The effects of the peptide-coupling agent, EEDQ, on 5-HT 2A receptor binding and function in rat frontal cortex

• Published in: Neuropharmacology Vol. 38; no. 9; pp. 1421 - 1430
• Main Authors: Kettle, C.J., Cheetham, S.C., Martin, K.F., Prow, M.R., Heal, D.J.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 1999
• Subjects: 5-HT 2A receptors; Coupling agent; EEDQ; Frontal cortex; Inositol phospholipid hydrolysis; 5-HT 2A receptors; Inositol phospholipid hydrolysis; Frontal cortex; EEDQ; Coupling agent
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/S0028-3908(99)00061-1

This ex vivo study in rat frontal cortex determined the influence of 5-HT receptor agonists and antagonists on EEDQ-induced depletion of 5-HT 2A binding sites and reduction in their functional coupling to phospholipid hydrolysis. Twenty-four hours after EEDQ (6 mg/kg) administration a marked reduction (66%) of cortical 5-HT 2A binding sites with no change in binding affinity was observed. The 5HT 2A antagonists ritanserin (1 mg/kg), ketanserin (1 and 5 mg/kg), metergoline (3 mg/kg) or the 5HT 2A agonist, DOI (3 and 10 mg/kg) also significantly reduced (by 15–44%) these binding sites 24 h after injection. Thirty minute pretreatment with ritanserin, ketanserin, metergoline or DOI (at the doses above) afforded 49–65% protection against the loss of 5-HT 2A binding sites induced by EEDQ (6 mg/kg). DOI (10 mg/kg) pretreatment (−24 h) decreased by 26% the accumulation of [ 3H]inositol phosphates (IPs) evoked by 5-HT (100 μM), but did not affect that produced by DOI (100 μM). Ketanserin (5 mg/kg, −24h) decreased 5-HT- and DOI-induced IP formation by 65% and 53%, respectively. The EEDQ (6 mg/kg, −24h)-evoked reductions (−50%) of 5-HT- and DOI-induced IP formation were not altered by DOI (10 mg/kg) or ketanserin (5 mg/kg) given 30 min before EEDQ. G-protein-stimulated IP accumulation was unaffected by EEDQ (6 mg/kg). Overall, EEDQ reduces 5-HT 2A binding sites and function in rat frontal cortex, whereas its effects on binding were attenuated by various 5-HT receptor antagonists and agonists, its effects on function was unaltered by these drugs.