Could the 5-HT 1B receptor inverse agonism affect learning consolidation?

Abstract

Diverse evidence indicates that, the 5-HT system might play a role in learning and memory, since it occurs in brain areas mediating such processes and 5-HT drugs modulate them. Hence in this work, in order to explore further 5-HT involvement on learning and memory 5-HT 1B receptors' role is investigated. Evidence indicates that SB-224289 (a 5-HT 1B receptor inverse agonist) post-training injection facilitated learning consolidation in an associative autoshaping learning task, this effect was partially reversed by GR 127935 (a 5-HT 1B/1D receptor antagonist), but unaffected by MDL 100907 (a 5-HT 2A receptor antagonist) or ketanserin (a 5-HT 1D/2A/7 receptor antagonist) at low doses. Moreover, SB-224289 antagonized the learning deficit produced by TFMPP (a 5-HT 1A/1B/1D/2A/2C receptor agonist), GR 46611 (a 5-HT 1A/1B/1D receptor agonist), mCPP (a 5-HT 2A/2C/3/7 receptor agonist/antagonist) or GR 127935 (at low dose). SB-224289 did not alter the 8-OH-DPAT (a 5-HT 1A/7 receptor agonist) learning facilitatory effect. SB-224289 eliminated the deficit learning produced by the anticholinergic muscarinic scopolamine or the glutamatergic antagonist dizocilpine. Administration of both, GR 127935 (5 mg/kg) plus ketanserin (0.01 mg/kg) did not modify learning consolidation; nevertheless, when ketanserin dose was increased (0.1–1.0 mg/kg) and SB-224289 dose was maintained constant, a learning facilitation effect was observed. Notably, SB-224289 at 1.0 mg/kg potentiated a subeffective dose of the 5-HT 1B/1D receptor agonist/antagonist mixed GR 127935, which facilitated learning consolidation and this effect was abolished by ketanserin at a higher dose. Collectively, the data confirm and extend the earlier findings with GR 127935 and the effects of non-selective 5-HT 1B receptor agonists. Clearly 5-HT 1B agonists induced a learning deficit which can be reversed with SB-224289. Perhaps more importantly, SB-224289 enhances learning consolidation when given alone and can reverse the deficits induced by both cholinergic and glutamatergic antagonist. Hence, 5-HT 1B receptor inverse agonists or antagonists could represent drugs for the treatment of learning and memory dysfunctions.