Date of Award


Degree Type


Degree Name

Doctor of Philosophy in Pharmaceutical Sciences


Pharmacy and Toxicology


Pharmacology and Toxicology

First Advisor

Harbans Lal


The present investigation was undertaken to demonstrate the comparisons and contrasts of the conditional stimuli's (CS's) actions with those of morphine in morphine withdrawn rats. The study shows that specific stimuli altered behavioral and physiological withdrawal signs such as: hypothermia, shakes, ptosis, piloerection, writhing and aggression. Also, one stimulus was able to effect two biochemical measures (blood glucose and striatal homovanillic acid) similar to the action of morphine.

Rats were given two equally spaced injections of morphine sulfate paired with different stimuli (bell, drug, oil of anise, saccharin). The stimuli were paired with an injection for 15-25 days. Twenty-four hours after the last morphine injection the appropriate stimulus was presented.

The rats learned to increase their body temperature, reduce wet shakes, increase ptosis, reduce writhing and reduce aggressive responses following the presentation of oil of anise. The bell stimulus only increased temperature. The gustatory stimulus increased temperature and the drug stimuli had no effect on withdrawal signs. The changes observed were specific only to animals that had the respective stimuli paired with morphine prior to challenge treatment. The duration of the CS in the oil of anise study was important, the onset required a time period of greater than 2 min but no more than 30 min for the maximal effect. When naïve animals were exposed to the stimuli, no changes were observed either behaviorally or physiologically. Those animals receiving random CS or no CS during addiction demonstrated no change in observed withdrawal signs when presented the CS 24 hr or 48 hr after the last morphine injection.

In the presence of naloxone, a pure narcotic antagonist, oil of anise-morphine paired animals receiving the CS, 24 hr after the last morphine-CS pairing exhibited no change in withdrawal signs which previously had been changed by the CS. This data implies, indirectly, the release of a morphine like substance in the production of the CS effects.

In addition to the behavioral and physiological measure brought under stimulus control, two biochemical measures (blood glucose and striatal homovanillic acid) were specifically increased by the CS (oil of anise) in a manner similar to that seen by morphine alone, therefore showing that the conditional responses of morphine addiction are not just behavioral but also involve biochemical systems.

These data indicate that the changes resulting from morphine presentation during withdrawal can be classically conditioned. The responses are of three types - behavioral, biochemical and physiological.



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