Date of Award

1978

Degree Type

Thesis

Degree Name

Master of Science in Pharmacology and Toxicology

Specialization

Pharmacology

Department

Pharmacology and Toxicology

Abstract

The biogenic amine hypothesis of affective disorders ascribes a functional depletion of neurotransmitters within critical regions of the brain as either the cause or, at the very least, a concomitancy of the depressive syndrome. Much indirect evidence has accumulated to suggest that the therapeutic effect of tricyclic antidepressants (TCA's) is mediated by their ability to block the re-uptake of physiologically released neurotransmitter leaving more neurotransmitter available within the synapse to interact with the post-synaptic receptor, thereby correcting the posited functional depletion. The evidence upon which the proposed mechanism of TCA's therapeutic activity is based is largely indirect. Most of the evidence comes from in-vitro studies of the ability of tricyclics to block neurotransmitter uptake into either brain slices, minces or preparations of pinched-off nerve endings (synaptosomes). The therapeutic response however cannot be demonstrated upon acute administration of these drugs and clinically effective activity is usually not observed until after several weeks of chemotherapy. The uptake inhibitory characteristics which have been demonstrated in-vitro, therefore, cannot explain the latency to the therapeutic effect. A time-course for the effect of protriptyline administration upon n3-l-norepinephrine (E3-l-NE) uptake into hypothalamic crude synaptosomal homogenate (CSH) was determined after acute, sub-acute and chronic treatment. In addition, the ability of a number of TCA's to block the uptake of three biogenic amines, the catecholamines, norepinephrine and dopamine, and the indoleamine, serotonin, was assessed using a CSH in-vitro test system. The results support the biogenic amine hypothesis as well as the proposed mechanism of action of TCA's. Uptake blockade could be demonstrated after acute and chronic administration but not after sub-acute administration. An attempt to describe some of the characteristic effects of individual TCA's as well as effects common to the class of drugs was approached on the basis of predominant neurotransmitter influences.

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