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The effect of putative 5-HT1A receptor antagonists on 8-OH-DPAT-induced hypothermia in rats and mice
1Merrell Dow Research Institute, Strasbourg, France.
Abstract:
The effects of three putative 5-HT1A receptor antagonists (NAN-190, BMY 7378 and WB 4101) were studied on the hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In order to control for the alpha 1-adrenoceptor antagonist activity of NAN-190 and WB 4101, the effects of prazosin were also examined. Both NAN-190 and WB 4101 lowered body temperature in the mouse. This effect appeared to be due to their alpha 1-adrenoceptor antagonist effects as prazosin had a similar profile. Neither NAN-190, WB 4101 nor prazosin antagonised the hypothermic effects of 8-OH-DPAT. BMY 7378 slightly lowered body temperature but to a lesser extent than 8-OH-DPAT and, in contrast to the other compounds studied, also prevented a fall in body temperature on injection of 8-OH-DPAT. In the rat there was much less interference from alpha 1-adrenoceptor antagonist activity as both NAN-190 and prazosin only slightly reduced body temperature. In this species, however, NAN-190 showed marked antagonist activity against 8-OH-DPAT hypothermia. This was not due to alpha 1-adrenoceptor antagonist activity as prazosin had no effect. In the rat, as in the mouse, BMY 7378 had a partial agonist profile, whereas WB 4101 behaved essentially as an agonist. These results suggest that NAN-190 is a pure antagonist of 8-OH-DPAT-induced hypothermia in rats and that BMY 7378 and WB 4101 are, respectively, a partial agonist and an agonist in this test.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
NAN-190 acts as a pure antagonist for 8-OH-DPAT-induced hypothermia in rats, while BMY 7378 and WB 4101 show partial agonist and agonist activity, respectively. These findings clarify the roles of these compounds in 5-HT1A receptor research.
Area of Science:
- Pharmacology
- Neuroscience
- Receptor binding studies
Background:
- The 5-HT1A receptor is a key target for various neurological and psychiatric conditions.
- Understanding the specific actions of receptor antagonists and agonists is crucial for drug development.
- 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is a known agent that induces hypothermia, often used to probe 5-HT1A receptor function.
Purpose of the Study:
- To investigate the effects of three potential 5-HT1A receptor antagonists: NAN-190, BMY 7378, and WB 4101.
- To determine the antagonist, partial agonist, or agonist profiles of these compounds in relation to 8-OH-DPAT-induced hypothermia.
- To control for potential alpha 1-adrenoceptor antagonist activity of NAN-190 and WB 4101 by examining the effects of prazosin.
Main Methods:
- Administration of NAN-190, BMY 7378, WB 4101, and prazosin to mice and rats.
- Induction of hypothermia using 8-OH-DPAT.
- Measurement of body temperature changes in response to drug administration and 8-OH-DPAT.
- Analysis of antagonist and agonist activities at the 5-HT1A receptor.
Main Results:
- In mice, NAN-190 and WB 4101 exhibited hypothermic effects attributed to alpha 1-adrenoceptor antagonism, similar to prazosin. None antagonized 8-OH-DPAT hypothermia.
- BMY 7378 showed a partial agonist profile in both species, reducing 8-OH-DPAT-induced hypothermia.
- In rats, NAN-190 demonstrated pure antagonist activity against 8-OH-DPAT hypothermia, unaffected by alpha 1-adrenoceptor activity. WB 4101 acted as an agonist in rats.
Conclusions:
- NAN-190 is identified as a pure antagonist of 8-OH-DPAT-induced hypothermia in rats.
- BMY 7378 functions as a partial agonist, and WB 4101 as an agonist in this experimental model.
- These findings provide valuable insights into the specific pharmacological profiles of these 5-HT1A receptor ligands.