Alcohol-induced c-Fos expression in the Edinger-Westphal nucleus: Pharmacological and signal transduction mechanisms

被引:78
作者
Bachtell, RK [1 ]
Tsivkovskaia, NO [1 ]
Ryabinin, AE [1 ]
机构
[1] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97201 USA
关键词
D O I
10.1124/jpet.102.036046
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Mapping inducible transcription factors has shown that the Edinger-Westphal nucleus is preferentially sensitive to alcohol intoxication. Herein, we characterize the pharmacological and signal transduction mechanisms related to alcohol-induced c-Fos expression in Edinger-Westphal neurons. Using immunohistochemistry, we show that pretreatment with gamma-aminobutyric acid (GABA)-ergic antagonists (4 mg/kg bicuculline and 45 mg/kg pentylenetetrazole) attenuates induction of c-Fos expression by alcohol (2.4 g/kg, intraperitoneal). In addition, 10 mg/kg 2-(2,3-dihydro-2-methoxy-1,4-benzodioxin-2-yl) 4,5-dihydro-1H-imidazole (RX 821002), an alpha(2A/D)-adrenoceptor antagonist, and 20 mg/kg haloperidol, a dopamine antagonist, also block alcohol-induced c-Fos expression in Edinger-Westphal neurons. No effects were seen in alcohol-induced c-Fos after the pretreatment of 20 mg/kg propranolol (beta-adrenoceptor antagonist), 10 mg/kg 2-(2-(4-(2-methoxyphenyl) piperazin-1-yl) ethy)-4,4-dimethyl-1,3-(2H, 4H)-isoquinolindione dihydrochloride (ARC 239) (alpha(2B/C)-adrenoceptor antagonist), or 30 mg/kg naltrexone (opioid antagonist). Although positive modulators for the GABA(A) receptor (20 mg/kg 3alpha-hydroxy-5alpha-pregnan-20-one and 10-30 mg/kg chlordiazepoxide) and opioid receptor (10 mg/kg morphine) produced significant elevations, agonists for alpha(2)-adrenoceptors (clonidine) and dopamine receptors (apomorphine) had no effect on Edinger-Westphal c-Fos expression. These findings suggest that alcohol-induced c-Fos expression in Edinger-Westphal results from direct interactions with GABA(A) receptors, which are modified by alpha(2A/D)-adrenoceptors and dopamine receptors. Also using immunohistochemistry to identify potential intracellular mechanisms associated with alcohol-induced c-Fos expression in Edinger-Westphal, we show time-dependent increases in serine 727 phospho-signal transducer and activator of transcription 3 (Stat3) but no changes in phospho-cAMP response element-binding protein and phospho-Elk1. Time-dependent increases in phospho-extracellular signal-regulated kinase (ERK) 1/2 were found to occur simultaneously with increases in serine 727 phospho-Stat3. Finally, blockade of ERK 1/2 phosphorylation with the mitogen-activated protein kinase (MEK) 1/2 inhibitor SL327 blocked alcohol-induced c-Fos expression, suggesting that alcohol induces c-Fos in Edinger-Westphal neurons through activation of the MEK1/2-ERK1/2-Stat3 pathway.
引用
收藏
页码:516 / 524
页数:9
相关论文
共 40 条
[1]   TOLERANCE OF LOCUS COERULEUS NEURONS TO MORPHINE AND SUPPRESSION OF WITHDRAWAL RESPONSE BY CLONIDINE [J].
AGHAJANIAN, GK .
NATURE, 1978, 276 (5684) :186-188
[2]   Interactive effects of nicotine and alcohol co-administration on expression of inducible transcription factors in mouse brain [J].
Bachtell, RK ;
Ryabinin, AE .
NEUROSCIENCE, 2001, 103 (04) :941-954
[3]   Alcohol drinking produces brain region-selective changes in expression of inducible transcription factors [J].
Bachtell, RK ;
Wang, YM ;
Freeman, P ;
Risinger, FO ;
Ryabinin, AE .
BRAIN RESEARCH, 1999, 847 (02) :157-165
[4]  
BACHTELL RK, 2002, IN PRESS NEUROSCIENC
[5]   BRAIN-STEM CONNECTIONS TO THE EDINGER-WESTPHAL NUCLEUS OF THE CAT - A RETROGRADE TRACER STUDY [J].
BREEN, LA ;
BURDE, RM ;
LOEWY, AD .
BRAIN RESEARCH, 1983, 261 (02) :303-306
[6]  
Bunney EB, 2000, J PHARMACOL EXP THER, V293, P383
[7]   α2A- but not α2B/C-adrenoceptors modulate noradrenaline release in rat locus coeruleus:: voltammetric data [J].
Callado, LF ;
Stamford, JA .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1999, 366 (01) :35-39
[8]   Signal transducer and activator of transcription-3 serine phosphorylation by insulin is mediated by a Ras/Raf/MEK-dependent pathway [J].
Ceresa, BP ;
Horvath, CM ;
Pessin, JE .
ENDOCRINOLOGY, 1997, 138 (10) :4131-4137
[9]   ACTIVATION AND DESENSITIZATION OF FOS IMMUNOREACTIVITY IN THE RAT-BRAIN FOLLOWING ETHANOL ADMINISTRATION [J].
CHANG, SL ;
PATEL, NA ;
ROMERO, AA .
BRAIN RESEARCH, 1995, 679 (01) :89-98
[10]   NO TRIAZOLAM-INDUCED EXPRESSION OF FOS PROTEIN IN RAPHE NUCLEI OF THE MALE SYRIAN-HAMSTER [J].
CUTRERA, RA ;
KALSBEEK, A ;
PEVET, P .
BRAIN RESEARCH, 1993, 602 (01) :14-20