Karolo ea mesocorticolimbic dopamine ho laola likamano pakeng tsa lithethefatsi tsa tlhekefetso le boitšoaro bo botle ba sechaba (2010)

Kimberly A. Nyane,^* Kyle L. Gobrogge, 'me Zuoxin Wang

Boitsebiso ba Mongoli ► Tlhahisoleseding ea Copyright le License ►

Tšebeliso ea lithethefatsi tse lemalloang e ka ba le litlamorao tse khutšoane le tsa nako e telele litloaelong tsa sechaba. Ka mokhoa o ts'oanang, liphihlelo tsa sechaba le ho ba teng kapa ho ba sieo ha likhakanyo sechabeng nakong ea nts'etsopele ea pele le bophelong bohle li ka susumetsa tšebeliso ea lithethefatsi le ho ba kotsing ea ts'ebeliso e mpe ea lithethefatsi. Tlhahlobo e latelang e hlakisa tšebelisano ena, e shebaneng le lithethefatsi tse tloaelehileng tsa tlhekefetso (mohlala, psychostimulants, opiates, joala le nikotine) le boits'oaro ba sechaba (mohlala, boimana, thobalano, papali, boitšoaro bo mabifi le bo kopanyang). Mekhoa ea neural e tsamaisang ts'ebetso ena e tšohloa, ka ho hatisa haholo ho kenella ha sisteme ea mesocorticolimbic dopamine.

1.1. Liphetho tsa lithethefatsi ho bo-mme ba basali

Pontšo ea boits'oaro ba 'm'ae kamora ho arohana e susumetsoa ka matla molemong oa mefuta eohle ea liphoofolo tse anyesang, leha ho le joalo liphuputso tse fapaneng li bontšitse hore bots'epehi ba eona bo ka pepesetsoa ke lithethefatsi tsa tlhekefetso. Lithutong tsa batho tse laoloang, litlamorao tse tlisoang ke litlamorao tsa boitšoaro ba bo-mme li tlalehiloe ka botlalo. Basali ba neng ba sebelisa mofuta o mong oa lithethefatsi nakong ea kemero ba ne ba qeta nako e nyane ba buisana le masea a bona a sa tsoa hlaha (Gottwald le Thurman, 1994), e bontšitse cheseho e nyane haholo nakong ea lipuisano tsa bo-mme le lesea (Burns et al., 1997), mme e bonts'a maemo a holimo a boits'oaro bo bobe ba botsoaliJohnson et al., 2002) le ho se nke karolo ha batsoali ka kakaretsoSuchman le Luthar, 2000) ho feta basali ba sa sebeliseng lithethefatsi hampe. Ho feta moo, bo-mme ba ileng ba tsoela pele ho sebelisa lithethefatsi ka mor'a ho ikopanya ba bontšitse karabelo e fokolang ea basali ho feta bo-mme ba sa kang ba sebelisa lithethefatsi (Johnson et al., 2002; Schuler et al., 2000), mme ba bonts'a ho se tsotelle ha bona 'meleng le maikutlong ho bana ba bona le ho lahleheloa ke thahasello ho fana ka tlhokomelo ha ba le tlasa ts'usumetso (Hawley et al., 1995). Liphuputso tsena le tse ling li bonts'a litlamorao tse mpe tse tlisoang ke tlhekefetso ea lithethefatsi ho bo-mme. Leha ho le joalo, lintlha tse ferekanyang tse fumanehang lithutong tsena — ho kenyelletsa boemo ba sechaba le bochaba, tšebeliso ea kelello ea li-psychopathologies le tšebeliso ea tšebeliso ea lipilisi tse ngata-li etsa hore ho be thata ho hlalosetsa monehelo oa lithethefatsi tse itseng kapa mokhoa oa nakoana oa ho pepesetsoa lithethefatsi liphellong tse bonoang.

Mofuta oa maemo ao e seng a batho (Schiorring le Hecht, 1979) le meetso ea litoeba e sebelisitsoe ho hlahloba litlamorao tsa ho pepesetsoa lithethefatsi ho bo-mme ba tlasa maemo a laolehileng haholoanyane. Bongata ba lithuto tsena li sebelisitse likhoto tsa laboratori ho ngola litlamorao tse mpe tsa opiate (Borokho le Grimm, 1982; Grimm le Bridges, 1983; Mayer et al., 1985; Slamberova et al., 2001), AMPH (Frankova, 1977; Piccirillo et al., 1980), methamphetamine (Slamberova et al., 2005a, 2005b), le cocaine (Febo le Ferris, 2007; Johns et al., 1994; Kinsley et al., 1994; Vernotica et al., 1996; Vernotica et al., 1999; Zimmerberg le Grey, 1992) ho pepeseha nakong ea ho emara le / kapa kamora ho ikarabela ka boits'oaro bo potlakileng bo tšehali bo atileng bo bontšitsoeng ke mefuta ena, ho kenyelletsa ho khutla, popiNuman le Stolzenberg, 2009). Mona, re tla hlahloba lithuto tsena, re tsepamisa maikutlo ho tse bokhuts'oanyane, le litlamorao tsa nako e telele tsa ho pepesetsoa lithethefatsi ho boits'oaro ba bo-mme nakong ea thipa (kamora).

Liphuputso tse fapaneng li bontšitse hore lithethefatsi tsa tlhekefetso li fetola boits'oaro ba 'm'a bona likotong nakoana kamora ho busa. Matamo a pepesitsoeng ke AMPH kapa cocaine nakong ea kamora ho pepa a bontšitse ho fokotsa ho nyeka ha bana, ho eketsa lits'oaetso ho hokahanya le ho khutlisa malinyane le / kapa boits'oaro bo fokolisitsoeng ba bocha ha bo bapisoa le taolo e kenyang letsoai (Frankova, 1977; Piccirillo et al., 1980; Zimmerberg le Grey, 1992). Ka mokhoa o ts'oanang, ho pepesetsoa hoa koae ka nako eohle ea boimana le nakong ea kamora ho pepa ho ile ha sitisa boits'oaro ba sehla mme ha fokotsa karolo ea basali e khutlileng malinyane le a sehlopha (Kinsley et al., 1994; Vernotica et al., 1996). Litlamorao tsena li ka ba tsa tikoloho ea boko ka ho khetheha, joalo ka cococaine microinfusion ka kotlolloho sebakeng sa medial preoptic (MPOA) le NAcc — libaka tse peli tse kenelletseng ka hare ho boitšoaro ba bo-mme.Numan le Stolzenberg, 2009) —Empa eseng ho "caudate putamen" (CP) kapa dorsal hippocampus, ho ts'oaroa ha sethoathoa (Vernotica et al., 1999). Ho bohlokoa ho hlokomela hore lithutong tse hlalositsoeng kaholimo, boitšoaro ba bo-mme bo ile ba lekoa nakoana kamora ho entoa (ke hore,, ha lithethefatsi li ntse li le teng maling (bokong). Ka hona, ho a khonahala hore litlamorao tsa lithethefatsi ho bo-mme ba basali li ne li le ka morao ho litlamorao ho boits'oaro bo bong, joalo ka ts'ebetso ea locomotor le stereotypy (Kunko et al., 1998). Ho joalo, liphuputsong tse lekileng mehato ena e fapaneng, hoo e batlang e le liphapang tsohle tse hlokometsoeng ketsahalong ea motsamaisi le / kapa maikutlo a pherekano lipakeng tsa lihlopha tse tšoaroang ke lithethefatsi le tsa saline (Frankova, 1977; Piccirillo et al., 1980; Vernotica et al., 1996; Vernotica et al., 1999). Leha ho le joalo, khang ea ketso e tobileng ea lithethefatsi tsa tlhekefetso ho bo-mme e ts'ehetsoa ke ho arohana hoa nakoana lipakeng tsa boitšoaro bo fetohang ba bo-mmeke hore,, boits'oaro ba 'm'ae bo ile ba lula bo senyehile kamora hore tšebetso ea toro e khutletse ho tloaelehileng) (Vernotica et al., 1999).

Tšitiso e kholo mekhoeng ea bo-mme ea basali e tsoela pele ho feta karolo e mpe ea ho pepesetsoa lithethefatsi. Mohlala, likhoto tse nang le bokhachane tse tšoaroang ka koae kapa methamphetamine nakong eo li emang ka eona, li ntšoa ka nako ea ts'ebeliso ea lithethefatsi nakong ea kotlolloho e kopaneng le / kapa malinyane a koetlisitsoeng hanyane mme li bonts'itse lits'oants'o tse telele tsa ho aha lihlaha le / kapa ho khutlisetsa malinyane kaofela sehlaheng ho feta ho phekoloa ka letsoai. tse tšehali ha li lekoa maemong a fapaneng a kamora ho hlaha (Johns et al., 1994, 1997b; Slamberova et al., 2005b). Ho feta moo, tsamaiso e pheta-phetoang ea morphine nakong ea kemolo e ile ea eketsa bokhoni ba ho khutlisetsa malinyane le ho fokotsa boitšoaro ba ho nyeka le ho ikoetlisa ha ho lekoa matsatsing a kamora 12 kapa 23, ka ho latellana (Slamberova et al., 2001). Ho fapana le litlamorao tsena, boits'oaro ba 'm'ae bo ile ba ntlafatsoa ha k'hok'heine e ne e fanoa pele ho bokhachane le ka regimen e lekaneng ho susumetsa boits'oaro bo mabapi le boitšoaro.ke hore,, ho mpefala ha lits'oants'o kapa ts'oaetso e akaretsang mabapi le ho pepesetsoa lithethefatsi khafetsa) (Febo le Ferris, 2007). Phuputsong ena, basali ba baroetsana ba ne ba fuoa li-ente tsa cocaine tsa letsatsi le letsatsi tsa matsatsi a 14, e leng paradigm ea kalafo e ileng ea fella ka maikutlo a boitšoaro. Kamora moo, tse tšehali li ne li lula le monna ea nang le bohlola ka matsatsi a 5 mme a tlohela ho se khathatsehe nakong ea boitšisinyo le matsatsing a pelehi a 1-2. Teko ea boits'oaro ba 'm'a matsatsing a pelehi a 3-4 e senotse tloaelo e khuts'oanyane ea ho khutlisa malinyane kaofela, e bonts'ang boitšoaro bo ntlafalitsoeng ba bo-mme ho matamo a anngoeng ke koae. Ho ka etsahala hore phello e khethollang litloaelo tsa bo-mme tse hlalositsoeng lithutong tsena ke ka lebaka la nako ea tlhahiso ea lithethefatsi (ke hore,, pele kapa ka nako ya gestation). Leha ho le joalo, hape ho ka etsahala hore nts'etsopele ea sensitization ho cocaine, e neng e hlokometsoe feela thutong ea morao-rao, e kanna ea eketsa tšusumetso ea ho batla ts'usumetso ea tlhaho, maemong ana a bana (Febo le Ferris, 2007). Taba ena ea "maikutlo a sefapano" e tla tšohloa haholoanyane hamorao.

Ts'ebeliso ea maemo a ikhethileng a sebaka se khethiloeng e ka lumella tlhaloso e lucid haholoanyane ea litlamorao tsa lithethefatsi tsa tlhekefetso ho khothatso ea bo-mme. E ipapisitse le maemo a maemo a maemo, sebaka se nang le maemo se bonts'a khethollo ea tikoloho (tšusumetso e nang le maemo) e pentiloeng ka matlafatso ea mantlha (tšusumetso e se nang boikemelo), joalo ka lithethefatsi (Bardo le Bevins, 2000). Ho sebelisa paradigm ena, koae e bontšitsoe e le motsoako o matla bakeng sa likhoto tsa basali tsa kamora ho pepa. Ha e lekoa nakong ea kamora nako ea pelehi kapa ea morao-rao, likhoto tsa basali li ithaopela ho etsa cocaine- empa eseng libaka tse nang le letsoai (Seip et al., 2008). Ho bohlokoa, malinyane le ona ke a khothaletsang ka matla. Basali ba batšehali ba etsa khetho ea sebaka se hlophisehileng habonolo likamoreng tse amanang le malinyane (Wansaw et al., 2008) hape e tla tobetsa makhetlo a mangata kapa e tšele gridi ea motlakase ho fihlella malinyane (Lee le al., 1999). Melemo e matlafatsang ea malinyane le koae e sa tsoa sebelisoa hampe ho fumana temohisiso mabapi le litlamorao tsa koae ka lebaka la ts'usumetso ea 'm'ae. Ho sebelisa mokhoa o ikhethileng oa sebaka se ikhethileng oa paradigm ho lekola boits'oaro bo khothalletsoang ke ngoana le koae, ho bonts'itsoe hore koae e ka nyenyefatsa ts'usumetso ea 'm'a le hore ts'oaetso ena e fapana nakong ea pelehi (Mattson et al., 2001; Seip le Morrell, 2007). Haholo-holo, matamo a pelehi a pelehi a ne a rata kamore e amanang le popo ka holim'a kamore e amanang le koae, ha matamo a kamora ho ea morao a rata kamore e amanang le koae. Liphetho tsena li bonts'a hore matamo nakong ea pelehi ea pelehi a na le tšusumetso e phahameng ea bo-mme, joalo ka ha ho bonts'itsoe libakeng tse ling (Wansaw et al., 2008), ha matamo a morao haholo ho isa ho morao a ka ba kotsing ea ho sebelisa thepa ea konkreite e matlafatsang.

1.2. Karolo ea mesocorticolimbic DA

Patlisiso e tobileng mabapi le mekhoa e ka fokolisang litekanyetso tsa ts'ebetso ea bo-mme ha e na thuso. Leha ho le joalo, bopaki bo fapaneng bo sa tobang bo fana ka maikutlo a hore liphetoho tse ka bang teng tsamaisong ea mesocorticolimbic DA li ka ameha. Bopaki bona bo tsoa lipatlisisong tse ngata tse hlalosang ho kenya letsoho ha mesocorticolimbic DA boits'oarong ba bo-mme le lingoliloeng tse ngata tse hlalosang liphetoho tse khutšoane le tse telele tse kentsoeng teropong ena ka lithethefatsi tsa tlhekefetso. Ha taba ea morao-rao e se e se na moeli oa tlhahlobo ena ebile e akarelelitsoe haholo libakeng tse ling (Di Chiara, 1995; Di Chiara et al., 2004; Hyman et al., 2006; Koob le Nestler, 1997; Kuhar et al., 1991; Nestler, 2005; Pierce le Kalivas, 1997; Thomas et al., 2008; Bosoeu le Kalivas, 1998), re tla shebana pele le bopaki bo fanang ka maikutlo a ho nka karolo ha mesocorticolimbic DA boits'ebetsong ba basali. Joale, re tla hlahloba lipatlisiso tsa morao-rao tse qalileng ho etsa lipatlisiso ka liphetoho tse tlisoang ke lithethefatsi sebakeng sena sa DAergic, haholo-holo matamong a basali, a ka sitisang boitšoaro ba bo-mme.

Sisteme ea mesocorticolimbic ho nahanoa hore e kenella ka botebo potolohong ea neural e laolang boits'oaro bo khothalletsoang ba boimana (bakeng sa tlhahlobo e qaqileng ea bona (Numan le Stolzenberg, 2009)). DA e lokolloa ho NAcc (Hansen et al., 1993) le mPFC (Febo le Ferris, 2007) ha likhoto tsa basali li kopana le malinyane a monyali kapa a monyali (Champagne et al., 2004), le blockade ea NAcc DA receptors (Keer le Stern, 1999) kapa lesion ea mPFC (Afonso et al., 2007) e sitisa mokhoa oa ho nyeka. Moaho oa Nest o kanna oa kopanngoa le ts'ebetso ea VTA, hobane lesion ea VTA e etsa hore ho hahuoe lihlaha tse se nang maemo ka matamo a kamora ho belehaGaffori le Le Moal, 1979). Ho feta moo, liphuputso tse fapaneng li bontšitse hore VTA, NAcc le mPFC kaofela li bohlokoa bakeng sa tlhahiso ea ho khutlisetsoa ha ngoana hantle. Mohlala, ho sebelisa electroencephalogram (EEG) ho lekanya tšebetso ea motlakase oa nako ea nnete nakong ea boimana, ho bontšitsoe hore ts'ebetso e eketsoa ho VTA le mPFC nakong ea ho khutla ha bana (Hernandez-Gonzalez et al., 2005). Ka lebaka leo, ka bobeli Vac inactivation (Numan le Stolzenberg, 2009) le lesela la mPFC (Afonso et al., 2007) ferekanya ho khutlisetsoa ha lintlafinyane ka morao ho litoeba. Tšusumetso ena e kanna ea kopanngoa le ts'ebetso ea dopaminergic libakeng tsena, ha litlamorao tse tšoanang tsa ho khutlisetsoa ha popo li hlokometsoe kamora ho putlama ha dopamine ho VTA kapa NAcc (Hansen, 1994; Hansen et al., 1991). Ha li kopantsoe hammoho, liphuputso tsena li bonts'a hore sisteme ea mesocorticolimbic DA e bapala karolo ea bohlokoa ponts'etsong ea boitšoaro ba bo-mme.

Le ha ho amoheloa hantle hore ts'ebetso ea receptor ea DA, haholo-holo ho NAcc, e bohlokoa ponts'etsong ea boitšoaro ba bo-mme (Keer le Stern, 1999), monehelo oa li-subtypes tse ling tse khethehileng o ntse o phehisana. Ho na le malapa a mabeli a ka sehloohong a li-receptor tsa DA, D1-like receptors (D1R) le li-receptors tse kang D2-D2R, tse fapaneng ka litlamorao tsa boits'oaro bo itseng, ho ajoa ha tsona kahare ho NAcc, le litlamorao tsa tsona litseleng tse sa ts'oaneng tsa ho saena (lebokose 1; Setšoantšo sa 2) (E tsamaisang hampe al al., 1998; Neve et al., 2004; Sibley le Monsma, 1992). RPatlisiso ea ecent mabapi le bohlokoa bo lekanyelitsoeng ba li-receptor subtypes bakeng sa boitšoaro ba bo-mme e hlahisitse phello e lumellanangs. Phuputsong e le 'ngoe, NAcc ente ea SCH23390, mohanyetsi oa D1R, empa eseng eticlopride, mohanyetsi oa D2R, libakeng tse fapaneng tsa kamora ho pepa li sitisitse ho khutla ho tloaelehileng ha ngoana (Numan et al., 2005), ho hlahisa karolo bakeng sa D1R, empa eseng D2R, ts'ebetso ea ts'ebetso ena. Leha ho le joalo, phuputsong e 'ngoe, NAcc D2R blockade e sitisitse ho khutlisoa ha popi, e fana ka maikutlo a karolo bakeng sa ts'ebetso ea D2R ka boits'ebetso ba bo mme le (Silva et al., 2003).

Ho nka karolo ho hoholo ha mesocorticolimbic DA boits'oarong ba bakhachane ho lebisitse bafuputsi hore litlamorao tsa lithethefatsi tsa tlhekefetso holima ts'ebetso ea bo-mme e ka ba litholoana tsa liphetoho tse tlisoang ke lithethefatsi ho methapo ea methapo ea DA (Vernotica et al., 1996; Vernotica et al., 1999). Ho joalo, lithethefatsi tsohle tse tsebahalang tsa tlhekefetso ka kotloloho kapa ka tsela e sa tobang li kenya tšebetsong mesocorticolimbic DAergic neurotransication le tšebeliso e mpe ea lithethefatsi li baka phetoho e sa feleng ho VTA, NAcc le mPFC (Koob, 1992; Nestler, 2005- - Libaka tsa bokhachane bo sebetsang ka tsela e tloaelehileng, joalo ka ha ho hlalositsoe kaholimo. Leha ho le joalo, lipatlisiso tse amanang ka kotloloho le methapo ea kutlo e ka bakang ts'oaetso ea bo-mme e sa tsoa qala le ho tsebo ea rona, e shebile feela koae.

Re sebelisa matla a ho etsa lintho tse sebelisang matla a khoheli (fMRI), patlisiso ea morao tjena e bonts'itse hore ts'ebetso ea ts'ebetso ea kahare ea cocaine e bakile ts'ebetso e fapaneng ea ts'ebetso ea ts'ebeliso ea kelello lipakeng tsa basali ba batšehali le matamo a pepeselitseng basali.Ferris et al., 2005). Ho baroetsana, kalafo ea koae e matlafalitse libaka tsa boko ba mesocorticolimbic, e kenyelletsa lets'oao le letle la li-oxygen-oxygenation-level (BOLD) ho NAcc le mPFC. Mokhoa ona oa ts'ebetso o ts'oana haholo le o boletsoeng ho likhoto tsa banna (Luo et al., 2003) le mefuta e meng (Breiter et al., 1997) kamora ts'ebetso ea ts'ebetso ea koae, le ho mohlala o ts'oaroang ke malinyane ho matamo a lining. Ho fapana le moo, kalafo ea koae ea ipocaine matamong a lactating e ile ea fella ka ho se bonahale ha ts'ebetso ea mPFC, ts'ebetso e fetotsoeng kahare ho NAcc, le phetoho e mpe ea matšoao a BOLD ho ts'ebetsong ea mesocorticolimbic DA kaofela (Ferris et al., 2005), ho bonts'a hore ho pepesehela cocaine ho ka kena-kenana le likarolo tsa DAergic ho matamo a lactating a bohlokoa bakeng sa boits'ebetso ba bo-mme. Phuputsong e 'ngoe, phello ea boiphihlelo ba nakong e fetileng ba koae ka litekanyetso tsa ts'ebetso ea bohlasoa ea popo ka har'a sisteme ea mesocorticolimbic ea DA ea matamo a lactating e ile ea hlahlojoa. Basali ba lemohuoa ka koae pele a ima e bontšitse ts'ebetso e fokolang ea BOLD mPFC nakong ea ts'ebelisano ea popo ho feta matamo a tšoaroang ke letsoai.Febo le Ferris, 2007). Ho feta moo, maemo a motheo a DA ho mPFC-joalo ka ha a lekantsoe ke Ka vivo ts'oaetso ea likokoana-hloko tsa boko - li ne li le tlase matamong a nkoang ke koae ho feta lithuto tse tšoaroang ke letsoai, leha ho le joalo tse khothalelitsoeng ke DA ho lokolloa sebakeng sena li ne li tšoana lipakeng tsa lihlopha (Febo le Ferris, 2007). Habohlokoa, liphapang tsena tse mabapi le ts'ebetso ea "neuronal activation" le li-basic bas DA li bile teng kamora matsatsi a 30 kamora ho ts'oaroa ka ente ea ho qetela ea koae, a fana ka maikutlo a hore ho pepesetsoa lithethefatsi khafetsa ho ka fella ka ho mamella liphetoho lipakeng tsa boko ba mesocorticolimbic. Leha bopaki bona bo supa hore liphetoho tse ka bang teng mesebetsing ea mesocorticolimbic DA li kanna tsa ameha, lipatlisiso tse ling lia hlokahala ho utloisisa mekhoa e sebelisang lithethefatsi tsa tlhekefetso ho fetola boits'oaro ba bo-mme.

2.1. Litlamorao tsa lithethefatsi ho tsa thobalano

Lithuto tse laoloang tse hlalosang litlamorao tsa lithethefatsi tsa tlhekefetso holima boitšoaro ba batho ba botona le botšehali ha li na seoelo. Le ha ho le joalo, litlhahlobo tsa boits'oaro li hlokometse hore lithethefatsi tsa tlhekefetso li ama haholo boitšoaro ba banna le basali. Litlamorao tsa ho ratana le batho ba bong bo fapaneng, ho kenyelletsoa le takatso e matla ea thobalano le takatso, ts'ebetso e ntlafalitsoeng le thabo, le li-orgasms tse matlafalitsoeng li tlalehiloe ke basebelisi ba AMPH, MDMA, cocaine le heroin ka mokhoa o ts'oanang (El-Bassel et al., 2003; Kall, 1992; McElrath, 2005; Rawson et al., 2002). Ka ho makatsang, litlamorao tse mpe tsa lithethefatsi tsena li boetse li tlalehoa hangata, ho kenyelletsa ho se sebetse ka thobalano le tahlehelo ea thobalano nakong ea bokhoba.De Leon le Wexler, 1973; El-Bassel et al., 2003; Mintz et al., 1974; Weatherby et al., 1992). Tataiso ea tšusumetso ena e bonahala e itšetleha ka lintlha tse ngata ho kenyelletsa mofuta oa lithethefatsi, tekanyetso, bong, le nalane ea ho ja, maemo a motheo a ketso ea thobalano le litebello tsa litlamorao tsa lithethefatsi.

Ho fumana temohisiso ka litlamorao tsa lithethefatsi tse ikhethang tsa tlhekefetso ka boits'oaro ba thobalano, lithuto tsa laboratori li sebelisitse rat joalo ka mohlala oa phoofolo. Joalokaha ho boletsoe ka holimo, lithethefatsi tsa tlhekefetso li fetola takatso ea lijo (mohlala, ho tsosa takatso ea botona kapa botšehali le takatso), le consummatory (mohlala, ho kopitsa ka nepo) likarolo tsa boitšoaro ba thobalano, 'me o etsa joalo ka liketso tse kopaneng lits'ebetsong tse bohareng le tse potelletseng. Mona, re tla shebana le liphetoho tse tlisoang ke lithethefatsi ka har'a takatso ea lijo (ke hore,, e susumetse) likarolo tsa boitšoaro ba thobalano, e le karolo ea mesocorticolimbic DA ts'usumetso ea thobalano e thehiloe hantle ('mali o fetisoa kae kapa kae bakeng sa puisano ea litlamorao tsa lithethefatsi ho boits'oaro bo kopanetsoeng ba thobalano (Pfaus et al., 2009)). Lenakeng la banna, boitšoaro bo lebisitsoeng ho basali bo etsang lipatlisiso (mohlala, ho fofonela le ho itlhophisa), maqhubu a ho hloa le ho kenella, lipakeng tsa nakoana, karolo ea banna ba ho sebetsana le liphetoho tse etselitsoeng boemo ba basali nakong ea lisebelisoa tsa maemo a hangata li sebelisoa e le litšusumetso tsa takatso ea thobalano (Everitt, 1990; Mendelson le Pfaus, 1989). Litekong tsa basali ho e-na le hoo, tšusumetso ea thobalano e ka hlalosoa ka ho ba le boits'oaro bo khahlisang kapa bo khothalletsang boits'oaro, ho kenyelletsa ho tlola, ho tsitsipana, ho tsikinyeha tsebe le ho tsosa takatso ea thobalano (Erskine, 1989).

Boithuto likotong tsa banna le tsa basali li bontšitse hore tšusumetso ea thobalano e ka fetoloa ke lithethefatsi tsa tlhekefetso ha e fanoa kapele pele ho liteko tsa boitšoaro. Psychostimulants, ho kenyelletsa AMPH, MDMA le cocaine, li fokotsa ho fokotseha hoa takatso ea thobalano ho banna ba nang le boiphihlelo ka thobalano.. Phokotso ena e bonahatsoa ke phokotso ea liphetoho tse lebeletsoeng le karolo ea banna ba kopang, hammoho le keketseho ea nako le nako kamora ho latela kalafo ea lithethefatsi (Bignami, 1966; Cagiano et al., 2008; Dornan et al., 1991; Pfaus et al., 2009). Leha ho le joalo, joalo ka ha ho hlalositsoe thutong e 'ngoe le e' ngoe, litlamorao tsena li bakoa haholo ke ts'ebetso ea phehisano ea locomotor le li-stereotypies tse hlahisoang ke kalafo ea lithethefatsi. Ho fapana le moo, ho pepesetsoa maikutlo ho ntlafatsa maikutlo a lerato ho ntlafatsa maikutlo a thobalano ho banna ba nang le thobalano. Kannete kalafo ea AMPH e fokolitse mekhoa e metle ea ho intša le ho kenella ho batona ba batšehali (Agmo le Picker, 1990). Ho basali, litlamorao tsa ho pepeseha ho hlohlontšang methapo ea maikutlo le lintho tse ling li rarahane ka tsela e tšoanang, kaha litekanyetso ka bobeli li ntse li eketseha le ho fokotseha ho latela mofuta oa lithethefatsi tse sebelisitsoeng le boemo ba lihormone ba liphoofolo.Guarraci le Clark, 2003; Guarraci et al., 2008; Holder et al., 2010; Pfaus et al., 2009). Ho hloka toka ho tlalehiloe malebana le litlamorao tse bohloko tsa khatello ea maikutlo ho maikutlo a thobalano ho likhoto tsa banna. Mohlala, ha keketseho ea boemo ba ho lebella e lebelletsoe kamora ho tsamaisoa ha joala haholo (Ferraro le Kiefer, 2004), ho fana ka maikutlo a ho thusa ho khothaletsa takatso ea thobalano, litheko tse ts'oanang tsa lietsahala ho araba ho fihlella mosali ea amohelang thobalano (Scott et al., 1994), ho bonts'a ho fokotseha hoa takatso ea thobalano. Ho feta moo, ente ea morphine ea hlobaetsang e matlafalitse boitšoaro bo lebisitsoeng ho basali, ho kenyeletsoa ho fofa, ho ikoetlisa, ho phehella le ho phahamisa thutong e le 'ngoe (Mitchell le Stewart, 1990), empa ha e na phello ho tsena kapa boits'oaro bo bong ba takatso ea lijo ho bo bong (Pfaus et al., 2009).

Ho lumellana ho finyeletsoe, leha ho le joalo, tlhahlobong ea litlamorao tsa ho pepesetsoa khafetsa psychostimulant — haholo-holo mekhoa ea kalafo e bakang maikutlo a boitšoaro — ka takatso ea thobalano ho likhoto tsa banna le tsa basali (Afonso et al., 2009; Fiorino le Phillips, 1999a, 1999b; Guarraci le Clark, 2003; Nocjar le Panksepp, 2002). Ka kopanelo, lithuto tsena li bontšitse ntlafatso e tsoelang pele ea takatso ea thobalano kamora ho felisoa ha kalafo ea lithethefatsi. Mohlala, thutong e ngoe, likhoto tsa banna li fuoe mofuta o khahlisang oa liente tsa AMPH (ip) mme tsa lekoa bakeng sa boitšoaro ba thobalano libeke tse tharo kamora taolo ea ho qetela ea AMPH (Fiorino le Phillips, 1999b). Ka letsatsi la teko ea pele, banana ba tšoaroang ke baroetsana ba AMPH ba bonts'etse bokhutšoanyane ho hola le ho kenella, empa ba sa bonts'e liphetoho mesebetsing ea popomotor, e bonts'ang hore kalafo ea AMPH e ntlafalitse ts'usumetso ea thobalano. ka bobeli. Ka lebaka leo, likhoto tse phekotsoeng ke AMPH le tsona li entse liphetoho tse kholo ho lebeletsoeng ho mosali ea amohelang thobalano ho fapana le likhoto tse tšoaroang ke letsoai ka letsatsi la ho qetela la liteko (Fiorino le Phillips, 1999b). Liphumano tse tšoanang li tlalehiloe ho basali, kaha ho pepesetsoa khafetsa AMPH nako le nako ho eketsa palo ea boipiletso, lits'oants'o le litsu tse bontšitsoeng boteng ba monna.Afonso et al., 2009) le ho theola tumellano ea ho khutlela ho monna nakong ea boits'oaro ba hae ba ho nyaloa (Guarraci le Clark, 2003) bakeng sa ho fihlela libeke tse tharo kamora ho khaotsa kalafo ea lithethefatsi. Ha li kopantsoe hammoho, liphuputso tsena li bonts'a hore mofuta o khahlisang oa ho pepeseha hoa AMPH o ka fella ka "sensitization sensitence" litlamong tsa thobalano.

2.2. Karolo ea mesocorticolimbic DA

Re tla shebana le mohopolo oa "maikutlo a fapakaneng" ho tšohla kamoo liphetoho mecheng ea mesocorticolimbic DA li ka ntlafatsang ts'usumetso e matla ea thobalano e susumetsoang ke ho pepesehela lithethefatsi tsa psychostimulant tsa tlhekefetso. Khopolo ea tšusumetso ea tšusumetso ea bokhoba ba tahi (Robinson le Berridge, 1993, 2008) li-postulate tse hlalosang khafetsa lithethefatsi tsa tlhekefetso (tlasa maemo a itseng) li lula li fetola li-circulation tsa neural tse ikarabellang bakeng sa ho fana ka litšusumetso. Li-neuroadaptations tsena li lebisa tlhokomelisong ea sesose e hlahisoang ke litheko tsa lithethefatsi, mme ka hona e ba lebaka le khothalletsang la ho batla lithethefatsi. Habohlokoa, li-neuroadaptations tse entsoeng ke lithethefatsi li ka boela tsa fetola mekhoa ea tlhaho ea tšusumetso, ho eketsa ts'usumetso ea litlatsetso tsa tlholeho, joalo ka sucrose (Avena le Hoebel, 2003), lijo (Bakshi le Kelley, 1994), kapa hona joale, Molekane ea amohelang thobalanoFiorino le Phillips, 1999b; Guarraci le Clark, 2003).

Boithuto mabapi le neurobiology ea sensitization bo bonts'itse hore mesocorticolimbic DAergic neurons e feta litokelong tsa pele le tsa post-synaptic kamora ho pepesetsoa lithethefatsi tse sa feleng, joalo ka ha li hlahlojoa ka botlalo libakeng tse ling (Pierce le Kalivas, 1997; Bosoeu le Kalivas, 1998). Mohlala, ha ho pepesetsoa lithethefatsi tse ngata tsa psychostimulant tsa tlhekefetso ho ile ha eketsa maemo a mang a DA ho NAcc (Di Chiara et al., 1993; Ho utloile bohloko le Ungerstedt, 1989), keketseho ena ea DA e ntlafalitsoe haholo kamora kalafo e phetoa-phetoang ka li-psychostimulants, sephetho ka lebaka la ts'ebetso e eketsehang ea li-neuron tsa DA le liphetoho liphatlalatsong tsa DA axon (bakeng sa tlhahlobo, bona (Pierce le Kalivas, 1997)). Ho feta moo, liphetoho mesebetsing ea li-receptor tsa DA li hlokometsoe ho latela taolo e pheta-phetoang ea psychostimulant, ho kenyelletsa le ntlafatso e phehellang ea NAcc D1R sensitivity (Henry et al., 1989; Henry le White, 1991, 1995; Simpson et al., 1995). Kamora nako, ho mamella liphetoho tsa sebopeho ho li-neuron tsa NAcc le PFC le tsona li etsahala, ho kenyelletsa bolelele bo eketsehileng ba dendritic, lekala le letsoalo la methapo ea methapo (dendritic spines (Robinson et al., 2001; Robinson le Kolb, 1997).

Liphetoho tse joalo tse susumetsang tsa psychostimulant li khahla moqoqo ona hobane tsamaiso ea mesocorticolimbic DA e bapala karolo ea bohlokoa ho susumetso ea thobalano. DA e lokolleloa ho NAcc ea likhoto tsa banna le basali holim'a tlhahiso ea molekane ea amohelang thobalano, pele ho papiso (Becker et al., 2001a; Pfaus et al., 1990; Pfaus et al., 1995). Ntle le moo, ho basali, ho lokolloa ha DA ho matlafatsoa nakong ea ts'usumetso ea thobalano (Becker et al., 2001a; Mermelstein le Becker, 1995). Ho banna, NAcc DA e tepelletse, mme ha ts'usumetso ea tokollo ea NAcc DA e fokotseha, ho phahama le ho phahama, leha ho le joalo ha ho na phello palong ea litefiso le ho kenella (Everitt, 1990), e bonts'ang ketso e tobileng ea NAcc DA neurotransmission mabapi le tšusumetso ea thobalano. Liphuputso tse ngata li bontšitse bohlokoa ba ts'ebetso ea receptor ea DA bakeng sa tšusumetso ea thobalano. Ho thibeloa ha li-receptor tsa NAcc DA ka haloperidol ho fokotsitse palo ea liphetoho tse lebelletsoeng pele ho kenyelletsoa ha mosali ho lisebelisoa tsa tlhahlobo ea bi-level, ho bonts'a hore ts'ebetso ea li-receptors tsa DA ho NAcc e kenya letsoho khothatsong ea thobalano (Pfaus le Phillips, 1991). Ho kenngwa tshebetsong ha D2Rs ho NAcc e kanna ea ba le bohlokoa bo boholo, ha D2R blockade e eketsa nyoloha le ho kenella kahare (Everitt, 1990), leha ho le joalo mananeo a eketsehileng a receptor ho NAcc a hlokahala ho netefatsa karolo bakeng sa lelapa le itseng la li-receptor tsa DA likarolong tse khahlisang tsa boitšoaro ba thobalano. Mesocorticolimbic DA e bile le tšusumetso ho feta takatso ea thobalano ha ts'usumetso ea motlakase ea VTA e fokotseha ka ho nyoloha, ho kenella le ho nyamela hoa morao hoa makeno a banna (Eibergen le Caggiula, 1973; Markowski le Hull, 1995), ha liso tsa VTA li ntse li eketseha nako le nako kamora ho hlonepha (Brackett et al., 1986).

Fuoa karolo ea bohlokoa ea mesocorticolimbic DA ho likarabo tsa thobalano tse monate (Everitt, 1990; Melis le Argiolas, 1995), liphetoho tse susumetsoang ke psychostimulant tse amanang le maikutlo a lithethefatsi li ka tlatsetsa ntlafatsong ea takatso ea thobalano. Ho tsebo ea rona leha ho le joalo, ke thuto e le 'ngoe feela e entseng lipatlisiso ka mokhoa ona ka kotloloho (Fiorino le Phillips, 1999a). Thutong ena, likhoto tsa banna li fuoe mofuta o khahlisang oa li-ente tsa AMPH (ip) mme li ile tsa lekoa kamora libeke tse tharo bakeng sa boitšoaro ba thobalano. Nakong ea tlhahlobo ea boits'oaro, microdialysis e ile ea etsoa ho NAcc ho lekanya DA efflux. Ha ho na liphapang maemong a basal extracellular a NAcc DA pakeng tsa likhofu tsa AMPH- le tsa saline tse fumanoeng. Leha ho le joalo, ho lokolloa ha DA ho ne ho phahame haholo ho likhoto tse matlafalitsoeng tsa AMPH ha li beoa haufi le mosali ea amohelang thobalano. Ho feta moo, ha e lumelloa ho sebelisana le basali, likhoto tse nang le maikutlo a AMPH li bile le keketseho e kholo ho sampuli ea DA nakong ea sampole ea pele ea 10 min ho feta likhoto tse tšoeroeng ke letsoai, 'me e bonts'a mekhahlelo e mekhutšoanyane haholo ea ho hloa. Liphetho tsena li bonts'a hore tokollo ea NAcc DA e ntlafalitsoeng ha e arabela ts'usumetso ea thobalano e kanna ea eketsa takatso e matla ea thobalano ho litheko tse lemosang maikutlo tsa AMPHFiorino le Phillips, 1999a). Ka hona, joalo ka ha ente ea priming ea lithethefatsi e phahamisa phahameng oa DA ho liphoofolo tse matlafatsang kelello (Pierce le Kalivas, 1997), joalo ka ho pepesehela mosali ea amohelang thobalano, ho ts'ehetsa maikutlo a hore mokhoa o khahlisang oa ho pepeseha lithethefatsi o ka etsa hore ho be le "ho tsitsipana maikutlo" litakatsong tsa thobalano. Patlisiso ea nako e tlang ea mekhoa e ka bakang tlholo ena ea hlokahala mme e ka fana ka leseli le sebetsang mabapi le kalafo bakeng sa mathata a takatso ea thobalano ho batho (Fiorino le Phillips, 1999b).

3.1. Litlamorao tsa lithethefatsi papaling ea sechaba

Tšoantšiso ea kahisano (eo hape e bitsoang play e thata le e tenang) lipakeng tsa liphoofolo tse anyesang ho nahanoa hore e nka karolo ho ntlafatseng, ho ikoetliseng le ho ntlafatseng litsebo tse hlokahalang bakeng sa ponts'o e tloaelehileng ea boits'oaro sechabeng ha e se e le motho e moholo.Panksepp et al., 1984). Ka lebaka leo, phokotso ea papali nakong ea nts'etsopele ea bacha e baka litlamorao tsa boits'oaro bo bobebe, ho kenyelletsoa le litloaelano tse fetotsoeng, tse mabifi le boitšoaro ba thobalano hamorao bophelong (ho hlahlojoa, bona (Vanderschuren et al., 1997)). Karolong e latelang re tla tšohla hore na ho pepesetsoa lithethefatsi tsa tlhekefetso, ho pepesehela bacha makhophong, kapa ho pepesetsoa khafetsa nakong ea kholo ea boimana ho ka fetola boitšoaro ba bona ba papali ea papali.

Papali ea boithabiso lipapaling e tšoantšoa le liketso tse ngata tsa boits'oaro ho kenyelletsa ho phina, ho hlasela, litlhaselo tsa nape, libeche, ho loana le ho ikoetlisa sechabeng (Panksepp et al., 1984; Vanderschuren et al., 1997), tseo kaofela li ferekantsoeng haholo ka mor'a ho pepesetsoa lithethefatsi tse fapaneng tsa tlhekefetso (ntle le morphine le ethanol) e ntle. Mohlala, ente ea pheriferale ea methylphenidate (MP), setlhare sa psychostimulant seo, joalo ka koae, se thibeleng ho pheta-pheta ha DA mme se phahamisa maemo a DA a kantle ho naha (Ferris le Tang, 1979), hoo e batlang e felisitse boits'oaro ba litšoantšiso ho likhoto tse nyane (Beatty et al., 1982; Vanderschuren et al., 2008). Litekong moo MP a ileng a fuoa setho se le seng feela sa sehlopha sa litšoantšiso, liphoofotsoana tsa MP ha lia ka tsa qhekella ho molekane ea tšoeroeng ke letsoai le ha molekane enoa a ne a leka ho kopa papali, ho bontša hore MP e hatella papali le papali ea ho e bapala. ts'ebetso (Vanderschuren et al., 2008). Habohlokoa le ho feta, ha ho liphetoho tse teng mesebetsing ea lipina tse ileng tsa bonahala nakong ena ea boithabiso. Ho kenella ka lehare la AMPH ho fokotsehile haholo nako ea papali ea sechaba le lipalo tse bonts'itsoeng nakong ea papali, leha ho le joalo lipatlisiso tsa sechaba li eketsehile lithutong tse ngata (Beatty et al., 1984; Beatty et al., 1982; Sutton le Raskin, 1986). Ho feta moo, caffeine le nikotini hape li sitisitse boitšoaro ba papali (Holloway le Thor, 1985; Thiel et al., 2009). Leha ho le joalo, litlamorao tse matla tsa nikotine li ka kenella ka nakoana ha nicotine e fokotsehile papali ea sechaba ha e fuoa ka tlase ho 5min ea tlhahlobo ea boits'oaro, mme e eketsa likamano tsa sechaba 10 le 30min kamora ho entoa (Irvine et al., 1999; Thiel et al., 2009; Trezza et al., 2009). Ntle le nicotine, ho pepesetsoa morphine (Normansell le Panksepp, 1990; Vanderschuren et al., 1995a; Vanderschuren et al., 1995b) le ethanolTrezza et al., 2009) hape e ntlafalitsoeng papali pakeng tsa balekane ntle le ho fetola boits'oaro bo amanang le ho tšoenyeha, boits'oaro ba sechaba kapa boits'oaro ba locomotor.

Ho pepesetsoa khafetsa, haholo ho pepesetsoa bongoana, lithethefatsing tsa tlhekefetso ho boetse ho etsa hore ho be le liphetoho lipapatsong tsa bacha tsa papali ea boithabiso. Ho batho, bana ba neng ba pepesetsoa koae kapa heroin ka tšohanyetso ba bontšitse liketsahalo tse fokolang tsa boithatelo ho fapana le taolo e senotsoeng ke lithethefatsi mme liketsahalo tsena tsa ho bapala li ne li sa hlophiseha e bile e se tsa sehlooho (Rodning et al., 1989). Litekong, bana ba pepesitsoeng ka koae ba hatiselitsoe ho bapala ba bapala tlase (Wood et al., 1994) le ho kopa likotlo tse tlase tsa ho bapala ho tsoa ho khokahano (Wood et al., 1995). Habohlokoa, litlamorao tsa ho pepesetsoa koae ea 'mele li ka tsoela pele ho ba motho e moholo. Likhoto tse senotsoeng ho pepeseha koae ka tšebeliso ea tšebelisano e tlase sechabeng, ho kenyelletsa ho lutla, ho latela, ho ikoetlisa, ho loana le ho loana le molekane, ho feta likhoto tse senotsoeng ha letsoai ha le lekoa e le batho ba baholo matsatsing a 120 ea lilemo (Overstreet et al., 2000). Litla-morao tse hanyetsanang lipapaling tsa sechaba li hlokometsoe kamora ho pepesetsoa ha moriana ho morphine. Ka ho khetheha, likhoto li senotsoe haholo ho bapalami ba li-morphine tse hatiselitsoeng haholo ho libeke tsa 3 le 4 mme li bonts'itse mokhoa o mong oa botsoalle le tšireletso e tlase ea sechaba ho batho ba baholo (Niesink et al., 1996).

3.2. Karolo ea mesocorticolimbic DA

Joalo ka boits'oaro bo bong bo susumetsoang ka tlhaho, papali ea boithabiso ea matlafatsa (mohlala, liphoofolo li tla buisana ka nako e telele bakeng sa ho bapala le batho ba bang nakong ea papali) ((Normansell le Panksepp, 1990), hape e arotsoe, ka karolo e 'ngoe, ke mesocorticolimbic DA (Panksepp et al., 1984; Vanderschuren et al., 1997). Papali ea sechaba e ile ea eketsa maemo a DA le phetoho ea DA mokhoeng oa litoeba tsa bana (Panksepp, 1993). Khafetsa le / kapa nako ea boits'oaro ba pinning le / kapa boits'oaro ba boithabiso bo ile ba fokotseha haholo ke haloperidol, mohanyetsi ea akaretsang oa receptor oa DA (Beatty et al., 1984; Holloway le Thor, 1985; Niesink le Van Ree, 1989). Ntle le moo, litekanyetso tse tlase tsa apomorphine, tseo ho nahanoang hore li khetha li-receptors tsa DA ka ho khetheha (ke hore,, autoreceptors), 'me ka hona ho thibela ho lokolloa ha DA, ho fokotse hangata le nako ea ho phina le ho itloaetsa boitlhopho (Niesink le Van Ree, 1989). Ka lehlakoreng le leng, litekanyetso tse phahameng tsa apomorphine, e ka 'nang ea tsosa li-receptors tsa DA tsa pele le tsa postynaptic, e ileng ea susumetsa boitšoaro ba pina (Beatty et al., 1984). Ha li kopantsoe hammoho, liphuputso tsena li bonts'a ho kenya letsoho ha methapo ea kutlo ea DA lipapaling tsa sechaba. Ho feta moo, likhoto tse neonatal tse fanoeng ka enteventricular enteventricular ea 6-hydroxydopamine (6-OHDA), li ne li fokolitse haholo maemo a DA maemong a dorsal striatum le NAcc mme a bonts'itse mekhoa e metle e ts'ireletso le e ts'ireletso joalo ka bacha ba ileng ba lebisa mofuteng oa lipapatso tse bapalang le phetisetso ho boits'oaro bo bong bo sa bapalang, joalo ka ho etsa papali (Pellis et al., 1993). Le ha mesocorticolimbic DA e ka ba bohlokoa bakeng sa papali ea sechaba, ho nka karolo ha likarolo tse ikhethang tsa boko le malapa a li-receptor tsa DA ho ntse ho sa tsejoe haholo.

Mekhoa eo ho pepeseha lithethefatsi tse mpe ho ka fetolang boitšoaro ba papali ha e hlake. Ha li-psychostimulants li eketsa ka kotloloho maemo a DA ho NAcc, litlamorao tsa boits'oaro ba lithethefatsi tsena hangata li hlahisoa ke tšusumetso ea tsona ho li-neurotransmission tsa DA. Leha ho le joalo, boitlamo bo fetisisang le bahanyetsi ba DA receptor ha bo a ka ba susumetsa pherekano e mpe ea MP- kapa AMPH e khothalletsang boitšoaro ba papali (Beatty et al., 1984; Vanderschuren et al., 2008), ho bonts'a hore li-neurotransication tse fetotsoeng tsa DA li kanna tsa se ke tsa ikarabella bakeng sa litlamorao tsa lithethefatsi tsena papaling ea sechaba. Ha litlolo tsena tsa meriana li ne li hlophisehile, ho ka hlokahala hore mahlale a mang a bohareng a hlahlobe ka botlalo ho kenya letsoho ha DA ea mantlha litlamorao tsa MP le AMPH papaling ea sechaba. Ts'ebetso ea receptor ea DA, leha ho le joalo, e bohlokoa bakeng sa litlamorao tse matla tsa nicotine le ethanol papaling ea sechaba, hobane litlamorao tsa boits'oaro ba lithethefatsi tsena li ne li koetsoe ke ho qhekella le DA receptor antagonist a-flupenthixol (Trezza et al., 2009).

Leha lithuto tse fokolang li hlahlobisitse ka kotloloho mekhoa ea neural e bakileng phetoho ea papali ea sechaba lithutong tse pepesitsoeng lithethefatsing tsa tlhekefetso, ho khothalelitsoe hore ho pepesehela lithethefatsi tsa tlhekefetso, haholo cocaine, ho fella ka phetoho ea ka mehla lits'ebetsong tse bohareng tsa DA, le hore liphetoho tsena li ka fokolisa boitšoaro ba hae hamorao bophelong (Spear et al., 1989). Kaha li-monoamines li bapala karolo ea bohlokoa ho nts'etsopele ea neural (bakeng sa tlhahlobo ea bona (Levitt et al., 1997)) le litumellano le li-receptor tsa DAergic li teng ka mokhoa o ikhethang libakeng tsa maoto nakong ea kholo ea boko (Schambra et al., 1994; Tennyson et al., 1973), libaka tsena li ka ba kotsing ea litlamorao tsa lithethefatsi tsa tlhekefetso nakong ena. Haele hantle, lithuto tse pepesitsoeng khafetsa cocaine li phatlalalitse liphetoho tsa sebopeho mme li fetotse li-protein tsa D1R-G libakeng tse ruileng tsa Cortex ea cereine (Levitt et al., 1997). Matšoenyeho a li-receptor tsa DA a boetse a fetoloa libakeng ka bobeli tsa mesocorticolimbic le nigrostriatal ka lebaka la ho pepesetsoa ha koae, 'me liphetoho tsena li bonahala li lekantsoe ke lilemo le bong ba bana (Dow-Edward et al., 1990; Ferris et al., 2007; Glatt et al., 2000; Leslie et al., 1994; Scalzo et al., 1990). Ho feta moo, boholo ba libaka tsena, ho kenyelletsa NAcc, VTA, amygdala, MPOA, showiganti ea nigra le CP li ile tsa fokotsa haholo ts'ebetso ea metabolism ka lebaka la ho pepesetsoa ha koae (crenine ea koae)Dow-Edward et al., 1990). Liteko tsa Psychopharmacological le tsona li tšehelitse tlhahiso ea hore ka utero ho pepesetsoa ha koae ho ka baka phetoho ea nako e telele lits'ebetsong tsa DA, joalo ka ha bacha ba senotsoeng ke koae ba fetotse maikutlo a manong a mokhatlo oa DAergic (Spear et al., 1989). Ntle le moo, tlhahlobo ea meta ea lingoliloeng tse seng e ntse e le teng e bonts'a hore lilemo li lekola litlamorao tsa cocaine ea prenatal maemong a DA ka kotloloho ho litekanyetso, e le hore litekanyetso tsa DA li kanna tsa fokotseha ho ba lilemong tsa bocha ba pepesitsoeng koae le ho eketseha ka matla ho batho ba baholo (Glatt et al., 2000). Le ha lithuto tsena li fana ka leseli la bohlokoa mabapi le litlamorao tsa ho pepesetsoa ha koae ka koae ho likarolo tsa DAergic neural, lithuto tsa nako e tlang li tla hloka ho hlahloba hore na liphetoho tsena kapa tse ling ke tsona tse bakang tšilafalo ea papali ea lithethefatsi.

4.1. Liphetho tsa lithethefatsi mabapi le boitšoaro bo mabifi

Tšusumetso e 'ngoe e tummeng ea tšebeliso e mpe ea lithethefatsi ho boitšoaro ba batho ke ho eketsoa ke pefo. Ha ba lekoa maemong a laboratori a laoloang ke placebo, banna le basali ba noang joala ba bonts'a mabifi a holimo ho ba bang (Chermack le Taylor, 1995; Giancola et al., 2009). Ho feta moo, tlhekefetso ea lithethefatsi e hokahane ka matla le pefo e amanang le libetsa le polao e bolaeang (Hagelstam le Hakkanen, 2006; Madan et al., 2001; Spunt et al., 1998), mabifi a molekane oa haufi-ufi, ho kenyelletsa mabifi a tataisoang ke 'mele le kelello (Chermack et al., 2008; O'Farrell le Fals-Stewart, 2000), tlhekefetso ea thobalano (El-Bassel et al., 2001) le tlhekefetso ea bana (Haapasalo le Hamalainen, 1996; Mokuau, 2002; Walsh et al., 2003). Ka kakaretso, tlhekefetso e amanang le lithethefatsi e lebisa ts'ebetsong ea malapa le ho kenngoa chankaneng (Krug et al., 2002), ho theha lipelaelo tsa bohlokoa sechabeng.

Le ha lipatlisiso tsa mabifi ho batho li fane ka leseli la bohlokoa mabapi le kamano lipakeng tsa tšebeliso e mpe ea lithethefatsi le pefo, mehlala ea batho bao e seng batho le litheko li sebelisitsoe ho lekola litlamorao tsa ho pepesetsoa lithethefatsi ho mabifi. Litapong, boitšoaro bo mabifi bo arotsoe ka mekhahlelo e 'meli e fapaneng: bo khopisang le ho itšireletsa. Mehlala ea khalefo e khopisang e kenyelletsa litšokelo, tlhaselo, ho loma le ho lelekisa ha ntoa e itšireletsang hangata e kenyeletsa ho chechisa morao le ho hlasela ka boiphetetso (Blanchard le Blanchard, 1977; Blanchard et al., 1977). Le ha mekhoa ena e hlekefetsang e atisoa hangata ho banna, nakong ea lipakeng tsa bohareng, e boetse e atisoa hangata ho basali kamora ho ba le bo bong, 'me tlasa maemo ana, ho thoe ke' mabifi a basali '(Gammie le Stevenson, 2006; Johns et al., 1998a; Johns et al., 1994; Numan, 1994; Siegel et al., 1983). Re tla shebana le lipatlisiso tse hlahlobang boits'oaro bona ho hlalosa litlamorao tsa ho pepesetsoa hoa lithethefatsi hampe le ho basali khafetsa.

Boithuto bo bongata bo bontšitse hore boitšoaro bo mabifi bo ka fetoloa nakoana kamora ho pepesetsoa lithethefatsi, le hore tataiso ea litlamorao tsena e ipapisitse le lithethefatsi le lethal dose tse fanoeng, hammoho le phapang lipakeng tsa lithuto. Mohlala, ha litoeba tse ling tsa banna li ile tsa bontša ho futuhela le ho itšireletsa ho motho ea kenang lipakeng ka mor'a taolo e fokolang ea joala, mabifi ho baahi ba bang ha a ka a ameha kapa a fokotseha (Berry, 1993; Miczek et al., 1998), mohopolo o fumanoang o itšetlehile ka phapang pakeng tsa lithuto. Gamma-hydroxybutyrate (GHB), sethethefatsi se secha se nang le thepa e lemalloang, se ekelitse mabifi a tšosang (litšokelo le tlhaselo) litšoeleng tsa banna ka tekanyetso e tlase, empa se fokotsa boitšoaro ba tlhaselo ka tekanyetso e phahameng (Navarro et al., 2007). Ho feta moo, taolo e tlase ea cocaine ho banna e ne e sena matla a ho baka mabifi, athe litekanyetso tse phahameng tsa cocaine kapa AMPH li kokobetse khalefo e mpe (Darmani et al., 1990; Tidey le Miczek, 1992a), e totobatsang bohlokoa ba tekanyetso ea lithethefatsi mabapi le sephetho sa boitšoaro. Joalo ka litlamorao tsa koae ho ba batona, kalafo ea cocaine e nang le litekanyetso tse ngata e fokotse mabifi a matla a basali ho basali (Vernotica et al., 1996). Tsamaiso ea lithethefatsi tsa opiate ea tlhekefetso, joalo ka morphine, e boetse e bontšitsoe ho fetola mekhoa ea khalefo, haholo e mabifi e mpe (Ferrari le Baggio, 1982; Li-Gianutsos et al., 1976; Li-Gianutsos et al., 1974; Puri le Lal, 1973; Rodriguez-Arias et al., 1999; Tidey le Miczek, 1992b). Mohlala, litoeba tsa banna tse kenngoeng ka morphine li bontšitse ho hlaseloa ka mokhoa o tenang ho batho ba bang ba banna (Rodriguez-Arias et al., 1997). Ka lehlakoreng le leng, ente ea morphine ho lactating likhoto tsa basali e fokotse mabifi a 'm'a ho basali ba batšo (Kinsley le Bridges, 1986).

Leha litlamorao tsa nakoana tsa ho pepesetsoa hoa lithethefatsi bokhobeng li bonahala li its'epahalla mabaka a mangata, joalo ka ha ho boletsoe kaholimo, ho pepesehela lithethefatsi tsa tlhekefetso ho ntlafatsa mekhoa ea bohanyetsi — haholo-holo e amanang le tlhekefetso e mpe — mme litlamorao li ea mamella. Mohlala, kalafo ea monna oa Sesyria (ke hore,, khauta) hamsters (Mesocricetus auratus) nakong ea bongoaneng ka koae (DeLeon et al., 2002a; Harrison et al., 2000a; Jackson et al., 2005; Knyshevski et al., 2005a; Knyshevski et al., 2005b; Melloni et al., 2001) ho eketseha ho hoholo hoa mabifi / ho hlekefetsoa ho hoholo ha motho e moholo. Ho pepesetsoa li-anabolic steroid — lintho tse hangata li hlekefetsoang hangata lilemong tsa bocha le tsona li fumanoe li matlafatsa lehloeo le matla ho ba motho e moholo.DeLeon et al., 2002b; Harrison et al., 2000b; Melloni et al., 1997; Melloni le Ferris, 1996). Ho feta moo, ho pepesetsoa lithethefatsi khafetsa nakong ea boitšisinyo ho phahamisitse mabifi a latelang ho a matona a tsoang ho banna. Ka ho khetheha, likhoto tsa bakhachane tse neng li fumana liente tsa cocaine letsatsi le letsatsi ho tloha matsatsing a ho beleha 1-20 li bonts'itse litšokelo le tlhaselo ho motho ea kenang hare ho eona libekeng tse peli kamora ho ikopanya (Johns et al., 1997b; Johns et al., 1998b). Ho khahlisang, ho pepesetsoa lithethefatsi bongoaneng ho ka ama boits'oaro bo mabifi hamorao bophelong. Matamo a basali ba baholo a pepesetsoeng koae ka tšohanyetso a bontša maemo a phahameng a ntoa e matla ea bo-mme ho motho ea kenang lipakeng (McMurray et al., 2008). Ho feta moo, litoeba tse tona li pepesehetse joala hanyane ka hanyane li bontša ho loantšana ho hoholo ha motho e moholo ka ho lekana le ba batona (Krsiak et al., 1977). Ho khaotsa ho pepesetsoa lithethefatsi khafetsa, haholoholo ho li-depressants tsa methapo ea methapo, ho boetse ho amahanngoa le ho kenella kapa ho matlafatsa pefo. Mohlala, litoeba tse tona tse tšoaroang ka ente ea letsatsi le letsatsi ea morphine bakeng sa matsatsi a 14 - e ts'episang ts'epahalo ea morphine, li bonts'a maemo a phahameng a tlhekefetso nakong e tlohang ea hora ea 48 ho feta batho ba nang le litšila tse tšoaroang ke koloi (Rodriguez-Arias et al., 1999). Boithuto bo bong bo boetse bo tlaleha tlhekefetso ena e bakang ho khaotsa ka mor'a ho phekoloa khafetsa ka morphine (Ferrari le Baggio, 1982; Li-Gianutsos et al., 1976; Li-Gianutsos et al., 1974; Puri le Lal, 1973; Rodriguez-Arias et al., 1999; Tidey le Miczek, 1992b), le lithethefatsi tse ling tse fapaneng tse kenyeletsang methadone (Singh, 1975), benzodiazepines (Nath et al., 2000) le ethanolFaele et al., 1991).

Boferefere bo susumetsoang ke lithethefatsi bo sa tsoa hlahlojoa sebakeng sa prairie vole (Microtus ochrogaster), mofuta oa setsoalle oa monogamous sechabeng o etsang litlamo tse peli kamora ho tlolelana. Leha maqhubu a banna ba boithati ba botona kapa botšehali a kopanetse ho liphoofolo tse sa tloaeloang, ba batona ba matšehali ba mabifi haholo (joalo ka boits'oaro bo bobe le boits'ireletso) ho batho bao ba sa ba tsebeng (Aragona et al., 2006; Gobrogge et al., 2007; Gobrogge et al., 2009; Insel et al., 1995a; Wang et al., 1997; Winslow et al., 1993). Tlhekefetso ena e khahlisang batho ba bang e se e bitsoa 'mabifi a khethiloeng' hobane e lebisitsoe ho basele ba batona le ba batšehali, empa eseng ho molekane ea tloaetseng oa mosali (Insel et al., 1995a; Wang et al., 1997; Winslow et al., 1993). Ho khahlisang, ho pepesetsoa khafetsa AMPH (1.0 mg / kg ip ente ka letsatsi bakeng sa matsatsi a 3) ho kentse moferefere (palo e kopaneng ea boits'oaro bo khopisang le boits'ireletso) ho liphoofolo tse sa tsebeng letho ka li-voles tsa banna tsa thobalano tsa na sexuallyve (Gobrogge et al., 2009). Ho feta moo, kalafo ena ea AMPH ha e ntlafatse feela mabifi ho batho bao re sa ba tsebeng, empa hape le ho tloaelo e tloahelehileng ea basali (Gobrogge et al., 2009). Liphetho tsena li bontša hore tlholeho ea prairie e ka sebelisoa lithutong tse tlang ho lekola tšebelisano lipakeng tsa phumaneho ea lithethefatsi le mabifi a tataisoang ke molekane, e leng e 'ngoe ea mekhoa e atileng ea ho susumetsoa ke lithethefatsi e tlalehiloeng bathong (Chermack et al., 2008; O'Farrell le Fals-Stewart, 2000). Liphetho tse tsoang mefuteng ena ea lithuto li na le monyetla oa ho senola li-neuromechanisms tse ka tlase ho ts'ebelisano ena ea boitsoaro mme li ka lumella nts'etsopele ea lingaka tsa bongaka tsa ho lemalla lithethefatsi le / kapa mabifi a methapo ho batho.

4.2. Karolo ea mesocorticolimbic DA

Leha lits'ebetso tse ngata tseo eseng tsa DAergic li kentse letsoho ho mabifi (Adams, 2006; Kavoussi et al., 1997; Miczek et al., 2002; Nelson le Mokoetlisi, 2007; Siever, 2008), mesocorticolimbic DA le eona e ka bapala karolo ea bohlokoa. Patlisiso ea pejana mabapi le taba ena e bonts'itse hore ts'usumetso e tlase ea motlakase ea VTA le NAcc e hatelletse boitšoaro ba tlhaselo bo susumetsoang ke ts'usumetso ea motlakase oa hypothalamic ho li-fctions (Goldstein le Siegel, 1980) le liso tsa methapo ea kutlo ea NAcc e thusitseng ho hlaseloa ka matla ho apomorphine litheong (Pucilowski le Valzelli, 1986). Haufinyane tjena ho bonahetse hore tokollo ea DA e eketsehile ho NAcc ea likhoto nakong ea tebello le ponts'o ea ketsahalo e mabifi (Ferrari et al., 2003). Ho feta moo, blockade ea NAcc D1Rs e fokotse mabifi ho li-Conspecifics tsa banna tse sa tsejoeng ka li-voles tse tlamahaneng tsa banna tse rorisoang, tse bontšang hore ts'ebetso ea NAcc D1R e ka ba ea bohlokoa bakeng sa boitšoaro bo mabifi (Aragona et al., 2006).

Bopaki bo sa tobang le bo tobileng bakeng sa karolo ea mesocorticolimbic DA ho liphetoho tse tlisoang ke lithethefatsi litloaelong tse mabifi li teng. Mohlala, khatello e matla ea bo-'mampoli ea koae e kopantsoe le ho eketseha ha litaba tsa DA libakeng tse fapaneng tsa boko ba mesocorticolimbic ho kenyeletsoa VTA le amygdala (Lubin et al., 2003). Ho feta moo, litšoene tsa vervet tse tšoaroang hampe ka methamphetamine li fokotsehile haholo dikahare tsa litaba tsa DA le maemo a tlamellang a DA ho feta taolo e kenngoeng ke letsoai (Melega et al., 2008), leha ho le joalo ho lokela ho hlokomeloa hore liphetoho tsena li ne li amahanngoa le maemo a fokotsehileng a mabifi ho pholletsa le kalafo ea lithethefatsi. Ho na le palo e lekanyelitsoeng ea lithuto tse lekotseng ka kotloloho karolo ea mesocorticolimbic DA bohlasong bo khothalletsoang ke lithethefatsi. Ho lithuto tsena, tse ngata li entsoe kamora matsatsi a seng makae kamora ho khaotsa kalafo ea lithethefatsi khafetsa (mohlala, nakong ea ho khaotsa lithethefatsi). Systemic blockade ea li-receptor tsa DA ka kakaretso, li-D1Rs feela, kapa D2Rs feela, e fokotse ka mokhoa o fetisisang tlhaselo ea morphine e khothalletsang batho ho hlaseloa (Rodriguez-Arias et al., 1999). Leha ho le joalo mananeo a ikhethang a sebaka sa marang-rang a bontšitse phello e fapaneng. Khetho e akaretsang ea li-receptor tsa NAcc DA kapa D2Rs feela e matlafalitseng mabifi a susumetsang a tlisoang ke ho tlosoa ke morphine literekeng (Harris le Aston-Jones, 1994), ha ts'ebetso ea D1Rs e fokotse pontšo ea boitšoaro bo mabifi nakong ea ho khaotsa morphine ntle le ho fetola boits'oaro bo bobebe (Tidey le Miczek, 1992b). Le ha lithuto tsena li hlile li bontša karolo ea li-neurotransmission tsa DA ho mabifi a bakoang ke lithethefatsi, lithuto tsa nako e tlang lia hlokahala ho hlakisa karolo ea mesocorticolimbic DA boits'ebetsong bona.

5.1. Liphetho tsa lithethefatsi ho tlamahanong ea bobeli

Sebopeho sa kamano e tšoarellang ea kamano, kapa maqhama a mabeli, pakeng tsa balekane ba thobalano e etsahala hoo e batlang e le mekhatlong eohle ea batho mme e tloaelehile har'a 3-5% ea mefuta ea liphoofolo tse anyesang tse latelang leano le lecha la bophelo (Kleiman, 1977). Leha e le sebopeho se matlafatsang haholo, ho tlamahana ka bobeli ho ka fokotsoa ke lithethefatsi tsa tlhekefetso, joalo ka ha ho bonts'oa ke litlamorao tse mpe tsa ts'ebeliso e seng molaong ea lithethefatsi botsitsong ba lenyalo (Kaestner, 1995). Haufinyane tjena, re thehile mofuta oa mofuta oa tlholeho o sebelisang lipatlisiso tsa methapo ea kutlo e amanang le kamano e rarahaneng lipakeng tsa lithethefatsi tsa tlhekefetso le tlamahano ea batho ba babeli. Joalokaha ho boletsoe pejana, li-voes tsa prairie li monate haholo sechabeng, ke litoeba tse ikhethileng tse etsang litlamo tsa nako e telele ka mor'a ho tlolelana (Aragona le Wang, 2004; Carter et al., 1995; Insel and young, 2001; Bacha et al., 2008a). Ha e qeta ho ba tlamahano, monna le mosali ba baholo ba tla lula hammoho ho fihlela molekane a hlokahala, mme le ka nako eo, ka seoelo a ka theha tlamo e ncha ea balekane (Getz le Carter, 1996; Pizzuto le Getz, 1998). Letšoao le tšepahalang la boits'oaro ba maqhama a kopantsoeng ka tlung ea prairie ke nts'etsopele ea khetho ea molekane ea tloahelehileng ho feta motho eo a sa mo tsebeng eo ho thoeng ke ea ratoang ke molekane (Insel le Hulihan, 1995b; Williams et al., 1992; Winslow et al., 1993). Ka laboratoring, sebopeho sa khetho ea molekane se bonoa ka mokhoa o ts'epahalang kamora 24 hrs ea cohabitation le mating, mme e mamella bonyane libeke tsa 2 kamora moo (Insel le Hulihan, 1995b).

Haufinyane, re bonts'itse hore khafetsa ho pepeseha hoa AMPH ho thibela ho theoa ha likhetho tsa balekane lihlopheng tsa banna ba rorisang (Liu et al., 2010). Thutong ena, li-voes tsa praemia tsa banna li ile tsa aroloa ka lihlopha tse 'ne tse sa kang tsa entoa (intact), ente ea saline, kapa ente ea 1.0 kapa 5.0 mg / kg AMPH (ip) hang ka letsatsi bakeng sa matsatsi a 3 a latellanang. Letsatsing le hlahlamang ka mor'a ente ea hoqetela, lithuto li ile tsa pentoa le mosali bakeng sa 24hrs ea ho tlolelana mme tsa lekoa ho theha khetho ea molekane. Tumellanong le lithuto tsa nakong e fetileng, li-prairie tsa mahlohonolo tse sa sebetseng hantle le tse sebelisoang ka letsoai li qetile nako e ngata haholo li na le balekane ba tsona ba tloaelo ho feta motho eo li sa mo tsebeng (ke hore,, e entseng likhetho tsa molekane oa moetsing)Aragona et al., 2003; Aragona et al., 2006; Winslow et al., 1993). Leha ho le joalo, ba batona ba kopantsoeng le AMPH ba qetile nako e lekanang le liphoofolo tseo ka bobeli, ho bonts'a hore ho pepesetsoa khafetsa ho AMPH ho thibetse ho ratwa ha molekane (Setšoantšo sa 3A). Ho bohlokoa ho ela hloko hore litlamorao tsa AMPH mabapi le sebopeho sa khetho ea molekane e ne e se litla-morao tsa litlamorao tse ling tsa boits'oaro, joalo ka ha ho se na phapang lipakeng tsa nako ea ho ikatisa nakong ea boiketlo kapa ts'ebetso ea tatellano nakong ea tlhahlobo ea khetho ea molekane e bontšitsoe pakeng tsa saline- le AMPH- tšoaroa liphoofolo.

    

Setšoantšo sa 3

Dopamine (DA) ho li-nucleus accumbens (NAcc) e kenella ho amphetamine (AMPH) -induction impression of pair bonding. A) Kamora 24hrs ea ho ruruha, phekolo e sa tsoakoeng le e nang le letsoai (0.0; 1 sindano / letsatsi / matsatsi a 3) maqhubu a banna ba basali ba sebelisang nako e ngata haholo ...

Lintlha tse hlalositsoeng ka holimo li totobatsa litlamorao tse mpe tsa ho pepesetsoa hoa AMPH khafetsa tlamahanong ea ka tlung ea banna ba rorisang basali, leha ho le joalo, ho pepesetsoa lithethefatsi khafetsa ho ka senya kamano ea basali le basali. Ho joalo, bopaki ba morao-rao ba liteko bo tsoang laboratoring ea rona bo bonts'itse hore ho pepesehela AMPH khafetsa ho thibela ho khethoa ha likhetho tsa balekane ba ratehang ho tsa basali tsa basali (Bacha et al., 2008b). Ho khahlisang, litekanyetso tse tlase tsa AMPH li ne li sebetsa hantle ho thibela khetho ena ea basali ho basali, ho bonts'a hore tse tšehali li kanna tsa ameha haholo ka litlamorao tsa AMPH ho feta tsa banna. Khopolo-taba ena e tšehelitsoe ke lithuto tsa nakong e fetileng lithutong tsa prairie-e bonts'a phetoho ea lets'ollo lenaneng la karabelo ea basali ho nts'etsopele ea likhetho tsa sebaka se nang le tšibollo ea AMPH (Aragona et al., 2007) - hape e ts'ehelitsoe ke liphuputso mefuteng e meng ea litoeba tse tlalehang litsoantso tsa thobalano ka karabelo ea boits'oaro le ea tlhaho ho lithethefatsi tsa psychostimulant tsa tlhekefetso (Becker, 1999; Becker et al., 2001b; Roth et al., 2004).

5.2. Karolo ea mesocorticolimbic DA

Mosebetsi o fetileng ho tsoa laboratoring ea rona le ba bang o bontšitse hore mesocorticolimbic DA - haholo-holo neurotransication ea DA ho NAcc-e bohlokoa bakeng sa ho theha khetho ea balekane (Aragona et al., 2003; Aragona et al., 2006; Curtis et al., 2003; Curtis le Wang, 2005; Gingrich et al., 2000; Liu le Wang, 2003; Wang et al., 1999). Ho nyala - ho thusang ho thehwa ha balekane-ho eketsa ts'ebetso ea DA ho NAcc ea maqhubu a banna le a basali ba rorisang (Aragona et al., 2003; Gingrich et al., 2000). Pharmacological blockade of NAcc DA receptors via haloperidol blockbling organference kaho e ratoang ke ho ruruha ha ts'ebetso ea li-receptors tsa NAcc DA ka tekanyetso ea apomorphine-ka tsela e itšetlehileng e etsa moralo oa molekane ha o le sieo.Aragona et al., 2003). Liphetho tsena li bonts'a hore li-neurotransication tsa DA ho NAcc li bapala karolo ea bohlokoa ho theheng ha tlamo ea maqhama. Liphetoho tse ling tsa pharmacological tse ling li bonts'itse hore taolo ea dopaminergic ea sebopeho sa khetho ea molekane e khethehile, joalo ka ha D1R activation inhibits, le ts'ebetso ea D2R e nolofalletsa khetho ea molekane. Kannete, ts'ebetso ea li-D2R, empa eseng D1Rs, ho NAcc e nolofalitse ho theoa ha likhetho tsa molekane ho li-voes tsa basali le tsa banna, athe blockade ea NAcc D2Rs e thibetse ho etsa khetho ea molekane.Aragona et al., 2003; Aragona et al., 2006; Gingrich et al., 2000). Ho kenyelletsa moo, tsamaiso ea "agonist" ea D1R ka har'a NAcc e thibetse khetho ea molekane e hlahisitsoeng ke mating kapa D2R (Aragona et al., 2006). Taolo e ikhethileng ea li-receptor e amanang le DA ea tšehetso ea balekane e tšehelitsoe ka ho fetesisa ke ho qhekella ha tsela ea kemolo ea methapo e kholo ea CAMP kahare ho NAcc (Aragona le Wang, 2007). Hopola hore ts'ebetso ea li-D1R le D2R, ka alpha subunits ea liprotheine tsa G tseo li sebelisanang le tsona, li na le litlamorao tse khahlanong le ho ts'oaroa hoa cAMP intracellular signaling (lebokose 1; Setšoantšo sa 2). Phuputsong ea morao-rao, ente-NAcc ea ente ea motsoako oa meriana e thibelang ts'ebetso ea ts'ebetso ea mofani oa PKA (phello e lumellanang le ts'ebetso ea D2R) (Aragona le Wang, 2007). Ho ekelletsa moo, ente-NAcc ea ente ea morekisi oa pharmacological e eketsang tšebetso ea PKA e thibetse sebopeho sa khetho ea molekane ea tsoang ho balekane (phello e lumellanang le ts'ebetso ea D1R) (Aragona le Wang, 2007). Ho khahlisang, mananeo ohle a meriana a hlalositsoeng kaholimo a amme maqhama a kopaneng ha feela a etsoa ka har'a khetla ea NAcc, ho fapana le mantlha ea NAcc kapa CP, a bonts'a hore melaoana ea DAergic ea maqhama a kopantsoeng le ona e boetse e le karolo ea boko- le subregion-itseng (Aragona et al., 2006; Aragona le Wang, 2007).

Ha mesocorticolimbic DA e bapala karolo ea bohlokoa sebopeho sa balekane ba khethollo mme e fetoloa ke ho pepesehela lithethefatsi tsa tlhekefetso, re ts'episitse hore liphetoho tse teng tsamaisong ena li ka baka tšenyo e mpe ea AMPH e bakang tšibollo ea khetho ea molekane. Ho etsa lipatlisiso ka monyetla ona, maemo a DA receptor gene le polelo ea liprotheine libakeng tsa boko ba mesocorticolimbic li ne li bapisoa pakeng tsa maqhubu a monna a butsoitsoeng ka letsoai le AMPH (le leng la 1.0 mg / kg ip ka letsatsi bakeng sa 3 matsatsi a latellanang — mofuta o le mong oa dosing o neng o thibela molekane oa hae) sebopeho sa thatohatsi). Ba batona ba tšoaroang ke AMPH ba bonts'a litekanyetso tse phahameng haholo tsa D1R, empa eseng D2R, mRNA le ho ngola liprotheine ho NAcc ho feta banna ba tšoaroang ke letsoai, ho bonts'a hore ho pepesoa ha AMPH ho eketsehile polelo ea D1R ho NAcc (Setšoantšo sa 3B) (Liu et al., 2010). Ha liphetoho matsong a mofuta o le mong feela oa li-receptor tsa DA li hlokometsoe, liphetho tsena li fana ka maikutlo a hore tsamaiso ea AMPH e ka fetola botsitso lipakeng tsa li-receptor subtypes tsa DA ho NAcc, e lebisang ho thibelleng ea likhetho tsa molekane oa mating ka palo e eketsehang ea D1Rs ho D2Rs sebakeng sena. Boitekong bo eketsehileng, pharmacological blockade ea D1Rs pele litekanyetso tsa li-ente tsa AMPH tsa letsatsi le letsatsi-ka botlalo li felisitse tšilafalo ea AMPH e bakiloeng ke khetho ea molekane.Liu et al., 2010). Ha e nkuoa hammoho, lintlha tsena li bonts'a hore ho pepesetsoa ha AMPH ho ka thibela sebopeho sa khetho ea molekane ka mochine o arolelanoang oa D1R. Mohopolo ona o tšehetsoa ke mosebetsi oa rona oa nakong e fetileng oa li-voili tsa prairie, o bonts'itseng hore ts'ebetso ea D1R ha e thibele feela ho thehwa ha litakatso tsa balekane empa e kanna ea bapala karolo ho thibela ho theoa ha litlamo tse ling tsa bobeli, hang ha e se e thehiloe.Aragona et al., 2003; Aragona et al., 2006). Mohlala, li-voles tsa tlamahanete tse kopantsoeng tsa banna li na le litekanyetso tse phahameng haholo tsa D1R e tlamang ho NAcc ho feta banna ba thobalano-naïve (Setšoantšo sa 3C). Boemo bona bo phahameng ba bophahamo ba D1R ho nahanoa hore bo tlase, ka karolo e 'ngoe, e le ponaletso ho mabifi ho basali ba tloaelaneng le basele (Aragona et al., 2006), ho kenyelletsa basali ba amohelang thobalano (Gobrogge et al., 2007; Gobrogge et al., 2009), ha NAcc D1R blockade ka banna ba tlamahantsoeng ba thibela pefo e ikhethileng ho basali ba sa tsebeng (Aragona et al., 2006) (Setšoantšo sa 3D). Ha ho le joalo, ho nahanoa hore mofuta ona oa tlhaho oa neuroplasticity (ke hore,, e eketsa NAcc D1Rs ka banna ba bonngoeng) e sebetsa ho boloka li-bond tse tsitsitseng ka ho thibela ho theoa ha tse ncha. Ha tlhahiso ea AMPH e ntse e eketseha polelo ea NAcc D1R, ho ka etsahala hore AMPH e thelise neuroplasticity ena ka boomo, e hlahisang tšilafalo e tlisoang ke lithethefatsi ea sebopeho sa khetho ea molekane. Ho joalo, kamora ho pepesehela khafetsa AMPH, li-voes tsa banna ba botona le botšehali li bonts'a mabifi a matla ho basali ba tloaetseng le ba sa tloaeloang (Setšoantšo sa 3E) (Gobrogge et al., 2009), e ka lebisang ho senyeheng ha tlamo ea lenyalo. Liteko tse ntseng li tsoela pele lefapheng la rona li etselitsoe ho etsa lipatlisiso tse ling tsa mekhoa eo AMPH e sitisang maqhama a kopanyang maqhubu a banna le basali ka ho shebana le tšebelisano lipakeng tsa mesocorticolimbic DA le lits'ebetso tsa neuropeptide tse hlokahalang bakeng sa boitšoaro ba sechaba.

6.1. Litlamorao tsa boiphihlelo ba sechaba ka tšebeliso e mpe ea lithethefatsi

Le ha ho hlakile ho tsoa lithutong tse hlalositsoeng kaholimo hore tšebeliso e mpe ea lithethefatsi e ka fetola boitšoaro ba sechaba haholo, ho na le bopaki bo ntseng bo eketseha ba ho fana ka maikutlo a hore kamano ena e ea iphetetsa. Liphihlelo tsa kahisano sechabeng le ho ba teng / ho ba sieo ha likhakanyo tsa setjhaba le tšebelisano nakong ea nts'etsopele ea pele le bophelong bohle li ka susumetsa tšebeliso ea lithethefatsi le ho ba kotsing ea ts'ebeliso e mpe ea lithethefatsi. Ka sebele, lits'oants'o tikolohong ea sechaba, haholo nakong ea nts'etsopele ea peleho, li ka eketsa tlokotsi ea ts'ebeliso e mpe ea lithethefatsi hamorao bophelong, ha nts'etsopele ea likamano tse matla tsa setjhaba, ho kenyelletsa kamano ea motsoali le bana le batho ba baholo e ka sireletsa khahlanong le tlhekefetso ea lithethefatsi. Khopolo ena e tšehelitsoe ke lithuto tse 'maloa tse hlalositsoeng ka tlase.

Liphokotso tikolohong ea sechaba nakong ea nts'etsopele ea pele le bophelong bohle li ka eketsa tekanyo ea tlhekefetso ea lithethefatsi. Ka sebele, ho se tsotelle ha bongoana ho batho ho amahantsoe le kotsi e eketsehang ea mathata a amanang le joala hamorao bophelong, phello e hlahelletseng ho basali (Widom et al., 1995). Ho litšoene tsa rhesus, tšebeliso ea joala e ne e bapisoa le lilemong tsa 4 tse neng li holisitsoe likhoeling tsa pele tse tšeletseng tsa bophelo mohlomong ke lithaka tsa bona ntle le phihlello ho batho ba baholo kapa ke bo-mme ba bona.Higley et al., 1991). Ha ba fuoa monyetla oa ho fumana tharollo ea ethanol / sucrose ka bobeli le tharollo ea tacrose, lithuto tse ntlafatsoang ke lithaka li ile tsa ja ethanol haholo ho feta lithuto tse holisitsoeng ke bo-mme, tse bontšang hore likamano tse senyehileng tsa bo-mme le masea li ka bapala karolo ho tlotlolloeng ha joala hamorao. Ho feta moo, thutong e ts'oanang, ha lithuto tsa selemo sa 4 li arotsoe matsatsi a mangata ho balekane ba bona ba chate, lithuto tse holisitsoeng ke bo-mme li ile tsa eketsa ts'ebeliso ea tsona ea ethanol, ho bonts'a hore ho sebelisana le batho hamorao bophelong ho ka ba le tšusumetso e kholo tšebeliso ea lithethefatsi (Higley et al., 1991).

Boithuto ba ho arohana ha basali nakong ea thipa ba bontšitse bohlokoa ba liphihlelo tsa pele tsa bophelo mabapi le likarabo tsa litlhare hamorao bophelong. Lithutong tsena, karohano ea bo-mme e ne e hlalosoa e le karohano ea litšila tsohle tse tlohang letamong la 1 kapa lihora tse ngata letsatsi le leng le le leng ka matsatsi a mangata nakong ea libeke tse 'maloa tsa pele ho pelehi. Ho imeloa ke 'm'ae ho ne ho tšoana le karohano ea bo mme, ntle le hore malinyane a ne a arohantsoe nako le nako ha a arohana letsatsi le letsatsi. Tumellanong le lipatlisiso tsa litšoene tsa rhesus tse boletsoeng ka holimo, likhoto tse arohaneng le 'm'a li ile tsa noa ethanol haholo ho feta taolo e tloaelehileng e holisitsoeng.Huot et al., 2001; Ploj et al., 2003). Taba ea bohlokoa ke hore lithutong tsena, ha ho na phapano ea phallo ea mokelikeli e felletseng, e bonts'ang hore karohano ea pelehi ea bo-mme e ile ea fetola ts'ebeliso ea joala ka kotloloho. Ka mokhoa o ts'oanang, likhoto tse fokotsoang ke bo-mme li bonts'itse ho eketseha ha morphine le AMPH le ho ntlafatsa mokhoa oa ho itlhokomela ka koae ha ho bapisoa le taolo e tloaelehileng e holisitsoeng (Kosten et al., 2000; Vazquez et al., 2006). Habohlokoa, thutong ea boits'ebetso, ha ho liphapang tse fumanoeng mohoebi ea arabelang lijo kapa mosebetsi oa popomoror tse boletsoeng (Kosten et al., 2000). Ha li kopantsoe hammoho, lithuto tsena li bonts'a litlamorao tsa ho senyeha hoa pele tikolohong ea sechaba le sechaba ka ho ba kotsing ea tlhekefetso ea lithethefatsi hamorao bophelong. Leha ho le joalo ho lokela ho hlokomeloe hore lintlha tsa liphatsa tsa lefutso le nako e tobileng ea pherekano ea sechaba le eona e bapala karolo (Matthews le al., 1999; van der Veen et al., 2008). Ho ekelletsa moo, ntle le ho fetola boits'oaro bo amanang le lithethefatsi, lits'oaetso tsa tikoloho tsa tikoloho le tsona li ka ba le phello e matla litloaelong tsa bochaba hamorao bophelong.Cushing le Kramer, 2005; Lee le Hoaken, 2007; Veenema, 2009). Ka hona, hoa hlolla ho nahana ka kamano lipakeng tsa boitšoaro bo fetotsoeng sechabeng le ho ba kotsing e phahameng ea tlhekefetso ea lithethefatsi e bontšitsoeng ke batho ba baholo e senotsoeng liketsahalong tse mpe tsa bophelo ba hae.

Boleng ba litšebelisano tsa bophelo ba bongoaneng bo ka ama tšebeliso ea lithethefatsi hamorao. Ho etsa mohlala, bathong, boleng ba likamano tsa motsoali le ngoana bo fumanoe bo susumetsa menyetla ea joala le ts'ebeliso ea lithethefatsi hamorao bophelong.Kendler et al., 2000). Ka mokhoa o ts'oanang, maemo a tlhokomelo ea bo-mme ka litoeba, a tšoauoa ka ho nyeka le boitlhopho ba bana, le ona a kopantsoe le ho itlhokomela ka bobeli cocaine le ethanol. Haholo-holo, maemo a tlaase a ho nyeka le boitlhopho a ne a hokahanngoa le litekanyo tse phahameng tsa tšebeliso ea lithethefatsi tsa pop le maemo a holimo a ho nyeka le boitlhopho li ne li amana le maemo a tlase a tšebeliso ea lithethefatsi tsa pupFrancis le Kuhar, 2008). Sena se hlahisa ntlha ea bohlokoa ea hore ho pepesetsoa lithethefatsi tsa basali, tse sitisang ponahalo ea ho nyeka le boitlhopho hammoho le boits'oaro bo bong ba basali, li ka susumetsa tlhekefetso ea tlhekefetso ea lithethefatsi ho bana.

Joalo ka ha litšebelisano tse senyehileng tsa sechaba li ka eketsa tlokotsi ea tšebeliso e mpe ea lithethefatsi, likamano tse matla tsa sechaba pakeng tsa batho li ka sireletsa khahlanong le tlhekefetso ea lithethefatsi. Ho batho, ho ba le lelapa le tiileng la nyutlelie ho amahantsoe hampe le mathata a tlhekefetso ea lithethefatsi ka kakaretso, le ts'ebeliso ea lithethefatsi tse "thata" tse kang AMPH le cocaine (Bell et al., 2000; Ellickson et al., 1999). Ho feta moo, likamano tse tsitsitseng, tse atamelaneng lipakeng tsa batho ba baholo li 'nile tsa amahanngoa le litekanyetso tse theohileng tsa ho khutla tšebelisong ea lithethefatsi (Kosten et al., 1987). Khopolo ena e ts'ehetsoa hape ke boithuto ba rona ba morao-rao moo li-voirs tsa banna tse kopantsoeng li kopanang le tekanyetso e phahameng ea AMPH ho hlahisa litlhahiso tsa sebaka se le betere ho feta banna ba amanang le thobalano, e fana ka maikutlo a hore boiphihlelo ba kopane bo ka fokotsa tšusumetso e amanang le AMPH (Liu et al., 2007).

6.2. Karolo ea Mesocorticolimbic DA

Leha ho tsebahala hanyane ka mekhoa e tlatselletsang litšebelisanong tsa boitšoaro tse boletsoeng kaholimo, ho se tsotelle ha bana ho batho le tlhekefetso ea bo-'m'e lithutong tseo eseng tsa batho le mefuta ea litoeba li amana le ts'ebetso e fetotsoeng ea litsamaiso tsa DA. Mohlala, bana ba hlekefetsoa hampe, eo tlhekefetso ea bana e leng mofuta o atileng haholo (Lekhotla la Naha la Lipatlisiso, 1993), nakong ea lilemo tsa pele tsa 6 ea bophelo e ne e theotse haholo beta hydroxylase ea DA (enzyme e fetolang DA ho etsa norepinephrine ka li-neurons) ho feta bana ba neng ba sa ts'oaroa hampe (Galvin et al., 1995). Maemo a phahameng a motheo a urine DA a boetse a amahanngoa le tšoaro e mpe ea bana (De Bellis et al., 1999). Leha bohlokoa ba tšebetso ba liphetoho tsena bo e-so tsejoe, ho fanoe ka maikutlo a hore liphetoho tse amanang le methapo ea kutlo tse bakiloeng ke pherekano sechabeng bongoaneng li ka beha tlokotsi ea tlhekefetso ea lithethefatsi hamorao (De Bellis, 2002; Gordon, 2002). Ts'ehetso ea mohopolo ona e tsoa lithutong tsa mehlala ea methapo. Mohlala, ho nyenyefatsoa ha bo-mme, ho neng ho ntlafatsa taolo ea lithethefatsi tse fapaneng tsa tlhekefetso (joalo ka ha ho hlalositsoe kaholimo) ho hlahisitse phetiso ea NAcc DA ho arabela AMPH le cocaine, ho fana ka maikutlo a eketsehang a mesocorticolimbic DA lithethefatsi tsa tlhekefetso. Ho feta moo, kutloisiso ena e matlafalitsoeng e ile ea bonoa litšoantšong tsa masea, a manyane le a batho ba baholo, e bonts'a phello e sa feleng ea khaello ea basali ho sisteme ea mesocorticolimbic DA (Kehoe et al., 1998; Kehoe et al., 1996; Kosten et al., 2003, 2005). Ts'ebeliso ea lithethefatsi e ka boela ea ama maemo a receptor a mesocorticolimbic ho latela boiphihlelo ba sechaba, kaha likhoto tse arohaneng le bo-mme li ne li theoletse maemong a tlamang a D1R libakeng tse ngata tsa boko, ho kenyeletsa le mantlha ea NAcc, kamora ts'ebeliso ea ethanol ha e bapisoa le likhoto tse sa phekoloang (Ploj et al., 2003).

Re leboha Claudia Lieberwirth, Kelly Lei, Melissa Martin, le Adam Smith ka ho bala ha bona ho tebileng ha buka e ngotsoeng ka letsoho le Charles Badland bakeng sa thuso ea hae lipalo. Mosebetsi ona o tšehelitsoe ke National Institutes of Health Grants DAF31-25570 ho KAY, MHF31-79600 ho KLG, le DAR01-19627, DAK02-23048, le MHR01-58616 ho ZXW.

Boitlhotlhollo ba Mohoeletsi: Ena ke faele ea PDF ea mongolo o ngotsoeng ka letsoho o sa amoheloang o amoheletsoeng bakeng sa ho hatisoa. Joaloka tšebeletso ho bareki ba rona re fana ka phetolelo ena ea pele ea mongolo o ngotsoeng ka letsoho. Mongolo o ngotsoeng ka letsoho o tla ba le ho kopitsa, ho kenya lihlopha le ho hlahloba bopaki bo hlahang pele o hatisoa ka mokhoa oa oona oa ho qetela. Ka kopo hlokomela hore nakong ea mekhoa ea tlhahiso ea lihlahisoa e ka fumanoa e ka amang litaba, le litsebiso tsohle tsa molao tse sebetsang koranteng e amanang le eona.

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