Naloxone ke haɓaka incubated sucrose sha'awar rats (2007)

. Rubutun marubuci; yana samuwa a PMC 2010 Yuni 5.

An buga shi a cikin tsari na karshe kamar yadda:

PMCID: PMC2881196

NIHMSID: NIHMS205439

Abstract

Bayanin

Sha'awar cuwa-cuwa ta haifar da koma bayan magunguna kuma tana taimakawa ciwan abinci. An nuna masu adawa da adawa don yin tasiri wajen rage sha'awar kwayoyi da abinci. Nasiha, kamar yadda aka ayyana azama don kara kuzari da aka danganta da lada, karuwa, ko sanya katako, akan tilasta maye wajan tsarin komawar dabbobi.

manufofi

Wannan takarda tana nufin gano tasirin maganin opiate antagonist, naloxone, akan shigarwar sha'awar fata na sucrose.

Hanyar

106 maza Long-Evans rats lever sun matse don 10% sucrose bayani 2 h / rana don kwanakin 10. A kowane ɗayan 1 ko 30 na ƙauracewar tilastawa, berayen sun amsa cikin ƙarewa don 6 h sannan an allura (ip) tare da ko dai saline ko naloxone (0.001, 0.01, 0.1, 1, ko 10 mg / kg). Raan berayen sun amsa wa 1 h don gabatar da sautin + haske da aka gabatar a baya tare da kowane isar da nasara yayin horar da kai.

results

Berayen sun amsa daɗin ƙonewa kuma suna bin Saline a ranar 30 da rana 1 (wani ɓoyayyen abubuwan buƙatu). Fãce don Trend don ragewa da bin 10 mg / kg a ranar 1, naloxone ya kasance da farko tasiri a ranar 30. A ranar 30 na rana, naloxone ya rage mahimmancin amsawa a duk allurai sai dai don 0.1 mg / kg.

karshe

Haɓaka lokacin dogaro ga mai adawa da opiate ya yi daidai da canje-canje na dogaro da lokaci akan tsarin opiate sakamakon kauracewa tilastawa daga maye. Waɗannan canje-canje na iya ɗayan ɓarkewar sha'awar fata na maye gurbinsu. Bugu da kari, waɗannan binciken za a iya amfani dasu don tallafawa amfani da naloxone azaman maganin hana ƙwaƙwalwar ƙwayar cuta a cikin maye.

keywords: Addiction, Cin, Naltrexone, Kiba, Opiate, Reinforcement, Sakewa

Gabatarwa

Shaye-shaye ga ƙwayoyi da kuma halaye masu jaraba da ke tattare da abinci sun zama ruwan dare ( ; ; ). Kiba, a lokuta da yawa sakamakon cin abinci mai yawa, matsala ce ta musamman ga lafiyar jama'a yayin da adadin a Amurka ya ninka sau biyu a cikin shekaru 20 da suka gabata (CDC). Don rage irin waɗannan matsalolin da suka shafi jaraba, yana da mahimmanci a fahimci hanyoyin da ke ba da gudummawa ga yawan shan ƙwayoyi da cin abinci.

Ladaran abinci da magani ana yin su ne ta hanyar amfani da irin waɗannan hanyoyin jijiyoyi ( ). Duk da cewa sakamakon dogon lokaci na shan miyagun ƙwayoyi na iya bambanta da halayen abinci marasa dacewa dangane da canje-canjen kwakwalwa na zamani ( ), daidaitawar jijiyoyi da ke shiga tsakani game da koyo game da lada na azuzuwan daban-daban (misali, abinci vs magani) wataƙila iri ɗaya ne ( ). Irin waɗannan daidaitawa, da canje-canjen halaye (koyo) da suka dace, galibi ana yin nazari ne ta amfani da samfuran dabbobi na halayen jaraba ( ).

Komawa ga neman lada da aka haifar ta hanyar amfani da na'urar aunawa ( ) da kuma kwanan nan fahimtar neman abinci ( , ; ). A cikin wannan samfurin dabba, beraye suna amsawa don gabatar da wani abu mai ƙarfafawa (sautin+haske) wanda a da yake da alaƙa da bayar da lada kai. Ana ɗaukar girman amsawa a matsayin ma'aunin neman lada kuma yana aiki a matsayin ma'aunin "sha'awa". Ta amfani da wannan samfurin, mu da wasu mun gano kuma mun siffanta ƙaruwar da ta dogara da lokaci wajen amsawa ga alamun magani da abinci yayin kauracewa shan kai ( ; don sake dubawa). Baya ga gano cewa "ƙullawa" sha'awar sucrose yana da juriya ga magudin da aka tsara don rage shi (misali, ƙoshi da sucrose; ), mun gano cewa beraye ba su da saurin amsawa ga tasirin cocaine mai ƙarfi a cikin wata 1 na daina shan taba idan aka kwatanta da kwana 1 ( ). Wannan binciken yana nuna canje-canje da suka dogara da lokaci a cikin yanayin lada na kwakwalwa kuma ya sa muka yi la'akari da yadda irin waɗannan tsarin watsawa za su iya shafar, ko kuma su ba da gudummawa ga, ƙulla sha'awar sucrose.

Magungunan opiates tsarin zaɓi ɗaya ne. An gano cewa masu adawa da opiate (yawanci naloxone ko naltrexone) suna rage sha'awar abinci da cin abinci ta hanyar masu cin abinci da/ko masu kiba ( ; ). Suna kuma rage sha'awar sigari da barasa ( ; ). A cikin nazarin da aka yi da beraye, naltrexone yana rage amsawa ga alamun cocaine ( ), barasa bayan fallasa alamun barasa ( ), da kuma amsawa a gaban wani abin ƙarfafawa na nuna bambanci tsakanin barasa ( ). Bugu da ƙari, a cikin berayen da aka horar da hodar iblis, sun gano cewa heroin yana da tasiri mafi girma daga baya a cikin daina shan ƙwayoyi idan aka kwatanta da farkon dawo da halayen neman hodar iblis - wani ra'ayi mai alaƙa da ke nuna cewa ko dai tsarin DA ko tsarin opiate (ko duka biyun) yana canzawa yayin da ake sha'awar sha'awa. Sakin DA a cikin ƙwayoyin nucleus (NAcc) yana ƙaruwa/raguwa ta hanyar allurar microinjection na opiate agonist/antagonist zuwa yankin ventral tegmental (VTA; ; ) da endogenous opiates suna daidaita yawan cin abinci a cikin beraye ( ) gami da sha'awar cin abinci ( ). Saboda haka, kamar yadda muka lura da tasirin tilasta daina shan ƙwayoyi kan ƙarfin DA da ya shafi amsawa ga alamar sucrose-paired ( ), mun yi hasashen cewa za mu kuma ga tasirin da ya dogara da lokaci na magudi don shafar tsarin opiate akan amsawa ga alamar sucrose-paired.

A cikin wannan binciken, mun tantance tasirin naloxone mai adawa da opiate akan shigar sha'awar sucrose. Ganin cewa tasirin adawar opiate akan lada mai kyau, balle shigar sha'awar lada, ba a riga an bayyana shi sosai ba, mun zaɓi kewayon allurai masu yawa don bincikenmu. Masu bincike na baya ( ; ; ; ; ; ; ; ) sun bayyana tasirin da ya dace da ɗabi'a na naloxone da makamancin naltrexone a cikin ultralow (ƙasa zuwa 1 pg/kg), ƙasa sosai (30 ng/kg), da matsakaici (1-5 mg/kg) zuwa matsakaicin adadin allurai (har zuwa 20 mg/kg). Mun zaɓi allurai a cikin matsakaicin matsakaici zuwa babban kewayon domin allurai a cikin ƙaramin/matsanancin kewayon na iya yin karo da hanyoyin da ba na gargajiya ba (marasa toshewar masu karɓa) ( ).

kaya da matakai

Animals

Abubuwan da aka gabatar da su sun kasance ratsan Long-Evans na 106 (350 – 450 g) a sashen Western University of Psychology Department vivarium. An auna berayen a kowace Litinin, Laraba, da Jumma'a tsawon lokacin gwajin. An kiyaye berayen a Mazuri Rodent Pellets, kuma ana bayar da ruwan sha na libitum banda kamar yadda aka sani a cikin Manyan hanyoyin. An kuma samar da pelits da ruwa a libitum a cikin ɗakunan sarrafa kai sai dai kamar yadda aka sani a cikin hanyoyin gaba ɗaya. Dukkanin berayen suna zaune a wuri guda cikin vivarium banda lokacin horo na yau da kullun ko lokacin gwajin lokacin da aka kawo su ɗakunan gudanar da kai. An kiyaye berayen akan wani abin da ya juyo da 12: 12 h light – waree-duhu tare da fitilu a kashe a 7 AM Dukkanin hanyoyin da aka yi akan berayen sun bi ka'idodin NIH don kula da dabbobi kuma Kwamitin Kula da Dabbobi da Amfani da Yammacin Jami'ar Washington Washington sun amince dashi.

inji

Bersakunan kai-da-kai, wanda ke kula da wani tsari na Med Associates (Georgia, VT), yana da damisa biyu, amma ɗayan guda ɗaya (mai aiki, mai iya koma baya) yana kunna famfon. An buga bayanan latsa na ɗayan lever (mai aiki mara ƙarfi, a cikin lele). An kawo nasarar maganin mafita na 10% cikin rarar rarar ruwa don yawan amfani da baka (Med Associates). Chamakunan suna da tsararraki huɗu da masu ganowa (Med Associates) a jere a cikin tsarin tic-tac-ean kafa (katako gaban kowace 10.5 cm daga bango; katako a gefe kowane 6 cm daga bango) a saman ɗakin gudanarwar kai-tsaye, kowane 4.5 cm a sama bakin karfe mashaya. An lika emitters / masu gano abin da za a jera su akan plexiglass na ƙofa ko bangon baya ko a kan shigar da allikan plexiglass a bangon gefe. An saita katako don kirga adadin cikakkiyar karyewar ƙarfe. An haɗa tsarin ayyukan locomotor cikin tsarin tattara bayanan Med Associates.

Janar hanyoyin

An hana berayen ruwa a cikin kejin gidansu 17 h kafin fara horo na farko. Ba a samo ruwa a cikin ɗakunan gudanarwa na farko ba, amma an mayar da shi zuwa ɗakunan gudanarwa na kai lokacin da beraye suka koya don amintaccen amsa ga sucrose (> 20 sucrose delivery / day), ko kuma bayan kwanaki 3 na horar da kai game da berayen da sun yi jinkirin koyon latsa don sucrose. Ruwa ya dawo cikin keji bayan 48 h na rashi. Gwajin ya haɗa da matakai uku: horo, ƙaura, da gwaji. Kamar yadda aka bayyana a cikin Gabatarwa, amsawa a lokacin gwajin (yanayin sake dawowa) an ɗauke shi azaman fihiris ɗin sha'awar. Ba a taɓa ƙarfafa latsawa yayin gwaji ba tare da sucrose ba. Horarwa da gwaji sun fara ne da ƙarfe 8:30 na safe

Lokaci na horo

An horar da berayen don sarrafa kansa da kansu (0.2 ml) wanda aka ba dashi cikin jigon jigilar ruwa. An gudanar da horo a cikin lokutan 10-kullun na 2-h a karkashin tsarin jadawalin karfafawa (kowane ɗayan lever latsa) tare da lokacin 40-s bayan kowane sakamako da aka samu. Lever presses aka kirga lokacin lokacin aiki amma ba tare da sakamako ba. Kowane zama yana farawa da shigar da lila mai aiki da kuma haskewar farin cikin gida wanda ya ci gaba da zama a zaman gaba daya. Sautin 5-s (2,900 Hz, 20 dB sama da baya) + haske (7.5 W farin haske sama da mai lever mai aiki) kwatancen fili mai ma'ana tare da kowane bayarwa mai bayarwa. A karshen kowane zaman, an kashe hular kwano sai kuma lever din da yake aiki ya dawo dashi. Babu iyaka ga sakamakon ladan da aka samu.

Lokaci na tilastawa

A ƙarshen lokacin horon, an sanya beraye ( n = 8–11 beraye/rukuni) bazuwar zuwa ɗaya daga cikin lokutan tilastawa hana shan ƙwayoyi (kwanaki 1 ko 30). An kwatanta halayen horo (cin abinci mai ɗauke da sinadarin sucrose, aiki, da amsawar lever mara aiki) tsakanin ƙungiyoyi don tabbatar da cewa ƙungiyoyi ba su bambanta sosai da juna ba yayin horo. Berayen suna rayuwa a cikin vivarium na tsawon lokacin da aka tilasta musu shan ƙwayoyi. An ba da saline da rana na kwanaki 2 kafin a yi gwaji don kwantar da dabbobin zuwa allurai.

Matakin Gwaji: Amsar cirewa

A ranar gwaji, an bai wa dukkan berayen 6, 1-h zaman mahaɗa wanda aka raba ta da 5 min har sai sun kai matsayin ƙaddara mafi ƙarancin martani na 15 / 1 h akan tsohuwar lever da ke aiki. Sautin + hasken mai hankali mai ma'ana bai kasance yayin wannan zaman ba. Kowane zaman 1-h ya fara ne tare da gabatarwar fa'idodi na aiki da kuma hasken gidan motsa jiki. A karshen kowane zaman, an kashe gidan, sai kuma lever din da yake aiki ya ja da baya. An ba da berayen biyu a wani ƙarin lokacin yankewa na 1-h don isa ga matakin 15-martani / 1 h.

Matakin Gwaji: Amsawa game da alama

Wannan zaman ya fara ne daga mintuna na 5 bayan kammala taron karewar 1-h na karshe. Abun allurar ciki ta saline ko naloxone (0.001, 0.01, 0.1, 1, ko 10 mg / kg) ya faru nan da nan kafin wannan zaman. Gwajin gwaji na neman shigar da karar nasara ya kunshi zaman 1-h inda aka sami martani kan tsohuwar mai aiki da ta gabata wanda ya kai ga gabatar da sautin + haske a kan jadawalin karfafa ci gaba tare da kawancewar 40-s.

Lokaci na Gwaji: Aikin buɗe ido

An tattara ayyukan locomotor a duk lokacin gwaji.

Bayanan bayanai

Lokaci na horo

An bincika gabatarwar gabatar da nasara na yau da kullun (infusions), amsoshin lever na aiki, da kuma ba da amsawa na iyawa tare da matakan maimaitawa ANOVAs (RM ANOVAs) ta amfani da Lokaci (kwanakin 1 – 10 na horo) da ƙarin tsakanin abubuwan-rukuni na Rana (1 ko 30) da Dose (saline, 0.001, 0.01, 0.1, 1, ko 10 mg / kg naloxone) don tabbatar da cewa berayen sun gwada a maki daban-daban kuma tare da allurai daban-daban na naloxone sun sami horo daidai.

Matakin Gwaji

An yi nazarin bayanai daga zaman ƙarewa (amsawar ƙarewa) da gwaje-gwaje don neman sucrose da aka haifar da cue-induced (amsawa don alama) daban-daban don jimlar martanin da ba a ƙarfafa ba akan lever mai aiki a baya da kuma martani akan lever mara aiki. An yi nazarin waɗannan bayanan ta amfani da ANOVA tare da abubuwan tsakanin rukuni na Day (1 ko 30) da Dose (saline, 0.001, 0.01, 0.1, 1, ko 10 mg/kg naloxone). An gudanar da RM ANOVA na gaba akan lever mai aiki da ke amsawa da Extinction don tabbatar da cewa ƙungiyoyin da za a gwada da saline ko naloxone ba su bambanta ba kafin sarrafa magunguna. A cikin wannan ANOVA, Lokaci shine zaman ƙarewa na awanni 6, 1. An kuma yi nazarin jimlar ƙidayar locomotor daga Extinction Response da Response don zaman alama tare da ANOVAs daban-daban ta amfani da abubuwan Day da Dose. An gudanar da gwaje-gwajen t guda biyu tsakanin mai aiki da ke amsawa a cikin sa'a ta shida ta ƙarewa da kuma lokacin amsawa don nuna alama ga ƙungiyoyin da aka yi wa saline don tabbatar da cewa tsarin dawo da martani ya haifar da amsawa mai ƙarfi a lokutan da aka tilasta kauracewa. An gudanar da gwajin t mai zaman kansa tare da mai aiki da ke amsawa a cikin zaman amsawa don nuna alama tsakanin ƙungiyar da aka yi wa saline da ƙungiyar da aka yi wa saline don tabbatar da kamuwa da sha'awar sucrose.

Duk kwatancen ilimin kididdiga an yi su ne ta amfani da SPSS sigar 12.0. Ana yin kwatancen Post hoc na bin ANOVA ta amfani da gwajin LSD. An gabatar da bayanan rukuni azaman ma'anar ± SEM a cikin rubutu da lambobi.

results

Lokaci na horo

An cire beraye biyar da suka kasa nuna halayen sarrafa kansu akai-akai (matsakaicin jiko fiye da horo ya fi karkata ga daidaito 2) daga binciken. Daga cikin waɗanda suka sami sarrafa kansu ( N = 106), adadin isar da sucrose ya ƙaru a cikin zaman horo goma na yau da kullun [tasirin Lokaci, F (9, 846) = 22.9, p <0.001]. Bugu da ƙari, amsawa akan liba mai aiki ya ƙaru a lokacin horo [tasirin Lokaci, F (9, 846) = 8.4, p <0.001] yayin da amsawa akan liba mara aiki ya ragu [tasirin Lokaci, F (9, 846) = 56.8, p <0.001] wanda ke nuna wariya mai ƙarfi tsakanin liba. Beraye sun matsa matsakaicin sau 167±11.4 akan liba mai aiki da sau 3.4±0.5 akan liba mara aiki a ranar ƙarshe ta horo. Babu wani muhimmin tasiri ko hulɗar Day ko Dose ga kowane ɗayan matakan da ke nuna cewa dukkan ƙungiyoyi daidai suke kafin ainihin ma'aunin Day da Dose don gwaji.

Matakin Gwaji: Amsar cirewa

An gwada berayen don halakarwa a rana ta 30 na tilasta daina shan taba sun fi mayar da martani kan lever mai aiki fiye da berayen da aka gwada a rana ta 1 [tasirin Rana, F (1, 94)=47.1, p <0.001], wanda ke nuna yadda sha'awar sucrose ta mamaye su. Lever mai aiki yana amsawa a rana ta 1 matsakaicin martani 63.3±5.2 a cikin awanni 6 idan aka kwatanta da martani 135±8.9 a cikin awanni 6 a rana ta 30. Kamar yadda aka nuna a cikin Kayan aiki da hanyoyin, RM ANOVA na gaba na lever yana amsawa a cikin awanni 6 na amsawar ƙarewa (zaman awanni 6, awanni 1-1) ya tabbatar da ƙaruwar dogaro da lokaci a cikin amsawa gabaɗaya tare da babban tasirin Rana, F (1, 94)=47.1, p <0.001 da muhimmiyar hulɗar Rana ta Lokaci, F (5, 470)=10.1, p <0.001. Wannan hulɗar tare da babban tasirin Time, F (5, 470)=157.6, p <0.001 ta tabbatar da raguwar amsawa a cikin awanni 6 na amsawar Extinction. Babu wani tasiri mai mahimmanci na Dose, ko wata muhimmiyar hulɗa banda hulɗar Day by Time, wanda ke nuna cewa ƙungiyoyi a rana ta 1 ko rana ta 30 da aka yi wa allurar saline ko naloxone sun yi kama da juna a kididdiga kafin a yi amfani da maganin. A ranakun biyu, lokacin amsawar Extinction na awanni 6 ya kasance raguwa mai ban mamaki a cikin adadin amsawar amsawa tare da amsawa a cikin awa 1 (amsoshin 36.6±3.5 vs 64.6±4.9, rana ta 1 vs rana ta 30) wanda ya fi girma fiye da a awa 6 (amsoshin 3.0±0.4 vs 7.8±1.1, rana ta 1 vs rana ta 30).

Amsar lever mara aiki kuma ta ɗan fi girma a rana ta 30 tare da matsakaicin martani na 7.4±1.8 da 20.2±1.7 a cikin awanni 6, kwanaki 1 da 30, bi da bi, F (1, 94)=26.6, p <0.001. Akwai kuma ƙarin fashewar photobeam a lokacin gwajin amsawar Extinction a rana ta 30 da rana ta 1 tare da matsakaicin 3,154.4±113.1 da 3,932.8±111.4 fashewar photobeam a cikin awanni 6, kwanaki 1 da 30, bi da bi, F (1, 94)=24.1, p <0.001. Babu wani tasiri mai mahimmanci na DOSE kuma babu wata muhimmiyar hulɗa ga ko dai amsawar lever mara aiki ko halayyar locomotor ( ƙimar p ta kama daga 0.2 zuwa 0.8) wanda hakan ya nuna cewa ƙungiyoyin magani ba su bambanta ba kafin allurar saline ko naloxone.

Matakin Gwaji: Amsawa game da alama

Ga rukunin gishirin da aka yi amfani da su, amsawar lila da ke aiki ya kasance mafi girma a cikin Amsar don taron cue vs awa ta shida na shafewa a cikin kwanakin biyu 1 da 30 na ƙauracewa tilastawa. Da t dabi'u sun kasance t (10) = - 2.6, p<0.05 na rana 1 da t (6) = −5.8, p<0.001 na ranar 30 (ba a nuna bayanan ba). Sabili da haka, berayen da ke cikin yanayin saline sun aminta da amintacciyar hanya don haɗuwa da sucrose. ANOVA na mai lever mai aiki da ke amsawa yayin amsawa ga lokutan zaman taro ya bayyana mahimmin tasirin Rana, F (1, 94) = 86.1, p<0.001, Kashi, F (5, 94) = 4.6, p<0.01, da yini ta Hanyar hulɗa, F (5, 94) = 3.8, p<0.01. Wannan, haɗe tare da gano babban bambanci tsakanin ranar saline 1 da saline day 30 amsa, t (16) = - 6.1, p<0.001, da kuma duba bayanan (Siffa 1) nuna alamar fashewar buƙatun don sifilin nasara. Kamar yadda aka nuna a Kayan aiki da hanyoyin, wannan guda t An yi gwajin ne azaman magudi na tabbatar da cewa an lura cewa an sanya bulbulan kwalaji a cikin berayen da aka yiwa ruwan gishiri. Bayan haka ya zama tilas a cire duk abubuwan da ke tattare da shiryawa don bincika abubuwan da ake amfani da su a cikin kowane lokaci. Munyi wannan ta amfani da hanyoyi biyu. Da farko, kawai mun bincika bayanai akan ranakun 1 da 30 daban-daban. ANOVA na liba mai aiki yana amsawa a ranar 1 da aka saukar ba wani babban tasiri naloxone, F (5, 46) = 1.6, p= 0.2. Koyaya, kwatanci tsakanin ƙungiyar saline da ƙungiyar 10 mg / kg sun nuna haɓakawa game da amsa ƙimar naloxone (p= 0.06). ANOVA na liba mai aiki yana amsawa a ranar 30 ya bayyana babban mahimman sakamako naloxone, F (5, 48) = 4.7, p<0.01. Ana nuna mahimmancin bambance-bambance na tarihi Siffa 1. Na biyu, don ƙoƙari mu bayyana daidai na tasiri naloxone a ranar 1 vs day 30, mun cire sakamakon shiryawa ta hanyar sauya bayanai zuwa kashi na matsakaiciyar saline mai amsawa (ranar 1 yana amsawa a matsayin kashi na rana na 1 saline da ranar 30 suna amsawa kamar kashi biyu na saline na 30 na rana). An yi ANOVA tare da waɗannan bayanan da aka canza ta amfani da abubuwan da ke tsakanin-ƙungiyoyi na Day (1 ko 30) da Dose (0.001, 0.01, 0.1, 1, ko 10 mg / kg naloxone). ANOVA saukar da wani tasiri sakamako na Rana, F (1, 78) = 4.7, p<0.05, Kashi, F (4, 78) = 2.6, p<0.05, kuma kusan wata muhimmiyar rana ta Hanyar hulɗa, F (4, 78) = 2.4, p= 0.05. Kamar yadda wannan ya kasance tsakanin tsari tsakanin al'amuran, wannan hanyar ba ta samar da adadin ƙarfin lissafi kamar kwatanta halayen da abin ya shafa ta hanyar magani zuwa tsarinta (ƙirar batutuwa); Koyaya, yana samar da hanyar ƙididdiga don kwatanta tasirin magunguna a cikin rukuni waɗanda sun riga sun bambanta saboda sakamakon wani canji. Kamar yadda aka nuna a ciki Siffa 2, naloxone ya kasance mafi inganci a ranar 30 vs rana 1 a mafi ƙarancin allurai da aka gwada (2 da 0.001 mg / kg). Figure 2 yana gabatar da kaso na bayanan saline da aka cire daga 100 don isar da tasiri naloxone a attenuating Amincewa da amsawa ga ayyukan cire masu aiki (100% zai zama cikakkiyar kawarda amsawa).

Siffa 1 

Sakamakon naloxone akan Amsawa ga kwatancen mai nasara a ranar 1 vs day 30. Ma'anar ± SEMs an nuna don amsawa na liba mai aiki. Alamar alama tana nuna banbanci mai mahimmanci daga ranar 1 (wanda aka nuna don kungiyoyin saline kawai don haskaka abubuwan shiryawa ...
Siffa 2 

Inganci naloxone akan Amsawa ga Cuerose-wanda aka haɗa a ranar 1 vs day 30. Ana nufin ± SEMs don ƙarancin raguwar 100 na saline mai amsawa (kashi kirkin da Saline ya ƙididdige ga kowane rukuni kamar yadda Amsa ga alama aka raba ta ...

Amsar lever mara aiki ta fi yawa a rana ta 30 idan aka kwatanta da rana ta 1, F (1, 94) = 8.8, p <0.01, amma babu wani tasirin Dose, kuma babu wata muhimmiyar hulɗa. "Incubation" na amsawar lever mara aiki a zahiri ƙarami ne, tare da matsakaicin martani na 0.8±0.4 a rana ta 1 da martani na 2.4±0.4 a rana ta 30.

Ayyukan motsa jiki yayin amsawa ga alama, kamar yadda yake tare da amsawar lever mara aiki, ya fi girma a rana ta 30 idan aka kwatanta da rana ta 1, F (1, 94) = 4.4, p <0.05. Haka kuma, babu wani tasirin DOSE kuma babu wata muhimmiyar hulɗa. Matsakaicin aikin motsa jiki ya kai 516±53.3 fashewar hasken rana a rana ta 1 idan aka kwatanta da 672±52.5 fashewar hasken rana a rana ta 30.

tattaunawa

Wannan binciken ya binciki ingancin opiate antagonist, naloxone, akan rage amsawar alamar sucrose-paired a farkon lokaci da kuma daga baya a lokacin da aka tilasta daina shan taba. An gano cewa Naloxone yana rage amsawar kusan kawai a wata 1 vs kwana 1 na tilasta daina shan taba ( Hoto na 1 ). Bugu da ƙari, an lura da alaƙar tasirin allurai a rana ta 30 inda naloxone ya rage amsawa a ƙananan allurai (0.001 da 0.01 mg/kg) da kuma manyan allurai (1 da 10 mg/kg), amma ba a matsakaicin allurai ba (0.1 mg/kg; Hoto na 1 ). Waɗannan sakamakon suna goyan bayan hasashenmu cewa naloxone zai yi tasiri wajen rage amsawar alamar abinci mai haɗin gwiwa. Wannan ya ƙara sa mu yi la'akari da cewa akwai canji mai dogaro da lokaci a wasu fannoni na tsarin opiate a cikin makonni da yawa na tilasta daina shan taba daga shan taba wanda yayi daidai da shigar sha'awar sucrose. Gabaɗaya, yayin da berayen suka fi saurin kamuwa da ƙarancin allurai na naloxone a rana ta 30 ( Hoto na 2 ), mun kammala da cewa wani ɓangare na tsarin opiate yana ƙara zama mai saurin kamuwa a cikin wata 1 na tilastawa daga shan sucrose kai.

Raguwar sha'awar naloxone a cikin wannan samfurin beraye na komawa baya ya bayyana tasirin hana sha'awar naloxone lokacin da aka fallasa shi ga sigari, barasa, da alamun abinci a cikin mutane ( ; ; ; ). A zahiri, an tabbatar da samfurin dabba. Duk da haka, wani bincike na baya-bayan nan game da tasirin allurai ɗaya na naltrexone akan amsawa a gaban abin ƙarfafawa na nuna bambanci, wanda a baya ya nuna samuwar sucrose, bai sami wani tasiri na naltrexone akan amsawar da aka sharaɗa ba ( ). Wannan rashin daidaito yana yiwuwa ne saboda matsaloli da yawa na hanyoyin. Da farko, muna nazarin komawa baya saboda gabatar da wani abu daban da aka haɗa da sucrose, yayin da suka kimanta tasirin abin ƙarfafawa na nuna bambanci. Sarrafa waɗannan nau'ikan alamu daban-daban ya bayyana yana buƙatar nau'ikan jijiyoyi daban-daban ( ; ). Na biyu, mun lura da mafi ingancin tasirin naloxone a rana ta 30 na tilasta daina shan ƙwayoyi yayin da suka gwada amsawa bayan kimanin kwanaki 15 na ɓacewa. Akwai kuma la'akari da bambance-bambance a cikin inganci don bayyana bambancin da ke tsakanin naloxone da naltrexone; duk da haka, wannan ba zai yiwu ba saboda yawan naltrexone (2.5 mg/kg) yayi kama da mafi girman allurai. Banda tsawon rabin rayuwa na naltrexone, allurai na naloxone da naltrexone suna kama da juna ( ).

Ba mu yi imani da cewa tasirin naloxone a cikin wannan binciken ya faru ne saboda danne halaye ta hanyar haifar da alamun janyewar somatic. Berayenmu ba su nuna wata alama ta damuwa ta somatic ba kafin ko bayan shan naloxone. Duk da cewa ba a tantance su ta hanyar tsari ba, ba mu lura da janyewar opiate na gargajiya ba (piloerection, gudawa, hirar hakora ko wani girgiza/girgiza) ko dai a lokacin daina shan taba ko a ranakun gwaji. Bugu da ƙari, nauyin jiki ya ƙaru fiye da daina shan taba da kuma aikin motsa jiki bai shafi naloxone ba (bayanan da ba a nuna ba). An bayyana irin waɗannan alamun janyewar naloxone daga shan taba bayan shan glucose ( ). Duk da haka, wannan tsarin (sa'o'i 12 na glucose 25% a cikin chow tare da azumin sa'o'i 12 na tilastawa kowace rana na tsawon kwanaki 8) ya bambanta sosai da wannan binciken duka dangane da adadin sukari da yanayin rashin abinci (berayenmu sun sami ƙarancin sukari kuma ba a taɓa hana su abinci ba). Bugu da ƙari, sun yi amfani da maganin naloxone sau biyu mafi girma, 20 mg/kg, a matsayin maganin da muke sha.

Ɗaya daga cikin iyakancewar binciken da aka yi a yanzu don fassara tasirin naloxone dangane da lokaci shine ƙarancin amsawa ga alamar sucrose-paired a rana ta 1. Duk da cewa wannan yana nuna yadda tasirin sha'awa ke ƙaruwa lokacin da aka kwatanta shi da rana ta 30, yana barin damar cewa rashin tasiri gabaɗaya akan naloxone akan amsawar rana ta 1 ya kasance saboda dogaro da ingancin naloxone akan ƙimar amsawa da/ko "tasirin bene." Duk waɗannan zato daban-daban suna sa mu yi taka tsantsan ga fassararmu game da ingancin naloxone a cikin wannan binciken; duk da haka, nazarin da aka yi kan dogaro da ƙimar yana goyan bayan gabaɗaya cewa ƙananan ƙimar amsawa yakamata su fi saurin kamuwa da katsewa ( ; ). Bugu da ƙari, kodayake ba mahimmanci ba ne a kididdiga, akwai yanayin da yawan adadin naloxone zai rage Amsawa don alama a rana ta 1 ( p = 0.06, 10 mg/kg vs saline, gabaɗaya ANOVA ns; duba Hoto na 1 ). Wannan yana nuna rashin tasirin bene.

Curarancin sakamako na sakamako naloxone akan Amsawa ga alama a ranar 30 yana da kyau. Haƙiƙar magungunan sun yi tasiri sosai a allurai kaɗan amma kuma ba a wani amfani na tsakiya ba, na iya nuna hanyoyin da yawa don inganta martani don kamannin maye gurbin kuɗin.

Tsarin tasirin biphasic na iya zama tasirin yanki na antagonist akan allurai da muka gwada. Misali, akwai ƙarin masu karɓar opiate a cikin NAcc vs VTA ( ; ) da nazarin microinjection da ke jagorantar opiate agonists ( ; ) cikin NAcc da VTA sun lura da nau'in mai karɓar opiate na musamman a wurin da bambance-bambancen tasiri na gabaɗaya. Zai iya zama ƙananan allurai na naloxone sun fi tasiri a ɗayan waɗannan yankuna, yayin da a mafi girman allurai duka yankuna biyu ke shafar. Matsakaicin allurai na iya haifar da "rashin daidaituwa" a cikin hana tsarin DA gaba ɗaya wanda ke haɗa waɗannan yankuna na kwakwalwa. A zahiri, wannan na iya haifar da ƙaruwa a cikin bambancin amsawar da aka himmatu. Wannan shine abin da muka lura bayan allurar 0.1 mg/kg. Binciken bayanan martani da aka gano, daga beraye goma da ke cikin rukunin, beraye uku a cikin rukunin 0.1 mg/kg sun yi martani 70 ko fiye (70, 70, 72) yayin da beraye uku suka yi martani ƙasa da 25 (15, 18, 24). Sauran beraye a cikin wannan rukunin sun amsa sau 29-41 (29, 32, 38, 41), yayin da matsakaicin gishirin shine 46.4. Don haka gabaɗaya, yanayin binciken bayanai daga beraye daban-daban shine raguwar amsawa idan aka kwatanta da gishirin bayan 0.1 mg/kg yayin da wasu beraye suka nuna ƙarfin amsawa.

A ƙarshe, kodayake naloxone ya rage amsawar da aka yi wa alama a ranar 30, bai rage ranar 30 yana amsawa ga matakan rana ta 1 ba ( Hoto na 1 ). Saboda haka, wataƙila mun lura da raguwar duk wani abu da ke haifar da neuroadaptations wanda ke haifar da shigar sha'awar sucrose. Sauran tsarin watsawa a matsayin masu daidaita sha'awar su ne 'yan takara don ƙarin bincike. Glutamate zaɓi ne mai yiwuwa kamar yadda suka gano kwanan nan cewa hana sakin glutamate tare da glutamate autoreceptor agonist LY379268 yana rage shigar sha'awar sucrose lokacin da aka yi shi ta hanyar tsari ko kuma aka kai shi tsakiyar amygdala ( ). GABA wani hari ne mai yiwuwa saboda VTA GABA neurons wataƙila suna hana mesolimbic DA neurons ( ; ); saboda haka, masu karɓar GABA za su zama manufa don shafar halayen da aka motsa. A ƙarshe, DA kanta za ta zama ɗan takara mai kyau, musamman idan aka yi la'akari da abin da muka lura a baya game da raguwar da ta dogara da lokaci a cikin tasirin cocaine-potential da ke amsawa ga alamar sucrose-paired ( ).

karshe

Ganin cewa naloxone ya fi tasiri daga baya a cikin hana shan giya, yana iya zama zaɓin magani mai kyau don rage sha'awar abinci. Misali, sama da kashi 90% na masu cin abinci ba sa cimma burin rage kiba ( ). Sakamakon yanzu kuma ya haɗa da nazarin asibiti ta amfani da naloxone da naltrexone don rage komawa ga sha'awar abinci da bulimia, shan barasa, da shan sigari ( ; ; ; ). Waɗannan binciken suna tallafawa babban rawar da tsarin opiate ke takawa wajen sake dawowa, gami da halayen sha'awar, waɗanda suka shafi azuzuwan lada da yawa.

Acknowledgments

Wannan binciken ya sami goyan bayan tallafin NIDA / NIH DA016285-01 da kuma lambar yabo mafi ƙarancin ɗalibin da ba a ba da izini ba (DA016285-01-S2).

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