5-Hydroxytryptamine 1A Receptor Blockade Facilitates Aversive Learning in Mice: Interactions with Cholinergic and Glutamatergic Mechanisms

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Abstract
The effects of 5-hydroxytryptamine 1A (5-HT1A) receptor ligands on aversive learning were examined in the passive avoidance (PA) task in mice. Anxiety and autonomic functions were investigated using the elevated plus-maze and heart rate measurements. The main findings from this study are as follows. 1) Pretraining administration of the 5-HT1A receptor agonist 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide] facilitated PA retention at low doses (0.01 and 0.03 mg/kg) but impaired PA retention at higher doses (0.1-1.0 mg/kg), consistent with previous findings in the rat. 2) Similar to the acetylcholinesterase inhibitor physostigmine, pretraining administration of the 5-HT1A receptor antagonists [(R)-3-N,N-dicyclobutylamino-8 fluoro-3,4-dihydro-3H-1-benzopyran-5-carboxamide hydrogen(2R,3R)-tartrate monohydrate] NAD-299 (0.1-2 mg/kg) and [N-2-4-(2-methoxyphenyl)-1-piperazinylethyl-N-(2-pyridinyl)cyclohexane carboxamide trihydrochloride] WAY-100635 (0.3-3 mg/kg) enhanced PA retention. 3) The impairment (1 mg/kg) but not the facilitation (0.03 mg/kg) induced by 8-OH-DPAT was fully blocked by NAD-299 (0.3 mg/kg). 4) 5-HT1A receptor ligands given immediate post-training failed to alter PA retention. 5) NAD-299 (0.3-1 mg/kg) blocked the impairment of PA retention caused by a) the nonselective muscarinic receptor antagonist scopolamine and b) the non-competitive N-methyl-d-aspartate receptor antagonist MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen maleate]. 6) A subthreshold dose of scopolamine completely blocked the facilitatory effect of NAD-299 on PA retention. 7) Anxiety-related behaviors and autonomic function were unchanged by NAD-299. 8) In situ hybridization showed that septal neurons expressing 5-HT1A receptor mRNA were codistributed with markers for cholinergic, GABAergic, and glutamatergic neurons. These results indicate that systemic administration of 5-HT1A receptor antagonists can facilitate cognitive performance, most likely by enhancing hippocampal/cortical cholinergic and glutamatergic neurotransmissions. Selective 5-HT1A receptor antagonists may be useful in the treatment of cognitive deficits such as Alzheimer's disease.