Njira yatsopano yowonetsera njuga-monga khalidwe mu makoswe a laboratory: kugwiritsa ntchito kudzipangitsa munthu kukhala wokondweretsa ngati chitsimikizo chabwino (2014)

Stephanie E. Tedford^1,2*, Nathan A. Holtz^1,2, Amanda L. Persons^{1,2 †} ndi T. Celeste Napier^1,2,3

• ¹Dipatimenti ya Pharmacology, Center for Compulsive Behaeve and Addiction, Rush University Medical Center, Chicago, IL, USA
• ²Dipatimenti ya Pharmacology, Rush University Medical Center, Chicago, IL, USA
• ³Department of Psychiatry, Rush University Medical Center, Chicago, IL, USA

Kutchova njuga kwawonetsero ndi chimodzi mwazomwe zimawonetsa zovuta kuzilamulira. Zomwe zimayambitsa zovuta izi pakadali pano ndizovuta ndipo chithandizo sichabwino. Mitundu ya zinyama yokhala ndi zovuta zowongolera ndi chida chofufuzira chofunikira kuti timvetsetse vutoli komanso popanga mankhwala. Kuyerekeza machitidwe ovuta ngati amenewa ndi kovuta, koma chifukwa cha kukonzedwa kwake, asayansi achulukanso minyama yovuta kwambiri pa kutchova juga. Gawo limodzi la njuga ndikupanga chisankho cha ndalama / phindu pamene munthu amayeza ndalama zomwe akuyembekezeredwa komanso phindu lochita. Ngozi / mphotho, zozengereza komanso chisankho pochita khama zonse zimayimira zosankha za mtengo / phindu. Izi zimawerengedwa mwa anthu ndipo zidasinthidwa kukhala mapuloteni amanyama kuti athe kuyesa popanga zisankho. Pachikhalidwe, cholimbikitsa chofunikira chomwe chimagwiritsidwa ntchito mu maphunziro a nyama ndi chakudya. Pano, tikufotokozera momwe kudzidulira kokhazikika komwe kumagwiritsidwira ntchito popanga ndalama / zopangira chisankho ndikuwunikira maphunziro athu aposachedwa omwe akuwonetsa momwe njira zamankhwala zimasinthira machitidwe amtundu wa labotale. Tikupangira kuti mitundu iyi ikhoza kukhala yothandiza pakuwunika zida zatsopano kuti athe kulimbikitsa ndi kupewa mbali za machitidwe a njuga.

Introduction

Vuto kapena kutchova njuga kosavomerezeka, kuphatikiza mkhalidwe wovuta kwambiri womwe umatchedwa kutchova njuga, umadziwika ndi zizolowezi zomwe nthawi zambiri zimapitilira kwa nthawi yayitali. Mavuto otchova njuga amatha kukhala ndi vuto lalikulu pa thanzi la munthu, ntchito komanso ndalama. Mu makumi awiri apitawa, mwayi wa njuga wawonjezeka kudzera pakusintha kwa malamulo ndikukhazikitsa malo atsopano (mwachitsanzo, kutchova juga pa intaneti). Chifukwa chake, kufalikira kwa vuto la kutchova njuga kwayamba. Palibe chithandizo chovomerezeka ndi FDA chothetsa vutoli, chifukwa chake, ndikofunikira kuti amvetsetse zamakhalidwe kuti apange njira zothandizira kwambiri.

Mavuto otchova njuga ndi chinthu chovuta, chomwe chimaphatikizapo kupanga zisankho mosafunikira (Alessi ndi Petry, 2003; Dixon et al., 2003; Holt et al., 2003; Kraplin et al., 2014) zomwe zimachokera pakuwunika koyipa kwa mtengo / mapindu. Kuyesedwa kwa kachipangizidwe popanga zisankho, zomwe nthawi zambiri zimagwiritsa ntchito kufufuza ndi zida zogwiritsa ntchito pakompyuta, zakhala zothandiza pofufuza zosankha zosankha zingapo m'mitundu yosiyanasiyana kuphatikizira otchovera njuga (Ledgerwood et al., 2009; Madden ndi al., 2009; Michalczuk et al., 2011; Petry, 2011; Miedl et al., 2012). Kuyesedwa kwamankhwala kumapangidwa pafupipafupi malinga ndi zosiyana zitatu, kuchuluka, kuchuluka kwa malingaliro / kupanga zisankho, kuphatikiza zotsatirazi: (i) kuchuluka kwazomwe zingachitike pakupeza mphotho (zowopsa / kupanga zisankho), (ii) kuchedwetsa zomwe zachitika musanafike pakubweza mphoto (kusankha mochedwa), ndi (iii) kuchuluka kwa khama lomwe mungafunike kuti mulandire mphotho (kupanga chisankho pofikira). Ntchito zingapo zakonzedwa kuti ziziwunika zofunikira popanga zisankho zochepa kuti timvetsetse njira zomwe zimapangira njuga. Mu ntchito izi, mutu umasankha pakati pa mphotho yaying'ono komanso yayikulu, iliyonse yomwe imalumikizidwa ndi zovuta zina zoyankhidwa. Kupanga chisankho / kupereka mphotho (mwachitsanzo, kuchotsera pamitengo), maphunziro amasankha pakati pa mphotho yaying'ono yomwe imaperekedwa mosasunthika pamitengo yayikulu (mwachitsanzo, mwayi wa 100% wolandila $ 10) ndi mphotho yayikulu yomwe iperekedwa pamiyeso yosiyanasiyana (mwachitsanzo, 10-80 % mwayi wolandila $ 100). M'maphunziro azachipatala komanso kafukufuku wam'mbuyomu, kusapezeka kwa mphotho yomwe mukuyembekeza ndi gawo lomwe limapangitsa mayankho ofanana a thupi (Douglas ndi Parry, 1994; Papini ndi Dudley, 1997). Makonda pazachikulu, "zowopsa" pazocheperako, kusankha kwina kumawoneka kuti kukuwonetsa kupanga zisankho zodziwikiratu, ndipo zalembedwa kaamba ka maupangiri angapo a anthu omwe amawonetsa kukhudzidwa kopitilira muyeso (Reynolds et al., 2004; Rasmussen et al., 2010; Dai et al., 2013). Popanga chisankho pozengereza (mwachitsanzo, kuchotsera kuchepa, kusankhika mwachangu), mphotho yaying'ono imaperekedwa posankha chisankho, pomwe mphotho yayikulu imaperekedwa pambuyo pa kuchedwa kosintha, mwachitsanzo, $ 10 tsopano kapena $ 100 m'masabata a 2). Anthu omwe akuwonetsa kukhudzidwa kwakukulu akuwonetsa zokonda zopezeka nthawi yomweyo (ngakhale zitakhala zazing'ono), mphoto zomwe zachedwa (ngakhale zitakhala zazikulupo) ngakhale njira yotsatirayi ikhoza kukhala yopindulitsa kwa iye (Crean et al., 2000; Reynolds et al., 2004; Bickel et al., 2012). Popanga chisankho pochita khama, mutu umasankha pakati pa mphotho yaying'ono yomwe yaperekedwa potsatira khama lochepa, kapena mphotho yayikulu yomwe wapatsidwa pambuyo poyesetsa kwakukulu. Mu ntchitoyi, kusankha kwa munthu aliyense payekha chifukwa cha khama lalikulu / mphotho yayikulu komanso "pompopompo" pomwe munthu wasinthira ntchito yotsimikiza / ya mphotho yaying'ono. Kafukufuku wopanga zisankho zoyeserera zamagetsi amtundu wa anthu pakadali pano sanachitikebe, koma angakhale ndi chidwi chofunikira pakuwunika ntchito yanthawi yayitali.

Ndondomeko zopangira zisankho zomwe zimagwiritsidwa ntchito pakuwunika kachipatala zimatha kusinthidwa kuti apange chisankho pakupanga ma labotale, ndipo zitsanzozi ndizofunikira pakuwunikira magwiridwe antchito ndi ma neuropharmacological pamasewera a pathological. M'makola, kusankha kwaubweya kumatha kuyesedwa ndikuyika nyamayo m'chipinda chogwiritsira ntchito, ndikuwalola nyamayo kuti isankhe pakati paopendekera awiri (kapena awiri-nose-poke hoppers) omwe amapezeka nthawi imodzi. Kukhazikitsidwa kwa mphotho kokhazikika kwa zotsimikizika zabwino muzogwira ntchito ndi chakudya (Stopper ndi Floresco, 2011; Eubig et al., 2014). Takambirana pano za njira yatsopano yomwe imagwiritsidwa ntchito mu labotore yomwe imagwiritsa ntchito njira zolimbikitsa zamagetsi zamagetsi (kutsatsa chidwi kwina; ICSS) kuwunika popanga zisankho / zopindulitsa mu makoswe komanso momwe operekera monoaminergic neurotransmitters posankha zochita (Rokosik ndi Napier, 2011, 2012; Tedford et al., 2012; Anthu et al., 2013).

Kulimbikitsa Kudzidalira

Chowonjezera cholimbikitsa ndi chotsitsimutsa, chomwe chimadalira pachitapo china, chimawonjezera mwayi obwereza womwewo. Intracranial kudzidzimutsa (ICSS) ndi machitidwe ogwirira ntchito pomwe nyama zimadziyendetsa zamagetsi kukondweretsa kumagawo aubongo amadziwika kuti amatenga nawo gawo pakulimbikitsa. ICSS idaphunziridwa koyamba mu 1950s pomwe James Olds ndi Peter Milner (Olds ndi Milner, 1954) adatsimikiza kuti makoswe abwereranso kumalo omwe ali m'bokosi momwe adalandirira magetsi kuti alandire madera okhudzana ndiubongo. Adalola makoswe kuti azigwira ntchito yolimbikitsa ubongo wamagetsi (EBS) poyankha pamanambala ogwiritsa ntchito (mwachitsanzo, kukanikiza wolumikizira, kupindika gudumu) (Olds ndi Milner, 1954). Kupeza kwa njirayi kwathandizira pakupanga njira zopangira muubongo wonse, ndipo ngakhale kuli zigawo zambiri zaubongo zomwe zingagwiritsidwe ntchito kuthandizira ICSS (Olds ndi Milner, 1954; Wanzeru ndi Bozarth, 1981; Wanzeru, 1996,, zidalembedwa bwino bwino kuti kukondoweza kwa mitsempha ya mandial forebrain (MFB) kumalimbikitsa zotsatira zabwino komanso zodalirika pakuchita (Corbett ndi Wise, 1980; Pirch et al., 1981; McCown et al., 1986; Tehovnik ndi Sommer, 1997). Magawo azomwe azidzalimbikitsa pano akhoza kuwongolera kuti akhudze phindu la EBS ndikusintha kachitidwe ka ICSS. Ndondomekozi zimaphatikizapo kukula (monga, amperes) zamagetsi zamagetsi komanso ma frequency amakono (mwachitsanzo, hertz). Kukweza m'magawo onsewa kumapangitsa kuti ma neurons oyenera alandire mphotho, mwina mwa kukulitsa kuchuluka kwa ma neuroni oyambitsidwa ndi kukondoweza (amperes) (Keesey, 1962; Wise et al., 1992) kapena mwakuchulukitsa kuchuluka komwe anthu a neurons fire (hertz) (Wanzeru ndi Rompre, 1989; Wanzeru, 2005). Kulipira kwachilengedwe kwamakono kumasintha kuchuluka kwa ma neuron ophatikizidwa, mwachitsanzo, mphamvu zazikulu zamakono zimakhudza kuchuluka kwa ma neuron kuposa mafunde ang'onoang'ono. Chifukwa chake, pamene gawo ili limasungidwa mosalekeza, kuchuluka kwa ma neuron okondweretsedwa ndi EBS kuli kofanana ngakhale kufalikira kwakanthawi. Kusintha kwapangidwe kosinthira kwa protocol izi ndizosinthasintha pakalipano, chifukwa kusankha kumeneku kumatilola kuwongolera kuwombera kwa gulu lomwelo la ma neurons omwe ali ndi zotsatira zochepa pa nthawi kapena malo osakanikirana. Mwa kuwongolera magawo awa a EBS, tapanga mitundu yazosankha zamagetsi / zopangira phindu zomwe zimagwiritsa ntchito ICSS (Rokosik ndi Napier, 2011, 2012; Tedford et al., 2012; Anthu et al., 2013). Kugwiritsira ntchito uku kukuimira kuchoka kwakukulu kuchokera pachikhalidwe chogwiritsa ntchito cholimbikitsa (mwachitsanzo, chakudya) pantchito popanga chisankho mu makoswe. ICSS ikhoza kukupatsirani maubwino angapo oyesera pazolimbikitsa chikhalidwe. Kupangitsa othandizira kuyankha chakudya, kudya tsiku ndi tsiku nthawi zambiri kumakhala koletsa (Feja ndi Koch, 2014; Hosking et al., 2014; Mejia-Toiber et al., 2014). Izi zitha kusokoneza mayendedwe, chifukwa kuchuluka mu mitsempha yama cell yomwe imasinthidwa panthawi yoletsa zakudya komanso yomwe imasankha zochita mwachisawawa (Schuck-Paim et al., 2004; Minamimoto et al., 2009). Kuphatikiza apo, nyama zomwe zimalimbikitsidwa ndi chakudya zimakhuta gawo lonse, zomwe zimachepetsa kufunika kwa chakudya chokwanira (Bizo et al., 1998,, ngakhale izi zitha kukhala zodalira kukula kwakuwezerera (Pereka et al., 1995). Mosiyana ndi kulimbikitsidwa kwa chakudya, mtengo wotsimikizika wa EBS ukhazikika pokhazikika, kulola kuwunika kokwanira komanso kosasintha kakhalidwe (Trowill et al., 1969). Izi zimathandizira kuti magawo oyeserera aoneke mobwerezabwereza tsiku lonse, zomwe zingakhale zothandiza pophunzira zovuta zamankhwala omwe amachitika chifukwa cha mankhwala. Kafukufuku wathu wotsitsa omwe adafotokozedwa (omwe tafotokozeredwa pansipa) anali kuchitidwa kangapo patsiku mukudwala matenda onse a dopamine agonist (pramipexole). Tikuganiza kuti mapindu ake amathandizidwe kuumoyo wa anthu ndipo potero amatipatsa zotsatira zakutanthauzira. Mpaka pano, kafukufuku wofanananso yemwe amawunika dopamine agonist pamapangidwe opanga chisankho pogwiritsa ntchito mphotho ya chakudya adangoyesa chithandizo chamankhwala chovuta kwambiri (St Onge ndi Floresco, 2009; Zeeb et al., 2009; Madden ndi al., 2010; Johnson et al., 2011; Koffarnus et al., 2011) ndipo zidzakhala zosangalatsa kwambiri kuyerekezera zotsatira zaumoyo wanu motsatizanatsatizana komanso pakukhazikika kwa chithandizo chamankhwala pakati pa othandizira awa osiyanasiyana. Ngakhale ICSS imapereka maubwino angapo pakulimbikitsa chakudya, ICSS imaperekanso zovuta zingapo. Mwachitsanzo, ICSS imafuna kuchitidwa opareshoni muubongo ndi kuchira, ndipo masiteji osakwanira am'mutu amatha kuchititsa kutaya maphunziro mu paradigm yamakhalidwe. Ngakhale zili zovuta izi, timakhulupirira kuti ICSS ndi njira yina yolimbikitsira chakudya ndipo imapereka zabwino zambiri pakulimbikitsa chakudya muzochita zathu.

Ntchito zopanga mtengo / phindu zimafunikira kusankha pakati pa zosankha zomwe zimagwirizanitsidwa ndi kuchuluka kosiyanasiyana kwamalipiro. Poyeneranso, othandizira omwe amagwiritsidwa ntchito ntchito izi akuyenera kuwonetsa kuthekera kopangira kusintha kwakukulu mukulumikizana kwa mphotho ndipo makoswe amayenera kusankhana pakati pa chosunga chocheperako (SR) ndi chosankha chachikulu (LR). Njira zomwe zimagwiritsidwa ntchito pophatikiza chakudya, zimakwaniritsidwa mwa kusintha kuchuluka kwa chakudya chomwe chapezeka pambuyo poyankha. Mu ICSS, EBS ikhoza kusinthidwa mwa kusintha makulidwe amakono kapena pafupipafupi. Chithunzi 1 ikuwonetsa kuyankha kwa lever komwe kumachitika pakulimba mphamvu zamtundu wamakono (mwachitsanzo, pafupipafupi zomwe zimachitika mobwerezabwereza; Chithunzi 1A) kapena ngati ma frequency amakono akusinthidwa (mwachitsanzo, mphamvu zamakonozi zinkachitika mosalekeza; Chithunzi 1B). Dongosolo lililonse likasinthidwa, makoswe amawonetsa zolumikizira zochepa za EBS ndikuwonetsa kuchuluka kwa kukakamiza kwa mfundo zazikulu za EBS, ndikuwonetsa kuti phindu lolimbikitsira lalikulikulikululi ndilakulirapo (posasamala ngati kuchuluka kapena kufalikira kwamakono). EBS imatha kugwiritsidwa ntchito ngati yolimbikitsira yaying'ono komanso yayikulu pakufunika kwa njira / phindu popangira zisankho. Izi zofunikira kutsimikizika zitha kutsimikiziridwa mu makoswe amtundu uliwonse mwa kupangitsa kukhazikika kwa zotsamira pamiyendo ya nyama iliyonse (Rokosik ndi Napier, 2011, 2012). Mwanjira ina, kupindika kwa anthu kumatha kupangidwa kuchokera ku gulu la makoswe omwe mtengo wokhazikika wa SR ndi LR ungatsimikizidwe (Tedford et al., 2012; Anthu et al., 2013). Njira yomalizirayi imapereka njira yogwiritsira ntchito nthawi yambiri komanso yodalirika yopezera SR ndi LR. Pazotsatira zingapo, tidagwiritsa ntchito maluso azachuma kapena pafupipafupi kukhazikitsa mfundo za SR / LR pantchito yochepetsa (mwachitsanzo, kuwopsa / kupanga zisankho). Zosintha pamalingaliro amakono olimbitsa mtima (mwachitsanzo, ma frequency amakono anali kuchitika mosasunthika) komanso mfundo zamakono zomwe zimachitika (mwachitsanzo, mphamvu zamakono zomwe zinali kuchitidwa mosalekeza) zonse zimatulutsa machitidwe ofunikira amtundu (makoswe) 1C, D). Kutengera mbali yotsika mtengo wopondaponda, kufalikira kwamakono kunatsimikizika kukhala njira yoyenera yolimbikitsira mfundo zolimbikitsira. Akakhazikika kuti makoswe amatha kusiyanitsa pakati pa ma pafupipafupi pano omwe amagwiritsidwa ntchito pa SR ndi LR, amatha kuyesedwa mumtundu uliwonse wamalingaliro athu opanga ma ICSS: (i) chiopsezo / kupanga zisankhoRokosik ndi Napier, 2011, 2012,, (ii) kusankha zochita posachedwa (Tedford et al., 2012,, kapena (iii) kupanga zisankhoAnthu et al., 2013).

 

Chithunzi 1. Zotsatira za magawo a kukondoweza kwa ubongo pamayendedwe atolankhani ndikuthekera kuchotsera. Magawo awiri a EBS omwe adayesedwa anali mwamphamvu pakali pano komanso pafupipafupi. Makina opangira makoswe amakakamizidwa ndi EBS (munthawi yowerengeka-1 yolimbitsa) momwe mphindi iliyonse ya 2, gawo limodzi la EBS linanyengedwa ndipo gawo lina linkasungidwa kosalekeza. (A) Kulakwitsa kwa mphamvu zamakono. Mphamvu zamakono kuyambira 10 mpaka 350 μA zidawonetsedwa mwachisawawa (n = 6); pafupipafupi zomwe zidachitika ku 100 Hz. (B) Kulakwitsa kwa pafupipafupi. Ma frequency apano kuyambira 5 mpaka 140 Hz adawonetsedwa mwachisawawa (n = 3); kulimba kwamakono kunachitika mosadukiza pamlingo wophunziridwa komanso wotsimikizika m'magawo aphunziro asanachitike. Kubwezera mwamphamvu pakali pano kapena pafupipafupi pakubweretsa njira zofananira za makina osunthira. Zambiri zikuwonetsedwa ngati zofunikira m'magawo atatu otsatizana. Makoswe adaphunzitsidwa ntchito yotsitsa komanso kufunika kwa othandizira ochepa komanso akulu adatsimikizika payekhapayekha nyama iliyonse pogwiritsira ntchito mphamvu zowonjezera zomwe zimachokera ku EBS vs. lever-Press curve curion that XicUMX and 60% Mwa okwera kwambiri osindikizira mayankho, motero. Kuthamangitsa kukula kwa mphamvu zamakono (C) kapena pafupipafupi pano (D) kunapangitsa kutsitsa kwakukulu kwa suppressor (LR) popeza kuthekera kwa kubala kunachepa (mwachitsanzo, kuchepa kwakusankha kwa lever yomwe imalumikizidwa ndi LR pazosankha zonse). Zambiri zikuwonetsedwa ngati zofunikira ± sem tsiku la kuchotsera pogwiritsa ntchito kulimbika kwaposachedwa ndi masiku a 2 achotsera pogwiritsa ntchito pafupipafupi. Chithunzi chosinthidwa kuchokera Rokosik ndi Napier (2011) komanso kusindikizidwa ndi chilolezo kuchokera kwa wofalitsa.

Kuthandizira Kugwiritsa Ntchito ICSS Kuunika Njira Zamphamvu Zopangira Chisankho komanso Kupanga Chisankho

Kupanga mitundu yatsopano ya zinyama kumafunikira kuganizira mozama zokhudzana ndi zovomerezeka. Chifukwa chake, pakupanga izi popanga zisankho zokhazikitsidwa ndi ICSS, tayesetsa kutsimikizira nkhope ndikumanga zowona, ndikuwonetsetsa kuti zingatheke.

Kutsimikizika kwa nkhope kumatanthawuza kuchuluka kwa momwe kuyeserera mosadukiza kumawonekera kuyeza zomwe zidakonzedweratu. Kapangidwe kamapangidwe asankha zodziyerekeza ndi ICSS kudakhazikitsidwa ndi mapuloteni apano omwe amagwiritsidwa ntchito mwa anthu kuti achedwetse komanso kuti athe kuchotsera mwayi (Rasmussen et al., 2010; Leroi et al., 2013) ndi ntchito zina zofunikira kupanga zisankhoTreadway ndi al., 2009; Buckholtz et al., 2010; Wardle et al., 2011). Mwa anthu, njira zowerengera mtengo / zopangira phindu zimachokera pakupempha anthu kuti asankhe pakati pa zosankha zingapo zomwe zikupezeka ndi zovuta zina zomwe zimayikidwa pakusankha kulikonse (mwachitsanzo, chiopsezo, kuchedwa, kapena kuyeserera). Timatengera mawonekedwewa popereka makoswe ndi ophatikizira awiri nthawi yomweyo, momwe kusankha kwa lever kumalumikizana ndi mphotho zazing'ono kapena zazikulu zomwe zimaperekedwanso mwatsatanetsatane wazovuta. Chifukwa chake, chilichonse mwamagawo athu opanga zisankho ku ICSS chikuwonetsa kuti ndizoyenera kuchita.

Kupanga kutsimikizika kumatanthawuza kuthekera kwa paradigm kuwunika molondola zomwe akufuna kuyeza. Zowopsa / kulandira mphotho komanso kupanga chisankho pang'onopang'ono, kukonda mphotho yayikulu kumachepera pamene mwayi woti ubweretsedwe umatsitsidwa, kapena kuchedwetsa kubweretsa mphotho kumawonjezeka, motsatira. Pakusankha zochita, anthu amawonetsa kukondera koyamba pa mphotho yayikulu. Kusunthira makonda pantchito yotsika / mphotho yaying'ono imawonedwa pamene kuyesayesa kwakukulu sikulinso kofunika kuti ndalama ziwonongeke. Zinalembedweratu kuti makoswe amawonetsa machitidwe ofanana ndi omwe ali pachiwopsezo / mphotho, zozengereza komanso zosankha zoyeserera poyerekeza ndi anthu (Rachlin et al., 1991; Buelow ndi Suhr, 2009; Jimura et al., 2009), ndipo taona izi m'machitidwe athu onse (Rokosik ndi Napier, 2011, 2012; Tedford et al., 2012; Anthu et al., 2013) (Mwachitsanzo, onani Chithunzi 2).

 

Chithunzi 2. Zotsatira za pramipexole pa chiopsezo / kupanga mphotho pogwiritsa ntchito mwayi wochepetsa. Chronic (±) PPX imatsitsa kuchotsera mu PD-ngati (A) ndi zamalamulo (B) makoswe. Pofotokoza mwachidule za ntchitoyi, PD-like (n = 11) ndi kuwongolera kwa sham (n = 10) makoswe amaphunzitsidwa ntchito yotsitsa yomwe ingagwiritsidwe ntchito ICSS. Zoyeserera zokhudzana ndi kutumiza kwa cholimbitsa chachikulu (LR) zimaperekedwa mwadongosolo la pseudo. Khalidwe lokhazikika litawonedwa, makoswe amathandizidwa mosapweteka ndi jakisoni kawiri tsiku lililonse la 2 mg / kg (±) PPX ya masiku a 13. Zomwe zikuwonetsedwa zinasonkhanitsidwa kuyambira nthawi yomwe tinawona momwe zimakhalira patsiku lomaliza la mankhwalawa (mwachitsanzo, jakisoni wa 6 h) ndipo timayerekeza ndi choyambira (BL). Chowonetsedwa ndi kuchuluka kwa kusankha kwa LR (mwachitsanzo, kusankha kosankha) motsutsana ndi mwayi womwe LR idaperekedwa. A r-njira ziwiri rmANOVA ndi posachedwa Newman-Keuls adawonetsa kuchuluka kwakukulu pakusankha kosatsimikizika, LR yotsatira PPX yothandizira (*p <0.05) yamagulu onse a PD-like and sham rat. Ngakhale kuchuluka kwamagulu kukuwonetsa kuwonjezeka kwa PPX pakuchepetsa zisankho / kupanga mphotho, makoswe awiri pagulu lirilonse adawonetsa kuchepa kwa 20% kuchokera pazoyambira pazoyesera zotsika kwambiri zoyesedwa; Chifukwa chake, makoswe ena amawoneka osaganizira kuthekera kwa mankhwalawa kuti athe kusintha kuchotsera komwe kungachitike. Chithunzi chosinthidwa kuchokera Rokosik ndi Napier (2012) komanso kusindikizidwa ndi chilolezo kuchokera kwa wofalitsa.

Kulosera zamtsogolo kumatanthawuza kuthekera kwamamodeli kuti muwone zamtsogolo zamtsogolo, ndipo tikuyesa kuti mitundu yathu itha kugwiritsidwa ntchito kulosera za kuthekera kwa mankhwala azachipatala asinthira kupanga zisankho za mtengo / phindu. Ndiye kuti, powonetsa chitsimikiziro chazinthu pobwereza zomwe ochita zamankhwala amachita pamakhalidwe opangira zisankho omwe akhazikitsidwa kale mwa anthu, tikupangira kuti mitundu yathu itha kukhala yothandiza kulosera momwe mankhwala ena angatithandizire kutengera izi kuchipatala . Mwachitsanzo, kagawo ka odwala omwe ali ndi matenda a Parkinson (PD) omwe amathandizidwa ndi mankhwala a dopamine agonist amawonetsa kuchuluka kwa njuga (Weintraub et al., 2010) ndikuchulukitsa kuchotsera pakupanga chisankho pofulumira (Housden et al., 2010; Milenkova et al., 2011; Voon et al., 2011; Leroi et al., 2013; Szamosi et al., 2013). Chifukwa chake, labotale yathu idayamba kutsata PD mu makoswe ndikuphunzira zovuta za pramipexole, dopamine agonist yemwe amagwiritsidwa ntchito ndi machitidwe amtundu wa juga (Weintraub et al., 2010), pa mtengo / kusankha popanga lingaliro pogwiritsa ntchito mwayi wotsitsa (ziwopsezo / kupanga mphotho) (Rokosik ndi Napier, 2012). Kuti tichite izi, makoswe adamasuliridwa "ngati PD" posankha masentensi am'malo a dopaminergic mkati mwa dorsolateral striatum kudzera infusions yapakati pa 6-OHDA, makoswe olamulira adalandira infusions wa galimoto ya 6-OHDA (Rokosik ndi Napier, 2012). Neurons mu dorsolateral striatum of the 6-OHDA kuphela makoswe othandizira amawonetsa kuchepa kwa tyrosine hydroxylase (Rokosik ndi Napier, 2012), chikhomo cha dopamine. Makoswe ngati PD akuwonetsa kusokonezeka kwamagalimoto ofanana ndi anthu omwe ali ndi PD-siteji yoyamba, yomwe imatha kubwezeretsanso mlingo-modalirika ndi chithandizo cha pramipexole. Mlingo wa pramipexole womwe tidapereka kuti tisanthule pochita zisankho zoopsa / za mphotho zimachepetsa zolakwika zamagalimoto, motero zimagwirizana ndi achire (Rokosik ndi Napier, 2012). Ngakhale sitimawona kusiyana pakakhalidwe ka "makina owopsa" pakati pa makoswe olamulira ndi makoswe okhala ngati PD, chithandizo cha pramipexole chokwanira chimawonjezera kusankha kwa LR yoopsa m'magulu onse a makoswe pamene kuthekera kwa kubereka kunali kochepa (Chithunzi 2A, B),, kuwonetsa kuti pramipexole imathandizira kupanga chiopsezo / kupanga mphotho. Izi zikugwirizana ndi maphunziro omwe ayesa zotsatira za pramipexole mwa anthu (Spengos et al., 2006; Pizzagalli et al., 2008; Riba et al., 2008). Komabe, timapereka chidziwitso chotsimikizika cha makanema athu pakuwonetsa ma mankhwala ena omwe atha kusintha pakati pa kupanga ndalama / phindu mwa anthu.

Tayesanso mirtazapine, anti-depressant wa-atypical, pantchito yopanga zisankho. Zizolowezi zokhudzana ndi chizolowezi komanso kugwiritsa ntchito mankhwala osokoneza bongo zimagawana zinthu zochulukirapo, kuphatikiza kupanga zisankho zochulukirapo, komanso maphunziro atsopano mwa anthu ndi nyama zosagwiritsidwa ntchito ndi anthu zimawonetsa kuti mirtazapine imathandiza kuchepetsa zizolowezi zomwe zimayambitsidwa ndi mankhwala osokoneza bongo (mwachitsanzo, opiates ndi psychostimulants) ngakhale zomwe zimagwirizanitsidwa. kubwereranso munthawi yakudziletsa (zowunikira, onani Manda et al., 2012). Zomwe zatulutsidwa kuchokera ku ICSS yolumikizirana pakati popanga zisankho pakuwonetsa ntchito zikuwonetsa kuti mirtazapine inachepetsa zokonda pakugwira ntchito molimbika / LR, kusinthira kuyesetsa kochepa / SR, ndikuwonetsa kuti kuchuluka kwa kufunikira kwa LR sikulinso "kofunika" iyo, ”kapena kuti mtengo wa LR udatsika (Anthu et al., 2013). Zotsatira izi zikuwonetsa kuti zingakhale zosangalatsa kudziwa zotsatira za mirtazapine pakuchita zisankho zochepa pamavuto omwe akutchova chipatala.

Kutsiliza

Mwachidule, tagwiritsa ntchito ICSS ngati cholimbikitsira chabwino muzolemba zingapo zomwe zimapangidwa kuti ziyeze zosiyana, komabe, zochulukirapo, zokhudzana ndi kupanga ndalama / kupanga zisankho zomwe zikuwonetsedwa mu njuga. Njirazi zitha kugwiritsidwa ntchito popitiliza kuthandizira p magawo osiyanasiyana a ma neuroanatomical substrates ndi ma neurotransmitter pamavuto a juga. Ntchito zophatikizidwa ndi ICSS zimapereka njira ina yabwino yolimbikitsira chakudya mu paradigms yovuta iyi. Tikukhulupirira kuti kutsimikizika kwa ntchitoyi kukuwonetsa kuti amatha kuthandizira kupenda mankhwala kuti athe kuyambitsa mavuto azovuta, monga kutchova njuga yamavuto, ndikuthandizira kuzindikira mankhwala omwe amachepetsa mavutowa.

Kutsutsana kwa Chidwi

Dr. Napier alandila chithandizo kuchokera ku National Institutes of Health, Michael J. Fox Foundation ndi National Center for Responsible Gaming. Dr. Napier adalandira chindapusa pa izi: kufunsira malo osapindulira phindu la maphunziro ndi maofesi amilandu pazinthu zokhudzana ndi zosokoneza ndi zovuta zowongolera; kuyankhula zakumwa pamisonkhano yamaholo amatauni, masukulu apamwamba, kusachita phindu, ndi misonkhano yamakhothi azachipatala; kupereka zowunikira za National Institutes of Health ndi mabungwe ena; ndi maphunziro ophunzira ndi kuzungulira bwino. Dr. Napier ndi membala wa Illinois Alliance pa vuto Kutchova Juga, ndipo amapereka upangiri waluso pakukonzekera kwa mankhwalawa ku Cures mkati mwa Research Foundation. Dr. Holtz, Dr. Persons, ndi Ms. Tedford alengeza kuti kafukufukuyu adachitika mopanda kuyanjana kwina kulikonse kwamalonda kapena ndalama komwe kumatha kuchitika ngati kusamvana kwa chidwi.

Kuvomereza

Ntchitoyi idathandizidwa ndi National Center for Responsible Gaming, a Michael J. Fox Foundation, a Daniel F. ndi Ada L. Rice Foundation, ndi USPHSGs NS074014 kwa T. Celeste Napier ndi DA033121 kwa Stephanie E. Tedford ndi T. Celeste Napier .

Zothandizira

Lolembedwa ndi:

Patrick Anselme, University of Liège, Belgium

Kuwunikira by:

Christelle Baunez, Center ya National de la Recherche Scientifique, France
Yueqiang Xue, The University of Tennessee Health Science Center, USA