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Modulation of the hypothermic and hyperglycaemic effects of 8-OH-DPAT by alpha 2-adrenoceptor antagonists
M J Durcan1, K M Wozniak, M Linnoila
1Laboratory of Clinical Studies, DICBR, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892.
Abstract:
1. The effects of pretreatment with two novel and relatively specific alpha 2-adrenoceptor antagonists on the hypothermic and hyperglycaemic responses induced by the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were investigated in mice. The alpha 2-adrenoceptor antagonists used were, atipamezole, which occupies both central and peripheral receptors, and L 659,066, which poorly penetrates the blood brain barrier. 2. Atipamezole (1 and 3 mg kg-1) alone had no effect on body temperature but significantly attenuated the 8-OH-DPAT-induced hypothermic response. The hyperglycaemic effect of 8-OH-DPAT was also attenuated by pretreatment with atipamezole; however, 3 mg kg-1 atipamezole did cause some hypoglycaemia when administered alone. 3. Pretreatment with L 659,066 (3-30 mg kg-1) failed to alter the hypothermic effects of 8-OH-DPAT. All doses of L 659,066 tested attenuated 8-OH-DPAT-induced hyperglycaemia, but the highest dose (30 mg kg-1) produced hypoglycaemia when administered alone. 4. The results suggest that the attenuation of 8-OH-DPAT-induced hypothermia by alpha 2-adrenoceptor antagonist may be centrally mediated whereas the blockade of 8-OH-DPAT-induced hyperglycaemia may involve peripheral mechanisms.
Insights
Novel alpha 2-adrenoceptor antagonists differentially affect 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) responses. Central mechanisms may mediate hypothermia, while peripheral mechanisms might be involved in blocking 8-OH-DPAT-induced hyperglycemia.
Area of Science:
- Pharmacology
- Neuroscience
Background:
- The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) induces hypothermic and hyperglycaemic effects in mice.
- Alpha 2-adrenoceptors play a role in modulating these responses.
Purpose of the Study:
- To investigate the effects of two novel alpha 2-adrenoceptor antagonists, atipamezole (central and peripheral activity) and L 659,066 (poor blood-brain barrier penetration), on 8-OH-DPAT-induced hypothermia and hyperglycemia in mice.
Main Methods:
- Mice were pretreated with varying doses of atipamezole or L 659,066 before administration of 8-OH-DPAT.
- Body temperature and blood glucose levels were monitored.
Main Results:
- Atipamezole attenuated both 8-OH-DPAT-induced hypothermia and hyperglycemia, suggesting central mediation for hypothermia and potentially peripheral for hyperglycemia.
- L 659,066 did not affect 8-OH-DPAT-induced hypothermia but attenuated hyperglycemia, indicating peripheral mechanisms are involved in blocking this effect.
- High doses of both antagonists caused hypoglycemia when administered alone.
Conclusions:
- The findings suggest that the attenuation of 8-OH-DPAT-induced hypothermia by alpha 2-adrenoceptor antagonists is likely centrally mediated.
- Blockade of 8-OH-DPAT-induced hyperglycemia may involve peripheral mechanisms.