5-Hydroxytryptamine 1A receptor blockade facilitates aversive learning in mice: interactions with cholinergic and glutamatergic mechanisms.
The effects of 5-hydroxytryptamine 1A (5-HT(1A)) 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-HT(1A) 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-HT(1A) 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-HT(1A) 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-HT(1A) receptor mRNA were codistributed with markers for cholinergic, GABAergic, and glutamatergic neurons. These results indicate that systemic administration of 5-HT(1A) receptor antagonists can facilitate cognitive performance, most likely by enhancing hippocampal/cortical cholinergic and glutamatergic neurotransmissions. Selective 5-HT(1A) receptor antagonists may be useful in the treatment of cognitive deficits such as Alzheimer's disease.
Madjid
Nather
N
Departmentt of Neuroscience, Division of Behavioral Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Tottie
Elin Elvander
EE
Lüttgen
Maria
M
Meister
Björn
B
Sandin
Johan
J
Kuzmin
Alexander
A
Stiedl
Oliver
O
Ogren
Sven Ove
SO
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects*; D017403:In Situ Hybridization; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D008815:Mice, Inbred Strains; D018727:Muscarinic Antagonists / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*
D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A