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The Effect of Intrahippocampal Injection of Diarylpropionitrile, a Selective Estrogen Receptor-Beta Agonist, on Passive Avoidanc

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The Effect of Intrahippocampal Injection of Diarylpropionitrile, a Selective Estrogen Receptor-Beta Agonist, on Passive Avoidanc Physiology and Pharmacology, 12 (4), 254 - 260 Winter 2009 [Article in Persian] The effect of intrahippocampal injection of diarylpropionitrile, a selective estrogen receptor-β agonist, on passive avoidance learning Zeinab Sharifkhodaei 1,2, Nasser Naghdi 2*, Shahrbanoo Oryan 3, Parichehr Yaghmaei 1 1. Dept. Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran 2. Dept. Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran 3. Dept. Biology, Tarbiat Moalem University, Tehran, Iran Received: 5 Mar 2008 Revised: 23 Aug 2008 Accepted: 25 Aug 2008 Abstract* Introduction: Neurohormones like testosterone and estradiol have an important role in learning and memory. The hippocampus is essentially involved in learning and memory, and is known to be a target for estradiol actions. Estrogen receptors (ERs) are highly expressed in CA1 of rat hippocampus, and mediate the effects of estrogen on learning and memory. Estradiol receptor belong to a family of transcription factors, the nuclear receptor superfamily, and has two subtypes ERα and ERβ. The current research has been conducted to assess the effect of ERβ selective agonist, diarylpropionitrile (DPN), on passive avoidance of adult male rats, by using passive avoidance task. Methods: Male adult rats were bilaterally cannulated into the CA1 area of hippocampus, and then received vehicle (dimethyl sulfoxide, DMSO) or DPN (0.2, 0.5, 1 µg/0.5µl/side), 30 min before training on passive avoidance task. Results: The results showed that pre-training intra-CA1 injections of DPN (0.5, 1 µg/0.5µl/side), significantly decreased step-through latencies and increased time spent in dark on passive avoidance learning (P<0.01). Conclusion: Our data suggest that intra-CA1 administration of DPN could impair learning and memory acquisition on passive avoidance task. Keywords: Estradiol; Estradiol receptor β; passive avoidance learning; Rat. * Corresponding author e- mail: [email protected] [email protected] Available online @: www.phypha.ir/ppj 32 ﻓﻴﺰﻳﻮﻟﻮژي و ﻓﺎرﻣﺎﻛﻮﻟﻮژي 12 (4)، 254 – 260 زﻣﺴﺘﺎن 1387 ﻓﻴﺰﻳﻮﻟﻮژي و ﻓﺎرﻣﺎﻛﻮﻟﻮژي ﺟﻠﺪ 12، ﺷﻤﺎرة 4، زﻣﺴﺘﺎن 1387 ﺗﺎﺛﻴﺮﺗﺰرﻳﻖ درون ﻫﻴﭙﻮﻛﻤﭙﻲ DPN (آﮔﻮﻧﻴﺴﺖ اﺧﺘﺼﺎﺻﻲ ﮔﻴﺮﻧﺪ هي ﺑﺘﺎ اﺳﺘﺮادﻳﻮل) ﺑﺮﺣﺎﻓﻈﻪ و ﻳﺎدﮔﻴﺮي اﺟﺘﻨﺎﺑﻲ ﻏﻴﺮﻓﻌﺎل در ﻣﻮش ﺻﺤﺮاﻳﻲ زﻳﻨﺐ ﺷﺮﻳﻒ ﺧﺪاﻳﻲ2،1، ﻧﺎﺻﺮ ﻧﻘﺪي2*، .ﺷﻬﺮﺑﺎﻧﻮ ﻋﺮﻳﺎن3، ﭘﺮﻳﭽﻬﺮ ﻳﻐﻤﺎﻳﻲ1 1. ﮔﺮوه زﻳﺴﺖﺷﻨﺎﺳﻲ، داﻧﺸﻜﺪه ﻋﻠﻮم، واﺣﺪ ﻋﻠﻮم و ﺗﺤﻘﻴﻘﺎت، داﻧﺸﮕﺎه آزاد اﺳﻼﻣﻲ، ﺗﻬﺮان 2. ﮔﺮوه ﻓﻴﺰﻳﻮﻟﻮژي و ﻓﺎرﻣﺎﻛﻮﻟﻮژي، اﻧﻴﺴﺘﻴﺘﻮ ﭘﺎﺳﺘﻮر، ﺗﻬﺮان 3. ﮔﺮوه زﻳﺴﺖﺷﻨﺎﺳﻲ، داﻧﺸﻜﺪه ﻋﻠﻮم، داﻧﺸﮕﺎه ﺗﺮﺑﻴﺖ ﻣﻌﻠﻢ، ﺗﻬﺮان درﻳﺎﻓﺖ: 14 ﺷﻬﺮﻳﻮر 87 ﺑﺎزﺑﻴﻨﻲ: 5 آﺑﺎن 87 ﭘﺬﻳﺮش: 22 آﺑﺎن 87 ERβ و ﻳﺎدﮔﻴﺮي اﺟﺘﻨﺎﺑﻲ ﻏﻴﺮﻓﻌﺎل ﺷﺮﻳﻒ ﺧﺪاﻳﻲ و ﻫﻤﻜﺎران ﭼﻜﻴﺪه ﻣﻘﺪﻣﻪ: ﻧﻮروﻫﻮرﻣﻮن ﻫﺎ ﻫﻤﺎﻧﻨﺪ ﺗﺴﺘﻮﺳﺘﺮون و اﺳﺘﺮادﻳﻮل ﻧﻘﺶ ﻣﻬﻤﻲ در ﻳﺎدﮔﻴﺮي و ﺣﺎﻓﻈﻪ ﺑﺮ ﻋﻬﺪه دارﻧﺪ. ﻫﻴﭙﻮﻛﺎﻣﭗ ﻧﻴﺰ ﺑﻄﻮر اﺳﺎﺳـﻲ در ﻳـﺎدﮔﻴﺮي و ﺣﺎﻓﻈـﻪ دﺧﺎﻟـﺖ دارد و ﺑﻌﻨﻮان اﻧﺪام ﻫﺪف ﺑﺮاي ﻋﻤﻠﻜﺮدﻫﺎي اﺳﺘﺮادﻳﻮل ﺷﻨﺎﺧﺘﻪ ﺷﺪه اﺳﺖ. ﮔﻴﺮﻧﺪ هﻫﺎي اﺳﺘﺮوژﻧﻲ(ERs) ﺑﻄﻮر ﻣﺘﺮاﻛﻢ در ﻧﺎﺣﻴﻪ CA1 ﻫﻴﭙﻮﻛﺎﻣﭗ رت ﺑﻴﺎن ﻣﻲﺷـﻮﻧﺪ و ﺗـﺎﺛﻴﺮات اﺳـﺘﺮاد ﻳﻮل ﺑﺮ ﻳﺎدﮔﻴﺮي و ﺣﺎﻓﻈﻪ را ﻣﻴﺎﻧﺠﻲﮔﺮي ﻣﻲﻛﻨﻨﺪ. ﮔﻴﺮﻧﺪه ﻫﺎي اﺳﺘﺮوژن ﻣﺘﻌﻠﻖ ﺑﻪ ﺧﺎﻧﻮاده ﻓﺎﻛﺘﻮرﻫﺎي روﻧﻮﻳﺴﻲ، ﻓﻮق ﺧﺎﻧﻮاده ﮔﻴﺮﻧﺪ هﻫﺎي ﻫﺴﺘ ﻪاي، ﻫﺴـﺘﻨﺪ و ﺑـﻪ دو ﻧـﻮع α و β ﺗﻘﺴـﻴﻢ ﻣﻲﺷﻮﻧﺪ. در اﻳﻦ ﻣﻄﺎﻟﻌﻪ، ﺗﺎﺛﻴﺮآﮔﻮﻧﻴﺴﺖ اﺧﺘﺼﺎﺻﻲ DPN) ,diarylpropionitrile, ERβ) ﺑﺮ ﻳﺎدﮔﻴﺮي اﺟﺘﻨﺎﺑﻲ ﻏﻴﺮﻓﻌﺎل در رت ﻫﺎي ﻧﺮ ﺑﺎﻟﻎ در دﺳـﺘﮕﺎه اﺟﺘﻨـﺎﺑ ﻲ ﻏﻴﺮﻓﻌـﺎل ﻣـﻮرد ﺑﺮرﺳﻲ ﻗﺮار ﮔﺮﻓﺘ ﻪاﺳﺖ. روشﻫﺎ: رتﻫﺎي ﻧﺮ ﺑﺎﻟﻎ ﺑﻄﻮر دو ﻃﺮﻓﻪ در ﻧﺎﺣﻴﻪ CA1 ﻫﻴﭙﻮﻛﺎﻣﭗ ﻛﺎﻧﻮ لﮔﺬاري ﺷـﺪﻧﺪ در ﮔـﺮوه ﻛﻨﺘـﺮل dimethyl sulfoxide) DMSO) ﺧـﺎﻟﺺ و در ﮔـﺮوه ﺗﺠﺮﺑـﻲ دوزﻫﺎي 2/0 و 5/0 و 1 ﻣﻴﻜﺮوﮔﺮم DPN ﺣﻞ ﺷﺪه در5/0ﻣﻴﻜﺮوﻟﻴﺘﺮ DMSO ﺗﻬﻴﻪ ﺷﺪ و 30 دﻗﻴﻘﻪ ﻗﺒﻞ از آﻣﻮزش در دﺳﺘﮕﺎه اﺟﺘﻨﺎﺑﻲ ﻏﻴﺮﻓﻌﺎل ﺑﻪ آﻧﻬﺎ ﺗﺰرﻳﻖ ﺷﺪ. ﻳﺎﻓﺘﻪﻫﺎ: ﻧﺘﺎﻳﺞ ﻧﺸﺎن دادﻧﺪ ﻛﻪ ﺗﺰرﻳﻖ دوزﻫﺎي 5/0 و 1 ﻣﻴﻜﺮوﮔﺮم DPN ﻗﺒﻞ از آﻣﻮزش در ﻧﺎﺣﻴﻪ CA1، ﺑﻄﻮر ﻣﻌﻨﻲداري زﻣﺎن ﺗـﺎﺧﻴﺮ در ورود ﺑـﻪ اﺗـﺎق ﺗﺎرﻳـ ﻚ را ﻛـﺎﻫﺶ ﻣﻲدﻫﻨﺪ و ﻣﻮﺟﺐ اﻓﺰاﻳﺶ ﻣﺪت زﻣﺎن ﺣﻀﻮر در اﺗﺎق ﺗﺎرﻳﻚ ﻣﻲﺷﻮﻧﺪ (P<0.01). ﻧﺘﻴﺠﻪﮔﻴﺮي: اﻳﻦ اﻃﻼﻋﺎت ﭘﻴﺸﻨﻬﺎد ﻣﻲﻛﻨﻨﺪ ﻛﻪ ﺗﺰرﻳﻖ DPN در ﻧﺎﺣﻴﻪ CA1 ﺑﺎﻋﺚ ﺗﺨﺮﻳﺐ ﻳﺎدﮔﻴﺮي و ﺣﺎﻓﻈﻪ ﻣﻲﺷﻮد. ﭘـﺲ ﮔﻴﺮﻧـﺪ هي ﺑﺘـﺎي اﺳـﺘﺮادﻳﻮل ﻧﻘـﺶ ﻣﻬﻤـﻲ در ﻳﺎدﮔﻴﺮي و ﺣﺎﻓﻈﻪ اﺟﺘﻨﺎﺑﻲ ﻏﻴﺮ ﻓﻌﺎل ﺑﺮ ﻋﻬﺪه دارد. واژهﻫﺎي ﻛﻠﻴﺪي: اﺳﺘﺮادﻳﻮل، ﮔﻴﺮﻧﺪه ﺑﺘﺎي اﺳﺘﺮادﻳﻮل، ﻳﺎدﮔﻴﺮي اﺟﺘﻨﺎﺑﻲ ﻏﻴﺮ ﻓﻌﺎل ﻣﻘﺪﻣﻪ* آﻧﺪروﺳــﺘﻨﺪﻳﻮن (AD)، ﺗﺴﺘﻮﺳــﺘﺮون و اﺳــﺘﺮادﻳﻮل از ﻛﻠﺴــﺘﺮول در ﻣﻐـــﺰ ﺳـــﺎﺧﺖ دﻫﻴـــﺪرواﭘﻲ آﻧﺪروﺳـــﺘﺮون (DHEA)، درون زا ﮔﺰارش ﺷﺪه اﺳﺖ [25،18]. ﻣﻄﺎﻟﻌﺎت اﺧﻴﺮ ﻧﺸﺎن داده اﻧﺪ ﻛﻪ ﻧﻮرون ﻫﺎي ﻫﻴﭙﻮﻛﺎﻣـﭗ ﺑـﺎ ﻣﺠﻤﻮﻋـﻪ اي از آﻧـﺰﻳﻢﻫـﺎ ﺳـﺎﺧﺖ اﺳﺘﺮادﻳﻮل و ﺗﺴﺘﻮﺳﺘﺮون از ﻛﻠﺴﺘﺮول را ﻛﺎﺗﺎﻟﻴﺰ ﻣﻲﻛﻨﻨﺪ [27،18]. * ﻧﻮﻳﺴﻨﺪة ﻣﺴﺌﻮل ﻣﻜﺎﺗﺒﺎت: [email protected] [email protected] ﻏﻠﻈﺖ ﭘﺎﻳﻪ اﺳﺘﺮادﻳﻮل در ﻫﻴﭙﻮﻛﺎﻣﭗ ﺣـﺪوداً nM 1 اﺳـﺖ ﻛـﻪ از وﺑﮕﺎه ﻣﺠﻠﻪ: www.phypha.ir/ppj ﻣﻴﺰان آن در ﭘﻼﺳﻤﺎي ﺧﻮن ﺑﻴﺸﺘﺮ اﺳﺖ [28]. 254 ﻓﻴﺰﻳﻮﻟﻮژي و ﻓﺎرﻣﺎﻛﻮﻟﻮژي ﺟﻠﺪ 12، ﺷﻤﺎرة 4، زﻣﺴﺘﺎن 1387 ﺷــﻮاﻫﺪي وﺟــﻮد دارد ﻛــﻪ اﺳــﺘﺮوﺋﻴﺪﻫﺎي ﮔﻨــﺎدي ﻣﺜــﻞ ﺿﺮوري اﺳﺖ. ﻳﺎدﮔﻴﺮي و ﺣﺎﻓﻈﻪ از ﺟﻤﻠﻪ ﺣﺎﻓﻈـﻪ ﻣﺮﺟـﻊ ﺗﻮﺳـﻂ ﺗﺴﺘﻮﺳــﺘﺮون، اﺳــﺘﺮادﻳﻮل، دي ﻫﻴﺪروﺗﺴﺘﻮﺳــﺘﺮون و ﭘﺮﮔﻨﻨﻮﻟــﻮن اﺳﺘﺮادﻳﻮل ﺗﺨﺮﻳﺐ ﻣﻲﺷﻮد. در ﻣﻘﺎﺑﻞ، ﺳﻄﺢ ﭘﺎﺋﻴﻨﻲ از اﺳـﺘﺮادﻳﻮل ﺑﺮدﺳﺘﮕﺎه ﻋﺼﺒﻲ ﻣﺮﻛﺰي اﺛﺮاﺗﻲ را اﻋﻤﺎل ﻣﻲﻛﻨﻨـﺪ [35]. ﺗـﺮاﻛﻢ ﻣﻤﻜﻦ اﺳﺖ ﺑﺎﻋﺚ ﺑﻬﺒﻮد ﺣﺎﻓﻈﻪ ﺟﺎري ﺷﻮد [33]. ﺑﺮﺧﻲ ﻣﻄﺎﻟﻌﺎت ﺑﺎﻻي ﮔﻴﺮﻧﺪ هﻫﺎي اﺳﺘﺮوژن و آﻧﺪروژن در ﻣﺮاﻛﺰ ﺑﻨﻴﺎدي ﻳﺎدﮔﻴﺮي ﻧﺸﺎن ﻣﻲدﻫﻨﺪ ﻛﻪ ERβ ﻳﻚ ﺗﻌﺪﻳﻞ ﻛﻨﻨﺪه ﻣﻬﻢ ﺗﻜﺜﻴﺮ ﺳـﻠﻮﻟﻲ و و ﺣﺎﻓﻈﻪ در ﻣﻐﺰ، ﻣﺜﻞ ﻫﻴﭙﻮﻛﺎﻣﭗ، ﻧﺸـﺎن ﻣـ ﻲدﻫـﺪ ﻛـﻪ اﺣﺘﻤـﺎﻻً ﺣﺎﻓﻈﻪ و ﻳﺎدﮔﻴﺮي اﺳﺖ [9]. در ﻣـﻮش ﻫـﺎﻳﻲ ﻛـﻪ درآﻧﻬـﺎ ERβ رواﺑﻄﻲ ﺑﻴﻦ ﮔﻴﺮﻧﺪه ﻫﺎي آﻧﺪروژن و اﺳﺘﺮوژن وﺟﻨﺒﻪ ﻫـﺎي ادراﻛـ ﻲ ﺣﺬف ﺷﺪه اﺳﺖ ﻳﺎدﮔﻴﺮي و ﺣﺎﻓﻈﻪ اﻛﺘﺴﺎﺑﻲ در ﻣﺎز آﺑﻲ ﻣـﻮرﻳﺲ دﺳﺘﮕﺎه ﻋﺼﺒﻲ ﻣﺮﻛﺰي ﺑﺮﻗﺮار اﺳﺖ [20،16]. در ﻣﻘﺎﻳﺴــﻪ ﺑــﺎ ﮔــﺮوه ﻛﻨﺘــﺮل ﺗﺨﺮﻳــﺐ ﺷــﺪه اﺳــﺖ [33]. اﺧﻴــﺮاً اﺛﺮات ﻫﻮرﻣﻮن ﻫـﺎي اﺳـﺘﺮوﺋ ﻴﺪي ﺗﻮﺳـﻂ ﮔﻴﺮﻧـﺪ هﻫـﺎي درون درﮔﺰارﺷﻲ ﭘﻴﺸﻨﻬﺎد ﺷﺪه اﺳﺖ ﻛﻪ ﻣﻮ شﻫﺎي ﻣﺎد هاي ﻛـﻪ در آﻧﻬـﺎ ﺳـﻠﻮ ﻟ ﻲ وﻳــﮋهاي در ﺑﺎﻓــﺖ ﻫــﺪف ﻣﻴـ ﺎﻧﺠﻲﮔــﺮي ﻣــ ﻲﺷــﻮد، ﻛــﻪ ERβ ﺣﺬف ﺷﺪه اﺳﺖ ﺳﻄﻮح ﺑﺎﻻرﻓﺘﻪ اي از اﺿـﻄﺮاب و ﺳـﻄﻮح ﻛﻤﭙﻠﻜﺲ ﻫﺎي اﺳﺘﺮوﺋﻴﺪ- ﮔﻴﺮﻧـﺪه ﻧﻘـﺶ ﻣﺮﻛـﺰي در ﺑﻜـﺎرﮔﻴﺮي ﺗﻘﻠﻴﻞ ﻳﺎﻓﺘﻪ اي از ﻓﻌﺎﻟﻴـ ﺖ را در آزﻣـﻮن ﻫـﺎي ﺑـﺎز از ﺧـﻮد ﻧﺸـﺎن ﻣﻜﺎﻧﻴﺴﻢﻫﺎي ﺳﻠﻮﻟﻲ ﻻزم ﺑﺮاي ﻓﻌـﺎل ﻛـﺮدن روﻧﻮﻳﺴـﻲ ژن ﺑـﺮ ﻣﻲدﻫﻨﺪ [21]، در ﺣﺎﻟﻴﻜﻪ ﻳﺎﻓﺘـﻪ ﻫـﺎي ﮔﺬﺷـﺘﻪ ﻧ ﺸـﺎن ﻣـ ﻲدﻫﻨـﺪ ﻋﻬﺪه دارﻧﺪ [8]. ﮔﻴﺮﻧﺪه ﻫﺎي اﺳـﺘﺮاد ﻳﻮل (ERs) ﺑﻄـﻮر ﻏﺎﻟـﺐ در ﻣﻮش ﻫﺎي ﻣﺎده اي ﻛﻪ در آﻧﻬﺎ ﮔﻴﺮﻧﺪه آﻟﻔﺎ اﺳﺘﺮادﻳﻮل ﺣـﺬف ﺷـﺪه ﺳﻴﺴﺘﻢ ﻟﻴﻤﺒﻴﻚ ﻣﺜﻞ آﻣﻴﮕـﺪال، ﺳـﭙﺘﻮم، ﻫﻴﭙﻮﻛﺎﻣـﭗ و ﻫﻤﭽﻨـﻴﻦ اﺳﺖ در آزﻣﻮن اﺟﺘﻨﺎﺑﻲ ﻏﻴﺮ ﻓﻌﺎل ﻳـ ﺎدﮔﻴﺮي ﺧـﻮﺑﻲ ﻧﺪارﻧـﺪ [12]. ﻫﻴﭙﻮﺗﺎﻻﻣﻮس ﻣﺘﻤﺮﻛﺰ ﺷﺪه اﻧـﺪ و در ﻣﺮاﺣـﻞ اﺣﺴﺎﺳـ ﻲ وادراﻛـﻲ اﻳﻦ ﻳﺎﻓﺘﻪ ﻫﺎ ﻣﺎ را ﺑﻪ اﻳـ ﻦ ﻓﻜـﺮ ﻣـ ﻲاﻧﺪازﻧـﺪ ﻛـﻪ دو ﻧـﻮع ﮔﻴﺮﻧـﺪه دﺧﺎﻟﺖ دارﻧـﺪ [37،29،1]. ﮔﻴﺮﻧـﺪه ﻫـﺎي اﺳـﺘﺮاد ﻳﻮل ﺑـﻪ ﺧـﺎﻧﻮاده اﺳﺘﺮادﻳﻮل اﻧﻮاع ﻣﺨﺘﻠﻔﻲ از ﺣﺎﻓﻈﻪ و ﻳﺎدﮔﻴﺮي را درﮔﻴﺮ ﻣﻲﻛﻨﻨـﺪ، ﻓﺎﻛﺘﻮرﻫﺎي روﻧﻮﻳﺴﻲ و ﻓﻮق ﺧﺎﻧﻮاده ﮔﻴﺮﻧﺪه ﻫﺎي ﻫﺴﺘﻪ اي ﻣﺘﻌﻠـﻖ ﻣﻤﻜﻦ اﺳﺖ ERα ﺑﺮاي ﻳﺎدﮔﻴﺮي اﺣﺴﺎﺳﻲ ﻛﻪ ﺑﻴﺸﺘﺮ ﻣﺮﺑـﻮط ﺑـﻪ ﻫﺴﺘﻨﺪ [23،22] و ﺑﻪ دو ﺗﻴﭗ ﮔﻴﺮﻧﺪه اﺳﺘﺮادﻳﻮﻟﻲ آﻟﻔﺎ و ﺑﺘﺎ ﺗﻘﺴـﻴﻢ آﻣﻴﮕﺪال ﻣﻲﺷـﻮد ﺿـﺮوري ﺑﺎﺷـﺪ در ﺣﺎﻟﻴﻜـﻪ ﻳـ ﺎدﮔﻴﺮي ﻓﻀـﺎﻳﻲ ﻣﻲﺷﻮﻧﺪ [5]. در ﺳـﺎل 1996 دوﻣـﻴﻦ ﺗﻴـﭗ ﮔﻴﺮﻧـﺪه اﺳـﺘﺮادﻳﻮل، واﺑﺴﺘﻪ ﺑﻪ ﻫﻴﭙﻮﻛﺎﻣﭗ ﺑﻪ ERβ ﻧﻴﺎز دارد [33]. ERβ، از ﭘﺮوﺳﺘﺎت و ﺗﺨﻤﺪان ﻣـﻮش ﺻـﺤﺮاﺋﻲ ﺟـﺪا ﺷـﺪ [22]. اﻳﻦ اﻃﻼﻋﺎت ﻣﺎ را ﺑﺮ آن داﺷﺖ ﺗـﺎ ﺑـﺎ اﺳـﺘﻔﺎده از آﮔﻮﻧﻴﺴـﺖ ﻣﺘﻌﺎﻗﺒﺎً اﻳﻦ ﮔﻴﺮﻧﺪه ﺗـﺎزه ي اﺳـﺘﺮادﻳﻮل در ﻣـﻮش [38] و اﻧﺴـﺎن اﺧﺘﺼﺎﺻﻲ ﮔﻴﺮﻧﺪه ي ﺑﺘﺎي اﺳـﺘﺮادﻳﻮل ﺑـﻪ ﺑﺮرﺳـﻲ ﻧﻘـﺶ آن در ﻛﺸﻒ ﺷﺪ [26]. اﻳﻦ دو ﻧﻮع ﮔﻴﺮﻧـﺪه اﺳـﺘﺮوژﻧﻲ ﺗﻮﺳـﻂ ژ نﻫـﺎي ﻣﻨﻄﻘﻪ CA1 ﻫﻴﭙﻮﻛﺎﻣﭗ ﻣﻮش ﻫﺎي ﺻﺤﺮاﺋﻲ ﻧﺮ ﺑـﺎﻟﻎ در دﺳـﺘﮕﺎه ﺟﺪاﮔﺎﻧﻪ اي ﻛﺪ ﻣﻲﺷﻮﻧﺪ (ﮔﻴﺮﻧﺪه آﻟﻔﺎ اﺳﺘﺮادﻳﻮل ﺗﻮﺳﻂ ﻛﺮوﻣـﻮزوم اﺟﺘﻨﺎﺑﻲ ﻏﻴﺮ ﻓﻌﺎل ﺑﭙﺮدازﻳﻢ. 6 و ﺑﺘﺎ ﺗﻮﺳﻂ ﻛﺮوﻣﻮزوم 14) و اﻳﺰوﻓﺮم ﻳﻜﺪﻳﮕﺮ ﻧﻴﺴـﺘﻨﺪ [38]. در اﻧﺴﺎن ﻣﻘﺪار ﻧﺴﺒﺘﺎً زﻳﺎدي از ERβ در ﻫﻴﭙﻮﻛﺎﻣﭗ، ﻗﺸﺮ، ﻛﻼﺳﺘﺮوم ﻣﻮاد و روشﻫﺎ ﻳﺎﻓﺘﻪ ﺷﺪه اﺳﺖ، در ﺣﺎﻟﻴﻜﻪ، ﺑﺮ ﺧﻼف ERα، ﻣﻘﺪار ﻛﻤﺘﺮي از آن در ﻫﻴﭙﻮﺗــﺎﻻﻣﻮس و آﻣﻴﮕــﺪال وﺟــﻮد دارد [29]. در ﭘﺮﻳﻤﺎدﻫــﺎ و ﻣﻮش ﻫﺎي ﺻﺤﺮاﺋﻲ ﻧﺮ ﺑﺎﻟﻎ ﻧﮋاد وﻳﺴـﺘﺎر (200 -250 ﮔﺮﻣـﻲ) از ﺟﻮﻧﺪﮔﺎن ﻫﺮ دو ﻧـﻮع ﮔﻴﺮﻧـﺪه اﺳـﺘﺮادﻳﻮل، آﻟﻔـﺎ و ﺑﺘـﺎ در ﻧـﻮاﺣﻲ ﺑﺨﺶ ﭘﺮورش و ﺗﻜﺜﻴﺮ ﻣﻮﺳﺴﻪ ﭘﺎﺳﺘﻮر اﻳﺮان ﺗﻬﻴﻪ ﺷﺪ. ﺣﻴﻮاﻧـﺎت در ﻣﺨﺘﻠﻔﻲ از ﻣﻐﺰ ﻳﺎﻓﺖ ﻣﻲﺷـﻮﻧﺪ، در ﻫﻴﭙﻮﻛﺎﻣـﭗ ﻧﺴـﺒﺖ ﺑـﺎﻻﻳﻲ از ﺷﺮاﻳﻂ 12 ﺳﺎﻋﺖ روﺷـﻨﺎﻳﻲ و 12 ﺳـﺎﻋﺖ ﺗـﺎرﻳﻜﻲ (روﺷـﻨﺎﻳﻲ از 7 ERβ/ERα وﺟﻮد دارد [31،14،1]. ﺻﺒﺢ) و دﻣﺎي 2 ± 23 درﺟﻪ ﺳﺎﻧﺘ ﻲﮔﺮاد ﻧﮕﻬـﺪاري ﺷـﺪﻧﺪ و آب و دﻳﺪه ﺷﺪه اﺳﺖ ﻛﻪ اﺳﺘﺮادﻳﻮل اﺛﺮات ﺣﺎدي ﺑﺮ ﻫﻴﭙﻮﻛﺎﻣﭗ دارد ﻏﺬا ﺑﻪ ﻣﻘﺪار ﻛﺎﻓﻲ در اﺧﺘﻴﺎر آﻧﻬﺎ ﻗﺮار ﮔﺮﻓﺖ. در اﻳﻦ ﻣﻄﺎﻟﻌﻪ ﻣﻄﺎﺑﻖ و ﺑﺎﻋﺚ ﺑﺎﻻ رﻓﺘﻦ ﺣﺎﻓﻈﻪ ﻓﻀﺎﻳﻲ ﻣـﻲ ﺷـﻮد ﻛـﻪ ﻣﻤﻜـﻦ اﺳـﺖ از ﺑﺎ ﺗﻮﺻﻴﻪ ﻫﺎي ﺑﻴﺎﻧﻴﻪ ي Helsinki و ﻗـﻮاﻧﻴﻦ ﭘﺬﻳﺮﻓﺘـﻪ ﺷـﺪ هي ﺑـﻴﻦ ﻃﺮﻳﻖ ﻓﻌﺎﻟﻴﺖﻫﺎي ژﻧﻮﻣﻴﻚ ﮔﻴﺮﻧﺪه ﻫﺎي اﺳﺘﺮادﻳﻮل ﺑﺎﺷﺪ [30]. ﻫﺮ اﻟﻤﻠﻠﻲ در ارﺗﺒﺎط ﺑﺎ ﺣﻴﻮاﻧﺎت آزﻣﺎﻳﺸﮕﺎﻫﻲ، ﺑﺎ ﺣﻴﻮاﻧﺎت رﻓﺘﺎر ﺷﺪ. دو ﻧﻮع ﮔﻴﺮﻧـﺪه ﺧـﺎرج ﻫﺴـﺘﻪ اي ERβ و ERα در ﻫﻴﭙﻮﻛﺎﻣـﭗ و 7-8 روز ﻗﺒﻞ از اﻧﺠﺎم آزﻣﺎﻳﺶ رﻓﺘﺎري ﺣﻴﻮاﻧﺎت ﺗﺤﺖ ﺟﺮاﺣﻲ آﻣﻴﮕﺪال ﻣﺘﻤﺮﻛﺰ ﺷﺪه اﻧﺪ، دو ﻣﻨﻄﻘﻪ اي ﻛـﻪ ﺗﻨﻈـﻴﻢ ﻛﻨﻨـﺪه ﻫـﺎي ﻗــﺮار ﻣــ ﻲﮔﺮﻓﺘﻨــﺪ. ﻣﺨﻠــﻮﻃﻲ از ﻛﺘــﺎﻣﻴﻦ (mg/Kg, i.p 100) و ﻣﻬﻤﻲ ﺑﺮاي ﻳﺎدﮔﻴﺮي و ﺣﺎﻓﻈﻪ ﻫﺴﺘﻨﺪ [19]. زاﻳﻠــﻮزﻳﻦ (mg/Kg, i.p 25) ﺑﺼــﻮرت درون ﺻــﻔﺎﻗﻲ ﺑﻤﻨﻈــﻮر اﺳﺘﺮادﻳﻮل ﺑﺮاي ﺑﺴﻴﺎري از رﻓﺘﺎرﻫﺎ از ﺟﻤﻠﻪ رﻓﺘﺎرﻫﺎي ادراﻛﻲ ﺑﻴﻬﻮش ﻛﺮدن ﺣﻴﻮاﻧﺎت ﺗﺰرﻳﻖ ﺷـﺪ [10،25]. ﺳـﭙﺲ ﺑﺼـﻮرت دو 255 ERβ و ﻳﺎدﮔﻴﺮي اﺟﺘﻨﺎﺑﻲ ﻏﻴﺮﻓﻌﺎل ﺷﺮﻳﻒ ﺧﺪاﻳﻲ و ﻫﻤﻜﺎران ﻃﺮﻓﻪ در ﻣﻨﻄﻘﻪ ﺑﺎﻻي CA1 ﺑﺎ اﺳﺘﻔﺎده از اﻃﻠـﺲ ﭘﺎﻛﺴـﻴﻨﻮس و ﻣﻴﻠﻲ آﻣﭙﺮو ﻣﺪت 5/1 ﺛﺎﻧﻴﻪ) ﺑﻪ ﻛﻒ دﺳﺖ و ﭘﺎﻫﺎي ﺣﻴﻮان داده واﺗﺴﻮن (AP:-3.8mm از ﺑﺮﮔﻤﺎ، ML: ±2.2mm از ﺧﻂ وﺳـﻂ ﻣﻲ ﺷﺪ 5 ﺛﺎﻧﻴﻪ ﭘﺲ از ﺷﻮك درب ﮔﻴﻮﺗﻴﻨﻲ ﺑـﺎز ﺷـﺪه و زﻣـﺎن و DV: -2.7mm از ﺳﻄﺢ ﺟﻤﺠﻤﻪ) ﻛﺎﻧﻮ لﮔﺬاري ﺷﺪ. دوﭘـﻴﭻ در ﺧﺮوج ﻣﻮش ﻣﺤﺎﺳﺒﻪ ﻣﻲ ﮔﺮدد. ﭘﺲ از ﺧﺮوج ﺣﻴﻮان 120 ﺛﺎﻧﻴﻪ اﻃﺮاف ﻛﺎﻧﻮل ﻫﺎ در ﺟﻤﺠﻤﻪ ﺑﺮاي ﺛﺎﺑﺖ ﻧﮕﻪ داﺷـﺘﻦ ﻛـﺎﻧﻮل ﻗـﺮار ﺑﻪ او اﺟﺎزه داده ﻣﻲ ﺷﺪ ﺗﺎ در ﻗﺴﻤﺖ روﺷﻦ ﺑﺎﻗﻲ ﺑﻤﺎﻧـﺪ، ﻋـﺪم دادهﺷﺪ و ﺗﻮﺳﻂ ﺳﻴﻤﺎن دﻧﺪاﻧﭙﺰﺷﻜﻲ ﻣﺤﻜﻢ ﺷﺪﻧﺪ. ورود ﺣﻴﻮان ﺑﻪ ﻧﺎﺣﻴﻪ ﺗﺎرﻳﻚ ﺑﻪ ﻣـﺪت 120 ﺛﺎﻧﻴـﻪ ﺑـﻪ ﻋﻨـﻮان ﺗﺰرﻳﻖ درون ﻫﻴﭙﻮﻛﺎﻣﭗ از ﻃﺮﻳﻖ ﻛﺎﻧﻮل ﻫﺎ ﺗﻮﺳﻂ ﺳﻮز نﻫـﺎي ﻳﺎدﮔﻴﺮي (اﻛﺘﺴﺎب) ﻣﻮﻓﻖ در ﻧﻈﺮ ﮔﺮﻓﺘﻪ ﻣـﻲ ﺷـﺪ.
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