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Dissertation
The effect of serotonin 5-HT2 receptor antagonists on classical conditioning of the rabbit nictitating membrane
Doctor of Philosophy (Ph.D.), Allegheny University of the Health Sciences
Jun 1997
DOI:
https://doi.org/10.17918/00008698
Abstract
Psychedelics such as D-lysergic acid diethylamide (LSD), which act as agonists at 5-hydroxytryptamine2 (5-HT2) receptors, significantly accelerate the rate of learning in classical conditioning of the rabbit's nictitating membrane (NM) response. However, the effects of 5-HT2 receptor antagonists have not been extensively studied in this paradigm. The goal of this study was to characterize the effects of 5-HT2 receptor antagonists on NM response conditioning and to examine the behavioral mechanisms by which they produce their effects. Since both the 5-HT2A and 5-HT2C receptor subtypes have been implicated as potential targets for psychedelic drug action, antagonists with different affinities for these sites were used. Ritanserin, a fairly selective antagonist for both 5-HT2A and 5-HT2C receptors, impaired CR acquisition, increased the threshold for responding to the tone CS and reduced the magnitude of the UR without altering the threshold for eliciting URs. Ritanserin also blocked the ability of LSD to enhance the rate of CR acquisition to both tone and light CSs, but did so at doses that, by themselves, impaired CR acquisition. Thus, physiologic antagonism could not be ruled out. However, these would be the anticipated results if ritanserin was acting as an inverse agonist or antagonizing a tonic level of endogenous serotonergic activity. In dose response studies, ritanserin and the selective 5-HT2A receptor antagonist, MDL-11,939, significantly decreased the rate of learning in a dose dependent manner. LY-53,857, an antagonist with reportedly greater affinity for the 5-HT2C receptor had no significant effect on learning. Control experiments indicated that ritanserin, MDL-11,939 and LY-53,857 had no effect on baseline responding or responding to nonreinforced tones. However, both ritanserin and MDL-11,939 (but not LY-53,857) significantly reduced the magnitude of URs on US alone trials. To examine further the effects of these drugs on motor function, dose response studies were carried out using six 5-HT2 receptor antagonists to examine drug effects on both the US threshold for eliciting URs and on the amplitude of the elicited UR. Ritanserin, MDL-11,939 and mianserin significantly reduced UR magnitude while LY-53,857, ketanserin and BOL had no significant effect. However, none of the 5-HT2 antagonists changed US threshold. Altogether, these studies suggest that many 5-HT2 receptor antagonists impair associative learning by impairing the performance of both the CR and UR. These findings are consistent with theories suggesting serotonin probably acts as a modulator in both motor and sensory systems.
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Details
- Title
- The effect of serotonin 5-HT2 receptor antagonists on classical conditioning of the rabbit nictitating membrane
- Creators
- Scott Welsh
- Contributors
- John A. Harvey (Advisor) - Drexel University, Allegheny University of the Health Sciences (1996-1998)
- Awarding Institution
- Allegheny University of the Health Sciences
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Allegheny University of the Health Sciences; Philadelphia, Pennsylvania
- Number of pages
- xi, 104 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Pharmacology [Historical]; Allegheny University of the Health Sciences (1996-1998); School of Medicine (1996-1998)
- Other Identifier
- 991021888850004721