Date of Award
Doctor of Philosophy in Pharmaceutical Sciences
Pharmacy and Toxicology
Investigation of the biological basis of anxiety is hampered by the lack of an appropriate animal model for research purposes. There are no known drugs that cause anxiety in laboratory animals. Pentylenetetrazol (PTZ) produces intense anxiety in human volunteers (Rodin, 1958; Rodin and Calhoun, 1970). Therefore, it was the major objective of this dissertation to test the hypothesis that the discriminative stimulus produced by PTZ in the rat was related to its anxiogenic action in man. It was also an objective to suggest the neurochemical basis for the discriminative stimulus property of PTZ through appropriate drug interactions. In an operant procedure of lever pressing on a FR 10 schedule of food reinforcement, male hooded rats were trained to respond with a lever on one side of a food cup 15 min following a 20 mg/kg PTZ injection and to respond with a lever on the alternate side 15 min following a 1 ml/kg saline injection. All of the rats learned this discrimination reliably in a mean of 30 training sessions. The discriminative stimulus produced by PTZ was dose- and time-dependent. The anxiogenic stimulants cocaine, R05-3663 and strychnine generalized to the PTZ discriminative stimulus whereas yohimbine partially generalized.
The discriminative stimulus produced by cocaine, R05-3663 and yohimbine was antagonized by the anxiolytic drug, diazepam. The discriminative stimulus produced by cocaine was not antagonized by haloperidol. The non-anxiogenic psychomotor stimulants d-amphetamine, methylphenidate or caffeine did not generalize to the PTZ discriminative stimulus. Bemegride was the only convulsant drug tested that generalized to the PTZ discriminative stimulus. Picrotoxin and 3-mercaptopropionic partially, but not significantly, generalized to the PTZ discriminative stimulus but bicuculline, garnma-hydroxybutyrate or nicotine did not generalize. The PTZ discriminative stimulus was dose-dependently antagonized by benzodiazepine-type, barbiturate-type, propanediol carbamate-type anxiolytics as well as valproic acid. Tolerance did not develop to antagonism of the PTZ of discriminative stimulus by diazepam or chlordiazepoxide. The discriminative stimulus produced by PTZ was not antagonized by an anticonvulsant or other central nervous system depressants that are not anxiolytics. There was a significant correlation between the potency of drugs effective in antagonizing the PTZ discriminative stimulus and their effective doses in a conflict test of anxiety as well as their clinically effective doses. The GABA antagonist ROS-3663 generalized to the PTZ discriminative stimulus whereas picrotoxin and 3-mercaptopropionic acid partially generalized. The PTZ discriminative stimulus was antagonized by the GABA mimetic, valproic acid. The glycine antagonist, strychnine, generalized to the PTZ discriminative stimulus. Neither acetylcholine nor serotonin agonists or antagonists generalized to or antagonized the PTZ discriminative stimulus. The catecholamine agonist, cocaine, generalized to the PTZ discriminative stimulus whereas yohimbine and apomorphine partially generalized. However, neither a-amphetamine nor methylphenidate generalized to the PTZ discriminative stimulus and catecholamine receptor antagonists did not antagonize the PTZ discriminative stimulus. Generalization to the PTZ discriminative stimulus by anxiogenic drugs and lack of generalization by non-anxiogenic psychomotor stimulants or convulsants as well as antagonism of the PTZ discriminative stimulus by anxiolytics but not non-anxiolytic anticonvulsant or depressants supports the hypothesis that the discriminative stimulus produced by PTZ in the rat is related to its anxiogenic action in man. Generalization to the PTZ discriminative stimulus by GABA antagonists and antagonism by GABA agonists but lack of generalization to or antagonism by drugs affecting other neurotransmitter systems suggests that the PTZ discriminative stimulus might be •mediated through decreased GABA neuronal activity.
Shearman, Gary Terence, "THE ANXIOMIMETIC PROPERTIES OF PENTYLENETETRAZOL IN THE RAT" (1980). Open Access Dissertations. Paper 165.