Date of Award

1963

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Specialization

Pharmacology

Department

Pharmacology

First Advisor

John J. De Feo

Abstract

The General Adaptation Syndrome (G.A.S.) was characterized for chronic forced restraint stress in normal and reserpinized (1 mg/kg, I.P.) male albino rats. This was accomplished by analyzing the interrelationships among brain neurohumoral levels (serotonin (5-HT) and norepinephrine (NE)), serum corticosterone (KS) levels, and various organ weights such as thymus, testes, pituitaries, and adrenals.

Reserpine was observed to prevent normal rats from adapting to this stress (mortality rate was 50%) possibly via inanition. It was suggested that the overall non-adaptive effects produced could ultimately be due to the ability of reserpine to induce a chemical sympathectomy. Thus, by depleting the A.N.S. of accessible NE, an animal would be unable to respond to a severe change in environment.

Control animals demonstrated both behavioral and neurochemical adaptation in response to this stress. Initial excitation associated with restraint was related to increased brain 5-HT levels and decreased brain NE levels. As the experiment progressed, stress animals became less excitable and easier to handle which was also associated with the return of both brain amines to normal levels.

In contrast, reserpinized animals subjected to chronic restraint stress became progressively more excitable and difficult to handle as the experiment proceeded. This behavior can best be described by C.N.S, depression associated with extreme hypersensitivity to handling. This progressive change in behavior was correlated with the progressive depletion of brain NE levels, since brain 5-HT remained at relatively normal levels. The progressive increase in excitation thus appeared to be dependent on NE depletion or release.

Reserpine (1 mg/kg, I.P.) induced a progressive depletion of brain NE while it did not do so with 5-HT. This was interpreted as indicating that 5-HT synthesis was equivalent to its release. In contrast 0.5 mg/kg, I.P., of reserpine was found to produce a progressive depletion of 5-HT as well as NE. On the other hand, higher doses of reserpine inhibited the serotonin depletion effects produced by the 1 mg/kg. In fact, some animals demonstrated levels above normal following the chronio administration of reserpine (2 mg/kg, I.P.). Therefore, a poss1ble serotonin-feedback mechanism involving the free and bound concentrations of this amine may be indicated.

Increased brain 5-HT levels twenty-four hours after the thirty-second dose of reserpine was also suggestive of an increased synthesis rate. Behavioral excitability was also found to characterize these increased serotonin levels in all experiments conducted. Norepinephrine, on the other hand, did not demonstrate any observable changes in the rate of synthesis under the influence of reserpine.

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