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 antidepressant. 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 μg, 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.