High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation

被引:100
作者
Caldarone, BJ [1 ]
Harrist, A [1 ]
Cleary, MA [1 ]
Beech, RD [1 ]
King, SL [1 ]
Picciotto, MR [1 ]
机构
[1] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06508 USA
关键词
nicotinic acetylcholine receptors; depression; learned; helplessness; forced swim; mecamylamine; tail suspension;
D O I
10.1016/j.biopsych.2004.08.010
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Background: A wide variety of antidepressants act as noncompetitive antagonists of nicotinic acetylcholine receptors (nAChRs), but the relationship between this antagonism and the therapeutic effects of antidepressants is unknown. Methods: Antidepressant properties of the noncompetitive nAChR antagonist mecamylamine in the forced swim test were tested alone and in combination with the tricyclic antidepressant amitriptyline. Mice lacking high-affinity nAChRs were tested in three behavioral effects of amitriptyline in common models of antidepressant models to determine whether these receptors are required for behavioral effects of amytriptyline in common models of antideppressant action. Finally, the brains of wild-type and knockout animals treated with amitriptyline were examined to determine whether high-affinity nAChRs are required for antidepressant-induced increases in hippocampal cell proliferation. Results: Inhibition of nAChRs by mecamylamine had antidepressant-like effects in the forced swim test and potentiated the antidepressant activity of amitriptyline when the two drags were used in combination. Mice lacking high-affinity nAChRs showed no behavioral response to amitriptyline. Finally after chronic treatment with amitriptyline, nAChR knockout mice did not show the increase in hippocampal cell proliferation seen in wild-type mice. Conclusions: These data support the hypothesis that antagonism of nAChRs is an essential component of the therapeutic action of antidepressants.
引用
收藏
页码:657 / 664
页数:8
相关论文
共 46 条
  • [1] Blockade of CRF1 or V1b receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression
    Alonso, R
    Griebel, G
    Pavone, G
    Stemmelin, J
    Le Fur, G
    Soubrié, P
    [J]. MOLECULAR PSYCHIATRY, 2004, 9 (03) : 278 - 286
  • [2] ALONSO R, 2003, MOL PSYCHIATR, V9, P224
  • [3] Acute intermittent nicotine treatment produces regional increases of basic fibroblast growth factor messenger RNA and protein in the tel- and diencephalon of the rat
    Belluardo, N
    Blum, M
    Mudo, G
    Andbjer, B
    Fuxe, K
    [J]. NEUROSCIENCE, 1998, 83 (03) : 723 - 740
  • [4] Gender differences in learned helplessness behavior are influenced by genetic background
    Caldarone, BJ
    George, TP
    Zachariou, V
    Picciotto, MR
    [J]. PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 2000, 66 (04) : 811 - 817
  • [5] Sex differences in response to oral amitriptyline in three animal models of depression in C57BL/6J mice
    Caldarone, BJ
    Karthigeyan, K
    Harrist, A
    Hunsberger, JG
    Wittmack, E
    King, SL
    Jatlow, P
    Picciotto, MR
    [J]. PSYCHOPHARMACOLOGY, 2003, 170 (01) : 94 - 101
  • [6] Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies
    Crawley, JN
    Belknap, JK
    Collins, A
    Crabbe, JC
    Frankel, W
    Henderson, N
    Hitzemann, RJ
    Maxson, SC
    Miner, LL
    Silva, AJ
    Wehner, JM
    WynshawBoris, A
    Paylor, R
    [J]. PSYCHOPHARMACOLOGY, 1997, 132 (02) : 107 - 124
  • [7] CHRONIC INESCAPABLE FOOTSHOCK PRODUCES CHOLINERGIC SYSTEM SUPERSENSITIVITY
    DILSAVER, SC
    ALESSI, NE
    [J]. BIOLOGICAL PSYCHIATRY, 1987, 22 (07) : 914 - 918
  • [8] STRESS INDUCES SUPERSENSITIVITY OF A CHOLINERGIC SYSTEM IN RATS
    DILSAVER, SC
    SNIDER, RM
    ALESSI, NE
    [J]. BIOLOGICAL PSYCHIATRY, 1986, 21 (11) : 1093 - 1096
  • [9] CHOLINERGIC MECHANISMS IN DEPRESSION
    DILSAVER, SC
    [J]. BRAIN RESEARCH REVIEWS, 1986, 11 (03) : 285 - 316
  • [10] Antidepressant effect of ingested nicotine in female rats of Flinders resistant and sensitive lines
    Djuric, VJ
    Dunn, E
    Overstreet, DH
    Dragomir, A
    Steiner, M
    [J]. PHYSIOLOGY & BEHAVIOR, 1999, 67 (04) : 533 - 537