychnine, a complex molecule, antagonizes in some unknown manner the action of glycine, an important inhibitory neurotransmitter in the spinal cord and brainstem of many vertebrates. To help understand the mechanism of this antagonism, we have employed modern computational methods to assess the similarities between these seemingly different molecules. An exhaustive comparison of topological and electronic features of both molecules was made. We have successfully located a glycine-like fragment in the strychnine molecule that, when compared to glycine, exhibits both topological and electronic charge congruence. The successful location of this glycine-like fragment allows us to speculate how the large strychnine molecule assumes its role as an antagonist against the inhibitory action of glycine, the simplest amino acid.

Animals↗
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

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↗
PubMed1977

A rapid column chromatographic procedure for the routine measurement of taurine in plasma of normals and depressed patients.

A rapid method has been developed for the routine measurement of taurine in plasma. A preliminary clean-up step has made it possible to assay multiple samples in a relatively short period of time using the excellent sensitivity and specificity of the analytical column of the automatic amino acid analyzer. The speed and specificity of the method permits its use for the routine measurement of taurine in blood samples. Employing this method, a value of 45+/-4nmol taurine per ml platelet free plasma (mean+/-S.E.M.) was obtained for normal healthy adults. Analysis of plasma from depressed patients who are free of drugs as well as from depressed patients under treatment with drugs gave values of 29+/-2 and 25+/-3 nmol taurine per ml platelet free plasma (mean+/-S.E.M.), respectively.

Adult↗