Thesis (Ph. D.)--University of Nevada, Reno, 2008. / "August, 2008." Includes bibliographical references (leaves 18-25). Online version available on the World Wide Web.

Thesis (Ph. D.)--University of Wisconsin, 1967. / Typescript. Vita. Includes bibliographical references.

Thesis (Ph.D.)--York University, 2009. Graduate Programme in Psychology. / Typescript. Includes bibliographical references (leaves 140-181). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:NR51681

The rat pineal gland provides a convenient model for investigating nor adrenergic receptor neurotransmission and the effects of various drugs on these processes in health and disease. The effect of a variety of antidepressant drugs on rat pineal gland function following acute and chronic administration is described. Antidepressants from several different classes increase melatonin synthesis in rat pineal gland cultures when administered acutely. This effect appears to be mediated by noradrenaline acting on postsynaptic β-adrenoceptors. Activation of these receptors, in turn, activates the enzyme serotonin N-acetyltransferase via a cyclic adenosine monophosphate (cAMP) second messenger system. Serotonin N-acetyltransferase catalyses the rate-limiting conversion of serotonin to melatonin. Blockade of postsynaptic β-adrenoceptors prevents the antidepressant-induced increase in melatonin synthesis. The possibility that atypical antidepressants as well as those that selectively inhibit serotonin reuptake may increase melatonin synthesis via a β-adrenoceptor mechanism is discussed. In contrast, however, antidepressants from different classes have variable effects on rat pineal gland function when administered repeatedly. Chronic treatment with antidepressants that selectively inhibit noradrenaline reuptake appear to down-regulate the β-adrenoceptor system while, simultaneously, increasing melatonin output. Atypical antidepressants and those that selectively inhibit serotonin reuptake appear to be without these effects when administered repeatedly. The pineal gland of normal rats may therefore not represent a suitable model for evaluating the biochemical effects of chronic antidepressant treatment. In an attempt to investigatc pineal gland function in rats with "model depression" , antidepressants were administered to chronically reserpinized rats. Treatment with reserpine produced an increase in the density of pineal β-adrenoceptors. In addition, pineal cyclic AMP accumulation and N-acetyltransferase activity were increased in reserpinized rats following exogenous catecholamine stimulation. Reserpine, by depleting intraneuronal catecholamine stores, prevented the nocturnal induction of N-acetyltransferase activity and reduced the synthesis of melatonin in pineal gland cultures. A variety of antidepressants, irrespective of their acute pharmacological actions, reversed these effects when administered chronically to resepinized rats. Acute antidepressant administration was not associated with a reversal of the reserpine-induced effects. These findings provide additional evidence against the hypothesis that antidepressant drugs act by reducing noradrenergic neurotransmission and casts doubt on the importance of β-adrenoceptor down-regulation in the mechanism of antidepressant action. The possibility that the pineal gland of the reserpinized rat may represent an alternative model for evaluating antidepressant therapies is discussed.

The effect of tricyclic antidepressants (TADs) on a variety of pineal functions was assessed. TADs affected the uptake of ³H-5HT into bovine pineal slices within a particular concentration range of these drugs, DESI, CLOMI and IMI appeared to inhibit uptake slightly, within a limited concentration range. Surprisingly, DESI appeared to be a relatively potent 5HT uptake inhibitor. The 5-HT re-uptake system in the pineal probably differes from that in brain tissue. TADs had a marked effect on the metabolism of ³H-5HT in the rat pineal, in an organ culture system, MEL and N-acetylserotonin synthesis increased for the first 11 days and thereafter a slight decrease was observed. HTOH and HIAA also showed an initial increase followed by a slight decrease in synthesis. The synthesis of MTOH and MIAA was decreased. The possibility that TADs could affect HIOMT and SNAT synthesis and thereby change the metabolic pattern of 5-HT was investigated. TADs appeared to stimulate SNAT initially and thereafter a slight decrease from peak activity was observed. This is probably due to stimulation followed by development of subsensitivity of β-receptors, HIOMT activity also appeared to be affected by TADs. The existence of two types of HIOMT is suggested. There is a possibility that these changes in the metabolism of 5-HT could be implicated in the mechanism of action of TADs. / KMBT_363 / Adobe Acrobat 9.53 Paper Capture Plug-in

No description available.

The purpose of this study was to investigate whether biological variables could predict how older adults would respond to different types of treatment for depression. Fifty-six adults over the age of sixty-five, diagnosed with major depression (DSM III criteria) were assigned to one of four treatment conditions: group Cognitive Behavior Therapy with alprazolam or placebo medications, and minimal support therapy with alprazolam or placebo medication. Before and after treatment, REM latency and REM density were measured by polysomnograph in the sleep laboratory and the Dexamethasone Suppression Test (DST) was administered. Depression was measured by weekly by the Hamilton Depression rating Scale and the Beck Depression Inventory. Subjects presented with normal (i.e. nondepressed) values on REM latency and REM density. Thirty five percent of subjects were DST nonsuppressors, a similar percentage to that found in other studies of depressed subjects, but mean DST for the whole group was below the selected cutoff of 4 mcg/dl. The expected correlations among the biological variables and between these variables and baseline depression levels were not found. It was concluded, therefore, that depression in this group of subjects was not characterized by biological abnormalities. Multiple regression analyses of baseline variables and depression scores at mid and end of treatment and at followup indicated that initial depression levels and DST predicted later depression levels for subjects who received Cognitive Behavior Therapy, regardless of medication assignment. Low baseline DST levels were associated with good response to psychotherapy, confirming the findings of previous studies. Sleep variables were not predictive of response to treatment at any time point.

Rigid analogues of the tricyclic antidepressant imipramine and the phenothiazine tranquilizer promazine were designed and their syntheses were attempted. Conformational rigidity was expected to reduce the side effects of these drugs by limiting their binding to multiple receptors. Ortho-directed metalation followed by acylation provided synthetic intermediates for the formation of the desired pentacyclic congeners. The known dilithiation of phenothiazine and iminodibenzyl and n-butyllithium, followed by acylation with dimethylformamide, gave carboxaldehydes at the 1 and 4 positions respectively. Ortho-lithiated nicotinamides were acylated by these aldehydes exclusively at the 4 position to provide the key intermediate alcohol amides. Difficulties in amide hydrolysis are discussed. Catalytic hydrogenation over palladium-on-carbon in refluxing acetic acid yielded carboxylic acids, apparently via the gamma-lactones formed in situ. The lactones could not be isolated easily due to instability to oxidation. Pentacyclic lactams were formed by dehydration, and borane was used to reduce the carbonyl function. Only the iminodibenzyl lactam was reduced, and problems encountered in subsequent pyridine ring reduction are discussed. Cis and trans ring fusion isomers were identified by ¹³C nmr. Attempted one-pot synthesis of this pentacycle and a regioisomer by double acylation of 4,5-dilithioiminodibenzyl with 2,3-pyridinedicarboxylic anhydride, and 3,4-pyridinedicarboxylic anhydride failed. Mechanistic considerations are discussed regarding regiochemistry and reactivity of the nitrogen and carbon anions involved. Ortho-lithiation of 3-bromopyridine to form 3-pyridyne in the presence of the preformed N-lithioiminodibenzyl-4-carboxaldehyde was unsuccessful in providing a pentacyclic benzonaphthyridinobenzazepine. The resulting 2- and 4-lithiated 3-bromopyridines were trapped by the aldehyde instead. Both hydroxymethylbromopyridines were identified by their proton coupling patterns in the pyridine ring. These compounds are discussed as potential precursors to pentacyclic benzazepinopyridobenzazepines. Several other attempts at forming benzonaphthyridinobenzazepines and naphthyridinophenothiazines were unsuccessful. Intermediates were obtained by carbon acylation of the dilithiated iminodibenzyl and phenothiazine with arecoline esters, arecaidine, and pyridine-3-carboxaldehyde. Dibenzylic alcohol reduction is discussed, as is its labile oxidation. None of the resulting pyridylmethyl heterocycles could be cyclized.

No description available.

This report describes the synthesis, chemical derivation, and pharmacological and behavioral characterization of several unique classes of opioid receptor modulators. In chapter one, a general overview of opioid receptor history, signaling biology, and therapeutic applications is provided. Also reviewed are several topics of high current interest, including, biased signaling, opioid receptor splice variants/heteromers, and applications of opioid modulators in the treatment of mood disorders. This introduction aims to frame the work that follows, and emphasize to the reader the untapped potential of the opioid receptor system, particularly in the realm of therapeutics development. Chapter two discusses the development of several new C-H activation reactions to provide rapid access to the core molecular scaffold of alkaloids from Tabernanthe iboga. The methods described permit the expedient construction of structurally diverse ibogamine analogs via a modular approach. In chapter three, this work is extended by applying the new reaction methodologies to explore a novel class of oxaibogamine analogs, which act as opioid receptor agonists and antagonists. The thorough exploration of structure-activity relationships within this skeleton is described, along with the pharmacological characterization of several select analogs as biased agonists at both the kappa- and mu-opioid receptors. This section concludes with a discussion of potential therapeutic applications for the synthesized compounds as new analgesics and antidepressants, and future goals and plans for this structural class. In chapter four, the isolation and pharmacological study of several alkaloids of Mitragyna speciosa is presented. Mitragynine, the primary natural alkaloid in this plant, is isolated, along with several naturally occurring analogs, and the modulatory activity of these compounds at the opioid receptors is fully characterized. Further, preliminary results are presented suggesting activity of these alkaloids at several other classes of central nervous system targets, including serotonin and adrenergic receptors. Also discussed are the preparations of semi-synthetic and fully synthetic mitragynine derivatives, including a total synthesis of mitragynine itself. These novel analogs are applied to explore key structure-activity relationships in this unusual opioid-active scaffold. Again, potential applications of Mitragyna alkaloid analogs in the treatment of pain and depression are discussed. In the final chapter, I describe our discovery that tianeptine, a clinically used atypical antidepressant of previously unknown mechanism of action, acts as an agonist of both the mu- and delta-opioid receptors. Activation of the mu-opioid receptor is thus proposed as the initial molecular-level event responsible for eliciting the beneficial therapeutic effects of this agent. This hypothesis is integrated with the large body of literature describing this compound, and mechanistic theories connecting the opioid activity of tianeptine to previous observations are described, with a particular emphasis on indirect modulation of glutamate signaling. Behavioral studies in mice employing both genetic knockout and pharmacological inhibition are then used to confirm the involvement of the opioid receptors in tianeptine's mechanism of action. Also described are thorough explorations of opioid structure-activity relationships within the tianeptine scaffold, and the design and synthesis of novel analogs having improved pharmacokinetic properties. It is hoped that these derivatives may one day serve as new therapeutic options for patients suffering from treatment-resistant depression.