Role of 5-HT1–7 receptors in short- and long-term memory for an autoshaping task: Intrahippocampal manipulations

It was previously reported that brain areas containing serotonin (5-hydroxytryptamine, 5-HT) receptors mediate memory consolidation as well as short (STM)- and long-term memory (LTM). Here the effects of systemic and intrahippocampal administration of 5-HT agonists and antagonists on an autoshaping learning task were explored, which requires hippocampal translation and transduction as well as 5-HT receptors expression. As previously reported ketamine (glutamatergic antagonist) and two well-known amnesic drugs, scopolamine (cholinergic antagonist) and dizocilpine (NMDA antagonist) impaired STM but not LTM; dizocilpine even improved the latter. Since ketamine produces hallucinations and impairs memory in humans, we address the question if well-known antipsychotic haloperidol and clozapine might affect STM deficit. Indeed, systemic administration of clozapine < haloperidol reversed the ketamine–STM deficit. Considering that clozapine and haloperidol are antagonists for dopaminergic D2 and 5-HT1A/2A/6/7 receptors, systemic and intrahippocampal administration of 5-HT drugs were further explored. The ketamine STM-induced deficit was blocked by 8-OHDPAT (5-HT1A/7 agonist) and SB-399885 (a 5-HT6 antagonist) but not by 5-HT1B, 5-HT2 and 5-HT7 antagonists, thus implicating 5-HT1A/7 and 5-HT6 receptors. These data also suggest that ketamine (at 10 mg/kg) represents a reliable pharmacological tool to explore memory deficits related to hippocampus and schizophrenia.