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.
Footnotes
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This work was supported by grants from the Swedish Medical Research Council (Vetenskapsrådet; Project Numbers 14X-11588 and 72X-10358), Karolinska Institutets fonder, Wallenberg Consortium North, Alzheimerfonden, Marianne and Marcus Wallenberg's Foundation, and Stiftelsen Gamla Tjänarinnor.
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This work has previously been presented in a thesis by M. Lüttgen from the Karolinska Institutet, Department of Neuroscience: Lüttgen M (2004) Serotonergic receptor subtypes in learning and memory, in Focus on 5-HT1A, 5-HT1B and 5-HT2A Receptors. Larserics Digital Print AB, Stockholm, Sweden.
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doi:10.1124/jpet.105.092262.
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ABBREVIATIONS: 5-HT, 5-hydroxytryptamine (serotonin); PA, passive avoidance; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide; NAD-299, (R)-3-N,N-dicyclobutylamino-8 fluoro-3,4-dihydro-3H-1-benzopyran-5-carboxamide hydrogen(2R,3R)-tartrate monohydrate; WAY-100635, N-2-4-(2-methoxyphenyl)-1-piperazinylethyl-N-(2-pyridinyl)cyclohexane carboxamide trihydrochloride; MK-801, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen maleate; ECG, electrocardiogram; ACh, cholinergic; VAChT, vesicular acetylcholine transporter; US, unconditioned stimulus; MSDB, medial septum/diagonal band of Broca; VGLUT2, vesicular glutamate transporter 2; ANOVA, analysis of variance; NAN-190, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine.
- Received July 8, 2005.
- Accepted October 12, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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