Influence of acute and chronic chlorimipramine treatment on the 5-HT receptor-mediated modulation of acetylcholine release from the cerebral cortex of freely moving guinea-pigs.
1. Acetylcholine (ACh) release from the cerebral cortex of freely moving guinea-pigs, implanted with epidural cups, was studied. 2. A single dose of chlorimipramine (Cl-Imip, 10 mg kg-1, s.c.), reduced the cortical ACh release both in normal and in chronically (10 mg kg-1 daily, s.c., for 14 days) Cl-Imip-treated guinea-pigs; the 5-HT3 antagonist MDL 72222 (1 mg kg-1, s.c.) antagonized this effect. 3. A single dose of Cl-Imip significantly reduced the effect of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylaminotetralin) (8-OH-DPAT, 0.1 mg kg-1, s.c.), which nearly doubled the cortical ACh release in control animals. MDL 72222 restored to normal the response to 8-OH-DPAT reduced by the anti-depressant. 4. A single dose of Cl-Imip did not change the inhibitory, MDL 72222-sensitive, effect induced by the 5-HT3 agonist 2-methyl-5-hydroxytryptamine (2-methyl-5-HT, 500 micrograms, i.c.v.). 5. In chronically Cl-Imip-treated guinea-pigs, the facilitatory effect of 8-OH-DPAT was no longer present, while the inhibitory, MDL 72222-sensitive, effect of 2-methyl-5-HT was maintained. 6. These results indicate that the 5-HT1A receptor-mediated increase in ACh release is reduced by prolonged Cl-Imip treatment, while the 5-HT3 receptor-mediated inhibition of ACh release is unaffected. The relevance of these findings to the antidepressant mechanism of Cl-Imip is discussed.
Siniscalchi
A
A
Institute of Pharmacology, University of Ferrara, Italy.
Bianchi
C
C
Beani
L
L
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D002997:Clomipramine / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D007276:Injections, Intraventricular; D008297:Male; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014326:Tropanes / Q000494:pharmacology
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013764:Tetrahydronaphthalenes; D014326:Tropanes; D012701:Serotonin; C045918:2-methyl-5-HT; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000109:Acetylcholine; D002997:Clomipramine; C042253:bemesetron