Date of Award

1982

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Specialization

Pharmacy and Toxicology

Department

Pharmacology and Toxicology

First Advisor

Al Swonger

Abstract

Reasons for the observed lag-time for clinical efficacy of the tricyclic antidepressant drug, protriptyline, have been investigated. Our results demonstrate that chronic protriptyline administration results in several compensatory neural mechanisms: (1) changes in endogeneous cytoplasmic norepinephrine levels, (2) changes in norepinephrine turnover rate/recovery rate following the last dose in a chronic series of test drug administrations and (3) adaptations of the pre-synaptic receptor. The time course for these adaptive changes parallel the time required for the onset of their clinical effectiveness.

We propose that acutely the action of the tricyclics on norepinephrine re-uptake is largely negated by compensatory adjustments in turnover rate of the neurotransmitter; but with chronic administration, adaptations in pre-synaptic alpha-receptors occur. This phenomena in turn reduces the extent to which the norepinephrine neurons can offset or compensate for the blockade of norepinephrine re-uptake. Specifically, pre-synaptic alpha-receptors become hyposensitive, and receptor tolerance develops; not to the direct action of the tricyclic drug on neurotransmitter re-uptake, but to the compensatory neural adjustments which offset the action of the acute tricyclic administration and delay their clinical efficacy.

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.