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5-HT1A receptor activation increases hippocampal acetylcholine efflux and motor activity in the guinea pig: agonist efficacy influences functional activity in vivo

LO Wilkinson, DN Middlemiss and PH Hutson

Merck, Sharp and Dohme, Neuroscience Research Centre, Harlow, Essex, England.

The effect of 5-hydroxytryptamine1A (5-HT1A) receptor activation on hippocampal acetylcholine (ACh) efflux measured by microdialysis and on motor activity was determined in the guinea pig. Administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin HBr (8- OH-DPAT) dose-dependently increased ACh efflux and motor activity. The effects of 8-OH-DPAT on ACh efflux may be mediated by activation of 5- HT1A receptors but are unlikely to be achieved through 5-HT1A receptors on cholinergic nerve terminals, because administering 8-OH-DPAT through the dialysis probe had no effect. Systemic administration of the 5-HT1A receptor partial agonists buspirone and ipsapirone produced marked increases in ACh efflux with less pronounced motor effects, whereas 8- [2-(2,3-dihydro-1,4-benzodioxin-2-yl- methylamino)ethyl]-8- azaspiro[4,5]-decane-7,9-dione methyl sulphonate (MDL 73005) modestly increased ACh efflux with no effect on motor activity. MDL 73005 did not influence the 8-OH-DPAT-induced increase in ACh efflux but attenuated the 8-OH-DPAT-induced increase in motor activity. Administration of 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine HBr (NAN-190) blocked the behavioral effects of 8-OH-DPAT and attenuated the 8-OH-DPAT-induced increase in ACh. These actions of NAN-190 may be influenced by its alpha 1-adrenoceptor antagonist properties, because administration of prazosin decreased ACh efflux. The differential actions of partial agonists influencing ACh efflux and motor activity in the guinea pig may be due to differing proportions of spare receptors available for each response.

Volume 270, Issue 2, pp. 656-664, 08/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1994 by the American Society for Pharmacology and Experimental Therapeutics.