Glutamatergic synaptic plasticity na usoro mesocorticolimbic na-eri ahụ (2015)

Plasticity synapti na mpaghara ventral tegmental (VTA)

Mgbanwe na nnyefe synapti emelarị mgbe mkpughe mbụ na ọgwụ na-eri ahụ. Otu otu na vivo ikpughe na ọgwụ na-eri ahụ na-ebute mmụba nke ike synapti na glutamatergic synapses na DA neurons nke VTA. A na-enye otu ntụtụ cocaine na-anaghị akwụsị akwụsị na vivo na ụmụ oke na oke, na 24 h mgbe e mesịrị, a na-edekọ mmiri na-akpali akpali postsynaptic (EPSCs) na dopaminergic neurons na midbrain mpekere nke ụmụ anụmanụ ndị a iji nyochaa mgbanwe na ike synapti (Ungless et al., 2001). Oke nke AMPAR- vs. NMDAR-mediated EPSCs (AMPAR/NMDAR ratio) na VTA DA neurons abawanyela nke ukwuu. Mmụba a nwere ike igosipụta mmụba na mmiri AMPAR ma ọ bụ mbelata na mmiri NMDAR ma ọ bụ ngwakọta nke abụọ. N'ezie, mmụba AMPAR na mbelata mmiri NMDAR na-eme ma na-ebute mmụba AMPAR/NMDAR mgbe ekpughere ọgwụ na-eri ahụ. N'agbanyeghị et al. (2001gosipụtara na mgbasa ozi AMPAR na-abawanye na glutamatergic synapses na DA neurons nke VTA, ebe ọ bụ na njupụta na ugboro ole nke AMPAR-mediated miniature EPSCs (mEPSCs) mụbara nke ukwuu mgbe e mesịrị. na vivo ikpughe na cocaine. Nke a kwadoro site na nchọta nke etinyere AMPA na VTA DA neurons butere nnukwu mmiri iyi AMPA na-ebute na mpekere sitere na ụmụ oke ndị natara ọgwụ cocaine karịa n'iberibe sitere na ụmụ oke ndị e tinyere saline. N'ụzọ dị mkpa, a na-egosipụta ike ogologo oge nke cocaine na-eme ka ikuku mgbasa ozi AMPAR bụrụ kpọmkwem maka DA neurons nke VTA, ebe ọ bụ na enweghi ike ịchọta na hippocampus ma ọ bụ na GABA neurons na VTA. Mmụba nke Cocaine na-abawanye na nha AMPAR / NMDAR emeghị mgbe a na-ejikọta cocaine na onye na-emegide NMDAR, na-egosi na mmụba nke AMPAR / NMDAR ruru dabere na ntinye NMDAR. Ya mere, otu ikpughe na cocaine na-ebute plasticity synaptik na synapses na-akpali akpali na VTA DA neurons nke yiri NMDAR-adabere ogologo oge ike (LTP). N'ikwekọ na nke a, plasticity synapti nke ọgwụ na-ekpuchi LTP na-esote, na-atụ aro na ụdị abụọ a nke plasticity na-ekerịta usoro dị n'okpuru (Ungless et al., 2001; Liu et al., 2005; Argilli et al., 2008; Luu na Malenka, 2008).

Mgbe nchọpụta nke na vivo Plasticity nke cocaine kpatara, a nyochara ma ọgwụ ndị ọzọ eji eme ihe na-akpata otu mgbanwe ahụ na nnyefe excitatory na VTA. Site na na vitro Ọmụmụ ihe a maralarị na ntinye nke nicotine dị ntakịrị na-akpalite LTP na synapses na-akpali akpali na VTA DA neurons (Mansvelder na McGehee, 2000), na-akwado echiche a. N'ezie, ọgwụ niile na-eri ahụ nwalere ruo taa (n'ime nke morphine, nicotine, benzodiazepines na ethanol) na-ebute ike nke nnyefe AMPAR na VTA DA neurons 24 h mgbe na vivo nchịkwa nke otu dose (Saal et al., 2003; Tan et al., 2010). Enweghi oke AMPAR/NMDAR ka emechara na vivo nchịkwa nke ọgwụ psychoactive na-adịghị eri ahụ fluoxetine na carbamazepine (Saal et al., 2003). Eziokwu ahụ bụ na klas ọgwụ dị iche iche, nke nwere usoro ihe omume dị iche iche, na-ebute ụdị ụdị synaptic plasticity na VTA DA neurons bụ ihe mbụ gosiri na ụdị synaptic plasticity a nwere ike jikọta ya na ihe na-eri ahụ nke ọgwụ ndị a.

Nnyocha ndị ọzọ n'ime usoro ndị na-akpata mmụba AMPAR / NMDAR gosipụtara na NMDAR-arụ ọrụ achọrọ maka plastik synapti nke ọgwụ na-ebute site na mkpali nke DA D.₅ ndị na-anabata ya, ebe ọ bụ na ọ nweghị ike ịkpata cocaine ka achọpụtara mgbe itinyechara D₁/D₅ receptor antagonist ma ọ bụ na D₅ ụmụ oke na-anabata knockout (Argilli et al., 2008). Plasticity synapti nke Nicotine kpatara na vitro dabere na DA D₅ ndị na-anabata ya (Mao et al., 2011). A na-ebute mgbasa ozi AMPAR site na ntinye nke AMPAR enweghị GluA2 n'ime synapse na-eso. na vivo ikpughe ọgwụ ndị na-eri ahụ (Bellone na Lüscher, 2006; Argilli et al., 2008). Ọrụ mbụ nke Fitzgerald et al. (1996) enyelarị ihe ngosi na plasticity nke ọgwụ na-ebute na glutamatergic synapses na DA neurons nke VTA gụnyere mgbanwe na GluA2-enweghị AMPAR. Nkwupụta nke ngalaba GluA1, mana ọ bụghị ngalaba GluA2, abawanyela na VTA DA neurons mgbe ekpughere ya na cocaine (Fitzgerald et al., 1996). Ịchọta ihe akaebe kpụ ọkụ n'ọnụ nke mgbanwe gaa na AMPAR enweghị GluA2, Bellone na Lüscher (2006) ejirila njirimara biophysical pụrụ iche nke AMPAR enweghị GluA2. AMPAR enweghị GluA2 bụ Ca²⁺-permeable, nwere omume ka ukwuu, na-edozi n'ime ime ma na-egbochi ya site na polyamines (Washburn na Dingledine, 1996; Isaac et al., 2007). Ndozi nke EPSC nke AMPAR na-emekọrịta ihe na-abawanye na-esochi nchịkwa cocaine, na nchịkwa nke polyamine toxin Joro spider toxin (JST) na-egbochi EPSC nke AMPAR na-emekọrịta ihe na ụmụ oke ndị na-agwọ cocaine, na-akwado ntinye nke GluA2-enweghị AMPARs (Bellone na Lüscher). 2006). Enwere ike itinye ndị nnabata ndị a n'elu ọdọ mmiri GluA2 nwere AMPAR dị ugbu a ma ọ bụ ha nwere ike dochie ndị nnabata GluA2 nwere, na-edobe ngụkọta nke AMPAR na synapse mgbe niile. Immunogold labeling nke GluA2 subunits gosiri na ọdọ mmiri cytoplasmic nke GluA2 nwere AMPAR ka emelitere mgbe ekpughere ya na cocaine, ebe akara GluA2 na synapse belatara (Mameli et al., 2007). Ya mere, ikpughe na ọgwụ na-eri ahụ na-akpata mgbanwe nke GluA2-nwere maka GluA2-enweghị AMPARs, nke na-eme ka nnyefe AMPAR dị elu n'ihi otu ọwa dị elu nke GluA2-enweghị AMPAR.

Na mbụ, ọmụmụ ndị kọrọ na ike ọgwụ sitere na mgbasa ozi mgbasa ozi AMPAR na VTA DA neurons ka emere awa 24 mgbe nchịkwa ọgwụ gasịrị, mana kedu oge n'ezie nke synapse na-ewusi ike na-eso mkpughe ọgwụ? Argilli et al. (2008) chọpụtara na plastik synapti mere ngwa ngwa mgbe nchịkwa gasịrị, ebe ọ bụ na ahụrụ ike AMPAR dị n'ime awa 3 (Argilli et al., 2008). Plastic synapti nke Cocaine kpatara na-adịru nwa oge, ebe ọ bụ na a ka na-ahụ ike synapti ka ụbọchị 5 gachara, mana ọ bụghị mgbe ụbọchị iri gachara (Ungless et al., 2001). Ebe ọ bụ na nnyefe na glutamatergic synapses na VTA DA neurons bụ nke a na-ahazi mgbe ihe dị ka otu izu gasịrị, a ga-etinyerịrị usoro na-egbochi mgbanwe ndị ọgwụ ahụ kpatara. N'ụzọ na-akpali mmasị, a na-atụgharị synapti plasticity nke cocaine site na ịgbalite ndị na-anabata mGluR1 na VTA. Kpọmkwem, ịgba ọgwụ intraperitoneal nke ezigbo modulator nke mGluR1 weghaara nkesa subunit AMPAR nke cocaine kpatara (Bellone na Lüscher, 2006). Mgbagha mpaghara nke ọrụ mGluR1 na neurons nke VTA n'aka nke ọzọ mere ka ike cocaine kpalitere na VTA (Mameli et al., 2009). Ya mere, na-esochi ikpughe na ọgwụ, glutamatergic synaptic nnyefe bụ nke mGluR-based LTD na-emezigharị, nke mejupụtara ngbanwe nke AMPAR na-enweghị GluA2 nwere obere omume GluA2 nwere AMPAR (Mameli et al., 2007).

Ka ọ dị ugbu a, a tụlere mgbasa ozi AMPAR ka ọ bụrụ ihe kpatara mmụba AMPAR/NMDAR na-ebute site na. na vivo ikpughe ọgwụ. Agbanyeghị, ntinye nke AMPAR enweghị GluA2 ga-ebelata oke AMPAR/NMDAR na +40 mV, ebe ọ bụ na AMPAR enweghị GluA2 na-eme nke ọma na ikike akpụkpọ ahụ dị mma n'ihi ngọngọ polyamine. Ya mere, mmụba nke AMPAR/NMDAR ga-abụrịrị ihe kpatara ya site na mbelata n'ọnụ mmiri NMDAR. N'ezie, a chọpụtakwara na ọnụọgụ AMPAR/NMDAR mụbara bụ n'ihi mbelata mgbasa ozi NMDAR (Mameli et al., 2011). Mbelata nke a sitere na ngbanwe nhazi nke subunit NMDAR. Ọnụ ọgụgụ GluN2B na GluN2A na-abawanye na-esochi ikpughe na cocaine (Yuan et al., 2013). Ọzọkwa, NMDAR nke GluN3A nwere, nke nwere Ca²⁺ permeability, na-etinye n'ime synapse mgbe ikpughe cocaine (Yuan et al., 2013). Ọnụ, nchoputa ndị a na-egosi na cocaine na-eme ka ntinye synapti nke tri-heteromeric GluN1/GluN2B/GluN3A nwere NMDAR nke dochie GluN1/GluN2As na GluN1/GluN2A/ GluN2Bs. Achọpụtara mgbanwe abụọ a na-akpata cocaine na nnyefe AMPAR na mgbanwe cocaine kpatara na nnyefe NMDAR dabere na ntinye nke GluN3A nwere NMDAR, ebe ọ nweghị plasticity nke cocaine dị na ụmụ oke GluN3A knockout ma ọ bụ mgbe ịgbanye ọgwụ nje metụtara adeno. vector na-ekwupụta mgbochi GluN3A mkpụmkpụ ntutu isi RNA (Yuan et al., 2013). N'ikpeazụ, mGluR1 na-arụ ọrụ, nke na-atụgharị ntụgharị nke AMPAR nke cocaine na-ebute, gbanwekwara redistribution nke NMDAR (Yuan et al., 2013). Ya mere, ntinye synapti nke GluN3A nwere AMPAR dị ka ọ dị mkpa maka ngosipụta nke plasticity nke cocaine kpatara.

Na mgbakwunye na ntinye glutamatergic, VTA DA neurons na-enwetakwa ntinye GABAergic, site na interneurons mpaghara yana amụma sitere na NAc na ventral pallidum (VP; Kalivas et al., 1993; Steffensen et al., 1998). Synapses inhibitory ndị a na VTA DA neurons na-enwetakwa plastik synapti mgbe ekpughere ọgwụ na-eri ahụ. E gosipụtara Morphine, cocaine na nicotine niile iji mebie ike ogologo oge nke GABAergic synapses na VTA DA neurons, n'agbanyeghị na usoro oge dị iche iche (Niehaus et al., 2010). N'aka nke ọzọ, ntinye GABAergic na interneurons inhibitory na VTA na-enwe ike mgbe e mesịrị. na vivo ikpughe ọgwụ ọjọọ, si otú a na-egbochi neurons DA (Tan et al., 2010; Bocklisch et al., 2013). Ọnụ, ụbara AMPAR / NMDAR na glutamatergic synapses na VTA DA neurons, mfu nke LTP nke GABAergic synapses na VTA DA neurons, yana nkwụsị nke VTA DA neurons site na ike nke GABAergic synapses na VTA interneurons nwere ike ime ka ọ dịkwuo mma. VTA DA neurons. N'ihe banyere nicotine, ntinye GABAergic na VTA DA neurons na-ebelatakwa site na nhụsianya nke nicotinic acetylcholine receptors (nAChRs) na neurons GABAergic (Mansvelder et al., 2002). Ebe ọ bụ na ịgbalite nAChRs depolarizes neurons GABAergic, nhụsianya a na-eduga na ịda mbà n'obi nke nnyefe GABAergic. Mmetụta a bụ nke kachasị na mpaghara nke neurons GABAergic nke na-enwekarị mmasị site na nnyefe cholinergic endogenous. Mmetụta ịda mbà n'obi nke ntinye GABAergic n'ihi nAChR desensitization nwere ike inye aka na mmụba na VTA DA neuron excitability, ọ bụ ezie na mmekọrịta dị mgbagwoju anya n'etiti GABA na DA neuron ọrụ yiri ka ọ na-ekere òkè (Tolu et al., 2013).

Plastic synapti nke ọgwụ na-akpata na VTA anaghị eme n'ụwa niile, na-emetụta akwara VTA DA niile n'otu aka ahụ. Nchoputa na nso nso a egosila na ọgwụ dị iche iche na-emetụta ọnụ ọgụgụ dị iche iche nke VTA DA neurons na amụma na mpaghara iche iche. (Lammel et al., 2013). Otu ntụtụ nke cocaine ahọpụtara glutamatergic synapses na DA neurons na-atụpụta na shei NAc mana ọ bụghị synapses na DA neurons na-atụpụta na mPFC (Lammel et al., 2011). Agbanwere synapses na-akpali akpali na DA neurons na-emepe na mPFC site na mkpali na-akpali akpali, na-atụ aro na ihe mkpali na-akwụghachi ụgwọ na nke mgbagha na-emetụta ọnụ ọgụgụ DA neuron dị iche iche na VTA. Ndị neurons DA na-atụba na shea NAc, nke ọgwụ na-emetụta, na-enweta ntinye ha site na tegmentum laterododorsal, ebe DA neurons na-atụpụta na mPFC, nke ihe mkpali na-emetụta, na-enweta ntinye ha site na habenula mpụta (Lammel et al. ., 2012).

Single na vivo ikpughe na ọgwụ ọjọọ eme ihe na-ebute mgbanwe synaptik nke ka dị ogologo oge ka ekpochapụchara ọgwụ ndị ahụ n'ahụ, ọ dịkarịa ala ụbọchị 5. Otú ọ dị, nke a adịghị adịte aka iji kọwaa mmetụta omume na-adịte aka nke a na-ahụ na ịṅụ ọgwụ ọjọọ. EỌbụna mgbe nchịkwa cocaine ugboro ugboro (ịgba ọgwụ asaa kwa ụbọchị), mmụba nke cocaine kpatara na AMPAR / NMDAR ruru na VTA DA neurons na-adịru nwa oge, a pụghịkwa ịhụ ya ụbọchị iri ka nkwụsị nke nchịkwa cocaine gasịrị, dị ka ike synapti kpatara site na. otu injection (Borgland et al., 2004). Agbanyeghị, n'ime ọmụmụ ihe ndị a niile, a na-eji nchịkwa ọgwụ na-anaghị akwụsị akwụsị. Mmetụta nke nchịkwa onwe onye nke ọgwụ ndị na-eri ahụ na-adịte aka karịa mmetụta nchịkwa ọgwụ na-adịghị agwụ agwụ. Mgbe ọnwa 3 nke abstinence na nchịkwa onwe nke cocaine, ike synapti nke cocaine ka dị na VTA DA neurons na oke. (Chen et al., 2008). Nnọgidesi ike nke ike synaptik nke ọgwụ na-akpata na neurons VTA mgbe nchịkwa onwe onye ọgwụ gasịrị na-egosi na ihe a nwere ike ịbụ isi ihe na-ebute mmepe nke omume riri ahụ.

Gịnị bụ mgbanwe akparamagwa nke na-ebute site na plasticity synapti nke ọgwụ na-ebute na VTA? Ụmụ oke nwere mkpochapụ mkpụrụ ndụ ihe nketa nke ngalaba GluA1 ma ọ bụ ngalaba GluN1 na-ahọrọ na DA neurons enweghị ike ọgwụ na-akpata ọgwụ na VTA DA neurons, mana cocaine ka na-ebute mmasị ọnọdụ ọnọdụ nkịtị (CPP) na mmetụta omume. n'ime ụmụ oke ndị a (Engblom et al., 2008). N'ọmụmụ ihe ọzọ, ụmụ oke na-enweghị ngalaba GluN1 naanị na DA neurons gosikwara mmetụta omume nkịtị, mana kagburu CPP na ụmụ oke ndị a (Zweifel et al., 2008), dị iche na nsonaazụ si Engblom et al. (2008). Nke a dị iche n'etiti ọmụmụ ihe nwere ike ịkpata ọdịiche dị na protocol CPP. N'ihe niile, ihe akaebe na-egosi na plasticity synaptic nke ọgwụ na-ebute na VTA DA neurons na-eme ka mmetụta omume dị mkpirikpi nke ikpughe ọgwụ dị oke oke. Agbanyeghị, plastik synapti nke ọgwụ butere na VTA DA neurons nwere ike ịbụ nzọụkwụ mbụ dị mkpa maka omume riri ahụ n'oge. N'ime ụmụ oke enweghị GluN1 na neurons DA, mweghachi nke omume ịchọ ọgwụ na CPP kwụsịrị (Engblom et al., 2008). Ọzọkwa, mmụba na-egbu oge nke nleba anya omume nke na-eme mgbe ndọpụ cocaine ogologo oge emeghị na ụmụ oke GluN1 knockout (Zweifel et al., 2008). Mgbanwe omume omume ndị a na-eme n'oge na-adịbeghị anya nwere ike ọ bụghị kpọmkwem nsonaazụ nke synapti plasticity na VTA, mana ọ ga-abụ na mgbanwe synapti na mpaghara ụbụrụ ndị ọzọ na-ebute site na synaptic plasticity na VTA. Plastic synaptic nke ọgwụ na-akpata na VTA na-eduga na synaptic plasticity na-esote na mpaghara ụbụrụ ndị ọzọ, nke dị mkpa maka mgbanwe omume a na-ahụ na ịṅụ ọgwụ ọjọọ karịa synaptic plasticity na VTA n'onwe ya (lee n'okpuru). Na VTA, ọgwụ ọjọọ eme ihe na-agbanwe iwu maka plasticity dabere na ọrụ ma si otú a mee ka mgbanwe ndị na-esote ala na-esote na mesocorticolimbic circuitry (Creed na Lüscher, 2013). Tmgbanwe hese na mpaghara ụbụrụ dị n'okpuru, ọkachasị na NAc na PFC, a na-eche na ọ ga-ejikọta ya na ajọ omume omume na-adịte aka nke a na-ahụ na iri ahụ.

Ikike nke plastic synapti nke ọgwụ na-ebute na VTA iji tụgharịa iwu maka plasticity dabere na ọrụ na-adabere na nkesa nke AMPAR na NMDAR subunits (Yuan et al., 2013). Dị ka ọ na-adịkarị, LTP na-adabere na NMDAR ma na-akpali ya mgbe mwepụta presynaptic glutamate dakọtara na depolarization nke akpụkpọ ahụ postsynaptic, n'ihi na Mg.²⁺-block nke NMDARs na-enwere onwe ya na ikike akpụkpọ ahụ mebiri emebi, na-enye ohere Ca²⁺ ntinye. Agbanyeghị, cocaine na-ebute ngbanwe nke ihe mejupụtara NMDAR, na-eke NMDAR nwere obere Ca²⁺ permeability (Yuan et al., 2013). Ya mere, ịgbalite NMDARs anaghịkwa ebute LTP. N'aka nke ọzọ, cocaine na-ebugharị ntinye synapti nke GluA2-enweghị AMPAR, nke bụ Ca.²⁺- permeable. Ya mere, mgbe ikpughe cocaine gasịrị, ụdị LTP nwere ike ịkpata na VTA neurons nke na-adabere na ntinye calcium site na AMPAR ma na-adabere na NMDAR (Mameli et al., 2011). Agbanyeghị, AMPAR na-enweghị GluA2 na-eme nke ọma na ikike akpụkpọ ahụ dị mma, n'ihi mgbochi polyamine na ikike akpụkpọ ahụ dị mma. Ka hyperpolarization na-abawanye, ka GluA2 enweghị AMPAR na-eme calcium ngwa ngwa. Ya mere, cocaine na-eme ka iwu nke ike synaptic dabere na ọrụ gbanwee, ebe ọ bụ na ntinye nke LTP chọrọ ugbu a ijikọ ọrụ presynaptic na hyperpolarization nke cell postsynaptic kama depolarization (Mameli et al., 2011). A ka ga-anwale ma nke a ọ̀ bụ eziokwu maka ọgwụ ọjọọ niile.

Dịka e kwuru n'elu, glutamatergic synaptic plasticity na VTA na-ebute plasticity synapti na-esote n'akụkụ ndị ọzọ nke usoro mesocorticolimbic. Mgbanwe synaptik na-ebute ụzọ na VTA tupu synaptic plasticity na mpaghara ndị ọzọ nke mesocorticolimbic usoro. Na mgbakwunye, mgbanwe na VTA na-eme mgbe otu ikpughe, ebe plasticity na mpaghara ala na-achọkarị ikpughe ọgwụ. (Kourrich et al., 2007), ọ bụ ezie na ọ dị mkpa ka a mara na Mato et al. (2004) gosiri na na ụmụ oke, otu na vivo nchịkwa nke THC gbanwere synaptic plasticity na NAc (Mato et al., 2004). Ọzọkwa, cocaine-evoked synaptic plasticity na NAc na-eme naanị ma ọ bụrụ na synaptic plasticity na VTA na-adịgide adịgide. (Mameli et al., 2009). Ntughari plasticity synapti na VTA site na intraperitoneal injections nke ezigbo modulator nke mGluR1 gbochiri synaptic plasticity na NAc (Mameli et al., 2009). N'aka nke ọzọ, mgbe nkwụsị nke mpaghara mGluR1 na-arụ ọrụ na VTA neurons, nke na-agbatị ike nke ọgwụ na-ebute na VTA, otu injection nke cocaine zuru ezu iji mee ka synaptic plasticity na NAc, nke na-adịghị emekarị. Nchọpụta ndị a na-atụ aro ụlọ ọrụ nhazi nke synaptic plasticity na-ebute ọgwụ, yana VTA dị ka ebe mbụ nke plasticity, na-esote glutamatergic synaptic plasticity na mpaghara ala nke usoro mesocorticolimbic. A na-atụle usoro ndị dị n'okpuru usoro nke plasticity n'ikpeazụ na ngalaba na-esonụ.

Plastic synapti nke sitere na ọgwụ na-eme n'ime nucleus accumens

Ndị isi akwara nke NAc, GABAergic medium spiny neurons (MSNs), na-enweta ntinye glutamatergic sitere na mpaghara ụbụrụ cortical na limbic, gụnyere PFC na amygdala. (Groenewegen et al., 1999). Nsonaazụ sitere na ọtụtụ ọmụmụ na-egosi na nnyefe glutamatergic na NAc na-arụ ọrụ dị mkpa n'ịchọ ọgwụ. Microinjection nke AMPA n'ime NAc na-eme ka mweghachi dị ukwuu nke omume ịchọ cocaine, ebe microinjection nke onye na-emegide AMPAR n'ime NAc na-egbochi iweghachite cocaine na-achọ (Cornish na Kalivas, 2000; Ping et al., 2008). Ọzọkwa, a na-eche na ọrụ dị n'ime NAc na-emezi nghọta omume (Koya et al., 2009, 2012). Ebe ọ bụ na akara ngosi glutamatergic na NAc na-arụ ọrụ dị mkpa na omume riri ahụ, plasticity synaptik na glutamatergic synapses na NAc MSN nwere ike itinye aka na riri ahụ.

N'adịghị ka VTA, otu injection cocaine ezughi oke iji kpalite plasticity synapti na NAc (Kourrich et al., 2007). Naanị mgbe ọgwụgwọ cocaine gasịrị ugboro ugboro, mgbanwe na ike synapti na-eme na glutamatergic synapses na NAc MSNs.. Ntuziaka nke plastic synapti a dabere na ogologo oge nkwụsị ọgwụ (Kourrich et al., 2007). Kourrich et al. (2007) na-enye ụmụ oke ọgwụ cocaine ise otu ugboro kwa ụbọchị wee nyochaa nha AMPAR / NMDAR na neurons NAc ma 24 h na 10-14 ụbọchị mgbe ntụtụ ikpeazụ gasịrị. N'oge mwepu n'oge, 24 h mgbe ịgba ọgwụ ikpeazụ gasịrị, ahụrụ mbelata dị ukwuu na oke AMPAR / NMDAR na akwara NAc shell nke ụmụ oke a na-agwọ cocaine. Agbanyeghị, mgbe oge enweghị ọgwụ nke ụbọchị 10–14, abawanyela oke AMPAR/NMDAR na neurons shei NAc. Ọzọkwa, otu mkpugheghachi ọgwụ ọjọọ mere ka mbelata na nha AMPAR/NMDAR 1 ụbọchị ka e mesịrị, na-atụgharị na mberede ike synapti. Mmetụta ịda mbà n'obi nke synapti na-esochi mkpughe cocaine ọzọ mgbe oge enweghị ọgwụ na-akọwakwa na ọmụmụ mbụ (Thomas et al., 2001; Brebner et al., 2005). Thomas et al. (2001) gosikwara na mbelata nke nha AMPAR/NMDAR na-egosipụta mbelata mgbasa ozi AMPAR.

Iji chọpụta ihe kpatara mmụba AMPAR / NMDAR na neurons NAc shei mgbe ogologo oge ewepụrụ, Kourrich et al. (2007) mEPSC ndị mgbasa ozi AMPAR dekọrọ. Ọnụ ọgụgụ na ugboro nke mEPSC nke AMPAR na-emekọrịta ihe na-abawanye nke ọma na ụmụ oke ndị na-agwọ cocaine (Kourrich et al., 2007), na-atụ aro ike nke mgbasa ozi synapti nke AMPAR na-eme ka ọ nwesịrị ogologo oge. Nsonaazụ ndị a dabara na nchoputa nke Boudreau na Wolf (Boudreau na Wolf, 2005), onye chọtara ngosipụta elu cell nke AMPAR dị na NAc nke oke mgbe ụbọchị 21 nwechara. Ọ bụ ezie na kpọmkwem usoro ndị na-akpata ike synapti nke ọgwụ a na-akpata na NAc shei mgbe ọ kwụsịrị ogologo oge, amataghị na ike synapti dabere na ịgbalite ụzọ kinase (ERK) na-achịkwa extracellular site n'ụzọ ERK phosphorylation. (Pascoli et al., 2012). Ugboro ugboro nke AMPAR mEPSCs, jikọtara ya na nchọpụta na ọnụọgụ abụọ-pulse (ihe maka ọrụ presynaptic) agbanweghị, na-atụ aro na ikpughe na cocaine ugboro ugboro nwere ike iduga n'ichepụta synapses ọhụrụ na NAc MSN. A na-akwado nke a site na nchọpụta na ọnụ ọgụgụ dendritic spines na NAc MSN mụbara mgbe ekpughere ya ugboro ugboro na cocaine, amphetamine na nicotine (Robinson na Kolb, 2004). Ya mere, ikpughe cocaine ugboro ugboro na-emepụta ike synaptik na shea NAc nke na-etolite n'oge nkwụsị ọgwụ, ikekwe n'ihi nhazi nke synapses ọhụrụ, bụ nke ịda mbà n'obi synaptik na-esote n'otu oge ọzọ. Otú ọ dị, ma mgbe nkwụsịtụ ogologo oge gasịrị na mgbe ekpughere otu ọgwụ ọzọ, nnyefe NMDAR agbanweghị (Kourrich et al., 2007). Ọzọkwa, ọ nweghị ihe akaebe maka mgbanwe na ọnụnọ GluA2-enweghị AMPAR na synapse ahụ, ebe ọ bụ na EPSCs na-emezigharị nke AMPAR na-agbanwe agbanwe agbanweghị na ụmụ oke na-agwọ cocaine mgbe ọ gbasasịrị ogologo oge na mgbe ekpughere cocaine ọzọ.

Ọmụmụ ihe ndị a na-eji nchịkwa ọgwụ na-adịghị akwụsị akwụsị iji kpalite plasticity synapti. N'ịgbaso nchịkwa onwe onye cocaine, a chọtara ịda mbà n'obi synaptik nke mgbasa ozi na-akpali akpali na NAc shei n'oge mwepụta mbụ na cocaine (Schramm-Sapyta et al., 2006), bụ nke na-esochi mgbasa ozi AMPAR na-abawanye mgbe ọ kwụsịrị ogologo oge (Conrad et al., 2008). Agbanyeghị, n'adịghị ka nchoputa nke Kourrich et al. (2007), Achọpụtara mmụba a n'ihi ntinye synapti nke GluA2 enweghị AMPAR. Belu ọzọ na intracellular GluA1 ọkwa abawanyela nke ukwuu na NAc mgbe ụbọchị 45 nke ndọrọ ego gasịrị, na imezi mmezi nke EPSC nke AMPAR na-emekọrịta ihe na-abawanye nke ukwuu na isi NAc nke oke oke cocaine (Conrad et al., 2008). Agbanweghị ọkwa GluA2, na-atụ aro na etinyere AMPAR enweghị GluA2 n'elu ọdọ mmiri GluA2 nwere AMPAR dị ugbu a. Ebe ọ bụ na Kourrich et al., enyocha mgbanwe synaptik mgbe 10-14 ụbọchị wepụrụ, ebe Conrad et al. enyocha mgbanwe synapti mgbe 42-47 ụbọchị wepụrụ, ọ ga-ekwe omume na ntinye synapti nke GluA2-enweghị AMPAR na NAc na-eme naanị mgbe ogologo oge nkwụsị. Nke a dabere na nchoputa na ọkwa NAc GluA1 ka abawanyela ntakịrị ka ụbọchị 21 ewepụrụ, na-egosi na ọkwa GluA1 na-abawanye nke nta nke nta ka ewepụrụ (Conrad et al., 2008). Ọmụmụ nke Mameli et al. (2009) na-akwado echiche ahụ A na-etinye AMPAR na-enweghị GluA2 n'ime synapses ka agbatịchara ogologo oge na ikpughe cocaine ugboro ugboro.. Achọtara nrụzi mmezigharị na NAc MSN mgbe ụbọchị 35 nke ndọrọ ndọrọ ọchịchị gasịrị mgbe nchịkwa cocaine na-enweghị isi na nchịkwa onwe nke cocaine (Mameli et al., 2009). Yabụ, ọkwa subunit AMPAR synapti na NAc MSN na-agbanwe ruo ọtụtụ izu na-eso mkpughe cocaine.

Ma Thomas et al. (2001) na Kourrich et al. (2007) hụrụ mbelata dị ukwuu na oke AMPAR / NMDAR na NAc shell neurons nke ụmụ oke a na-agwọ cocaine n'oge mwepụta mbụ, nke ekwuru na mbelata na nnyefe AMPAR (Thomas et al., 2001). Agbanyeghị, oke AMPAR/NMDAR belatara nwekwara ike bute ya site na ọgbọ nke synapses gbachiri nkịtị. Synapses gbachiri nkịtị bụ glutamatergic synapses nwere NMDAR, mana enweghị AMPAR na-arụ ọrụ (Isak et al., 1995). Thomas et al. (2001) ahụghị mgbanwe ọ bụla na-akpata cocaine na nnyefe NMDAR, ma nke a anaghị ewepu ohere na ọnụ ọgụgụ nke synapses na-agbachi nkịtị na-abawanye site na ikpughe cocaine. N'ezie, na-esochi ikpughe cocaine na-adịghị agbanwe agbanwe ugboro ugboro, ọnụọgụ synapses gbachiri nkịtị na-abawanye na NAc shell MSNs (Huang et al., 2009). Eji nwayọọ nwayọọ mepụta synapses ọhụrụ ndị a na-agbachi nkịtị n'oge ikpughe cocaine, na-eme ka mmụba dị ukwuu na pasent nke synapses dị jụụ site na ụbọchị nke atọ nke ọgwụgwọ cocaine. Ọgbọ nke cocaine kpatara synapses gbachiri nkịtị bụ onye ogbugbo site na ntinye akpụkpọ anụ nke GluN2B nwere NMDAR ọhụrụ (Huang et al., 2009). Mbara elu na mkpokọta ọkwa GluN2B, mana ọ bụghị GluN2A, ka abawanyela, yana mgbakwunye elu elu nke subunits GluN1. Ọzọkwa, mgbe ahọpụtara igbochi GluN2B nwere NMDAR nke nwere, enweghị mmụba na synapses nkịtị enweghị ike ịchọpụta. N'oge ndọrọ ndọrọ ọchịchị, ọnụ ọgụgụ synapses gbachiri nkịtị jụrụ ọzọ (Huang et al., 2009). Agbanyeghị, nke a apụtaghị na synapses emepụtara apụọla ọzọ. Ọ nwekwara ike ịpụta na synapses emebere nkịtị ka agbachighị ọnụ site na ntinye synapti nke (GluA2-enweghị) AMPAR. Nke a nwere ike ịbụ otu n'ime usoro dị n'azụ nkwuputa elu cell nke ngalaba AMPAR yana mmụba AMPAR/NMDAR na neurons NAc shei mgbe ọ nwesịrị ogologo oge. Ya mere, mgbanwe ndị a hụrụ na nha AMPAR/NMDAR na mgbanwe ndị a hụrụ na ọnụọgụ synapses dị jụụ nwere ike ịga n'aka. Ọzọkwa, ọgbọ nke synapses nkịtị nwere ike ịkwado plasticity synapti na-esote.

Mkpa omume nke mbelata na oke AMPAR/NMDAR n'oge mwepụta mbụ amabeghị. Atụpụtala na ịda mbà n'obi synapti nke ọgwụ na-akpata nwere ike ime ka akwara NAc shea ghara inwe mmetụta na-emetụta ihe mkpali na-akwụghachi ụgwọ eke, nke nwere ike ibute mmetụta nke anhedonia na dysphoria (Van den Oever et al., 2012). Nke a nwere ike ịbawanye agụụ ọgwụ. A na-eche na nsonaazụ omume nke ịda mbà n'obi synapti na-esochi mkpugheghachi otu ọgwụ bụ nnukwu ngosipụta nke mmetụta omume (Brebner et al., 2005). Na-egbochi ntinye nke ịda mbà n'obi nke synapti site na intra-NAc infusion nke akpụkpọ anụ peptide permeable nke na-akpaghasị endocytosis nke GluA2 gbochiri ịba ụba ọrụ locomotor nke amphetamine re-exposure.

Ike nke nta nke nta nke mgbasa ozi AMPAR n'oge ịwepụ ogologo oge nwere ike mebie "mmụba nke agụụ ọgwụ ọjọọ", ihe omume na-akpali agụụ mmekọahụ na ịchọ ọgwụ na-abawanye nke ọma n'ime ọnwa mbụ mgbe ọ kwụsịrị ọgwụ ọjọọ (Grimm et al., 2001). Ike nke mgbasa ozi AMPAR na-eme ka nzaghachi nke NAc MSNS na atụmatụ metụtara ọgwụ, na-eduga n'ọchịchọ ọgwụ na-achọsi ike. Ịchọ cocaine na-akpata na-achọ mgbe ogologo oge na-ewepụ na nchịkwa onwe onye cocaine belatara site n'itinye onye na-emechi nhọrọ nke GluA2-enweghị AMPAR n'ime NAc (Conrad et al., 2008). Ọzọkwa, ntinye nke GluA2-enweghị AMPAR na amygdala-to-NAc synapses site na. na vivo mkpali optogenetic mgbe mwepu ogologo oge belatara nnabata nke agụụ cocaine (Lee et al., 2013). Mmetụta nke ime ime a bụ ịgbachi nkịtị nke ụfọdụ synapses na-agbachi nkịtị, na-atụ aro na ntozu oke nke synapses na-agbachi nkịtị na-enyekwa aka na ntinye nke agụụ cocaine.

Mgbanwe synapti nke ọgwụ a kọwara na NAc duziri Bellone na Lüscher (2012na Dong na Nestler (2014) iji kwupụta echiche nke rejuvenation nke mgbasa ozi synaptik n'oge ịṅụ ọgwụ cocaine, na-emepụta ụdị synapses nke na-ejikọta ya na mmalite ụbụrụ ụbụrụ (Bellone na Lüscher, 2012; Dong na Nestler, 2014). Ọmụmaatụ bụ ọgbọ nke synapses gbachiri nkịtị yana ntinye synapti nke GluA2 enweghị AMPAR. Ngosipụta na cocaine na-emepeghachi oge dị oke egwu nke mmepe synapse na usoro mesocorticolimbic. Synapses ndị na-eto eto nwere ikike dị elu nke ịme mgbanwe plastik dabere na ahụmahụ na-adịte aka. A na-eche na nke a na-akọwa otú ọgwụ nwere ike isi nweta mgbanwe rọba siri ike na nke na-adịte aka, na-eduga n'icheta ihe metụtara ọgwụ siri ike ma dịgidere (Dong na Nestler, 2014). Echiche mmeghari ahụ gbatịkwara na mgbanwe synapti na VTA, dị ka mweghachi nke GluN3A nwere NMDAR. Eziokwu ahụ bụ na synapses ndị na-eto eto nwere ikike dị elu iji nweta mgbanwe mgbanwe plastik na-adabere na ahụmahụ nwere ike ịkọwa ihe mere ndị na-eto eto ji enwe ike ịṅụ ọgwụ ọjọọ.

Plastic synapti Glutamatergic abụghị naanị n'oge mkpughe ọgwụ na mwepụ. Ọ na-apụtakwa n'oge nlọghachi azụ na ịchọ ọgwụ ọjọọ. Ngosipụta nke ihe jikọrọ cocaine na enweghị cocaine ka achọpụtara na ọ na-eme ka mmụba ngwa ngwa na nha spine dendritic na nha AMPAR / NMDAR na isi NAc nke oke nwere akụkọ ihe mere eme nke nchịkwa onwe onye cocaine (Gipson et al. , 2013a). Mmụba ndị a adịlarị 15 min mgbe ngosipụta nke ihe metụtara cocaine na mmụba nke AMPAR / NMDAR na dayameta isi azụ azụ na 15 min nwere njikọ chiri anya na ike ịchọ ọgwụ. Nke a na-egosi na ike synaptik na-ebute ngwa ngwa na NAc isi MSN nwere ike ịbụ usoro na-ebute nlọghachi azụ. Ka awa abụọ gachara ibido nkwụghachi azụ azụ, nha spine dendritic na oke AMPAR/NMDAR alaghachila n'ọkwa nlọghachi azụ. Arụ ọrụ na prelimbic cortex (PL), mpaghara nke medial PFC (mPFC) nke na-eziga amụma glutamatergic na isi NAc, gosipụtara na ọ na-etinye aka na ya, ebe ọ bụ na microinjection nke GABAR agonists n'ime PL gbochiri ma mgbanwe synapti na-akpata. ịchọ ọgwụ ọjọọ (Gipson et al., 2013a). Ma arụrụ ọrụ nke glutamatergic PL-to-NAc synapses zuru oke iji kpalite nlọghachi azụ n'ezie, ma ọ bụ na mgbanwe synapti kpatara ọ dị mkpa yana maka nlọghachi azụ ka ga-ekpebisi ike. Otú ọ dị, nnyocha e mere n'oge na-adịbeghị anya na-arụrịta ụka maka njikọ dị n'etiti cocaine na-akpata plasticity nke glutamatergic mPFC-to-NAc synapses na nlọghachi azụ (Pascoli et al., 2014).

Mmetụta nke ọrụ na-akpata cue na glutamatergic PL-to-NAc synapses na-eme ka ọ dịkwuo mma site na mbelata ọkwa basal extracellular glutamate na NAc jikọtara ya na iwepụ ọgwụ na-eri ahụ (Gipson et al., 2014). A na-ebelata ọkwa glutamate nke basal na NAc mgbe ma cocaine na-adịghị agbanwe agbanwe na ikpughe nicotine n'ihi arụrụ arụ ọrụ nke glial cystine-glutamate Exchanger, nke na-ebuga glutamate na oghere extracellular (Kalivas, 2009). Nke a na-ebute mbelata ụda glutamate na presynaptic inhibitory mGluR2 na mGluR3 ndị na-anabata ya, nke na-ebelata mgbochi nke ntọhapụ glutamate presynaptic (Gipson et al., 2014). Nke a na-eduga na ntọhapụ synaptik nke glutamate na-azaghachi na atụmatụ metụtara ọgwụ. Ọzọkwa, a naghị ewepụ glutamate a tọhapụrụ nke ọma na synapse, n'ihi na okwu nke glial glutamate transporter 1 (GLT-1), nke na-eme ka glutamate na-eri nri, na-ebelata mgbe ikpughe ọgwụ (Knackstedt et al., 2010; Shen et al., 2014). Ya mere, akara ndị metụtara ọgwụ na-ebute oke glutamate na NAc glutamatergic synapses, nke nwere ike ịkọwa ihe kpatara njirimara ndị a nwere ike inwe mmetụta omume siri ike.

Na mgbakwunye na ịgbanwe ike synapti ozugbo na NAc, a na-echekwa na ọgwụ ọjọọ eme ihe ga-agbanwe ikike NAc synapses iji nweta plastik synapti na-esote. Ejikọtara ọgwụ ọjọọ riri ahụ na mmebi nke NMDAR dabere na LTP na LTD na glutamatergic synapses na isi NAc (Martin et al., 2006; Moussawi et al., 2009; Kasanetz et al., 2010). LTD nwere nsogbu na isi NAc, mana ọ bụghị na shea NAc, mgbe ụbọchị iri abụọ na otu nke abstinence na oke oke nwere cocaine ji aka ya (Martin et al., 2006). Mmebi sitere na ọgwụ ọjọọ na synapti plasticity nwere ike inye aka na-agbanwe agbanwe, omume mmanye nke bụ njirimara riri ahụ ma nwee ike ịkọwa ịṅụ ọgwụ ọjọọ n'agbanyeghị nsonaazụ ahụike na-adịghị mma na ụmụ mmadụ. Mkparịta ụka NMDAR na-adabere na LTD na-adịghị mma n'ihe gbasara ịṅụ ọgwụ ike cocaine ka e mesiri ike site na nchọpụta na ọ bụ naanị oke cocaine na-ejide onwe ya nke mepụtara àgwà ndị dị ka ịṅụ ọgwụ ọjọọ gosipụtara LTD na-adịghị agwụ agwụ, ebe a na-enweta LTD n'ime anụmanụ ndị nọgidere na-eji ọgwụ ọjọọ eme ihe (Kasanetz). et al., 2010). Achọpụtara nsonaazụ yiri nke ahụ mgbe nchịkwa ethanol nke onwe ya gasịrị. NMDAR dabere LTD nwere mmerụ ahụ nke ukwuu mgbe ọ nwesịrị ogologo oge na ụmụ oke nwere mmetụta ethanol, mana ọ bụghị n'ime ụmụ oke a na-agwọ ethanol nke na-etoliteghị mmegharị omume a (Abrahao et al., 2013). D-serine, onye na-emekọ ihe ọnụ nke NMDAR, nwere ike ịrụ ọrụ na mmerụ ahụ na-akpata ọgwụ na NMDAR-based synaptic plasticity (D'Ascenzo et al., 2014). D-serine dị mkpa maka NMDAR na-adabere na LTP na LTD na NAc isi na D-serine ọkwa na-ebelata na NAc isi nke oke oke cocaine (Curcio et al., 2013). N'ime mpekere sitere na oke ndị a na-agwọ cocaine, mmịnye na D-serine weghachiri eweghachi LTP na ntinye LTD. Ya mere, ụkọ cocaine kpatara na NMDAR na-adabere na synaptic plasticity na NAc bụ n'ihi na ọ dịkarịa ala akụkụ ụfọdụ, iji belata ọkwa D-serine.

Dị ka ọ dị na VTA, e nwere ụfọdụ ihe àmà na-egosi na ọ bụghị nanị na ọgwụ ọjọọ na-akpata mgbanwe synaptik zuru ụwa ọnụ na NAc, kamakwa ọ nwere ike imetụta ụdị dị iche iche nke MSN (Wolf na Ferrario, 2010; Creed na Lüscher, 2013). A na-eche na ike synaptik na shei NAc nke na-etolite n'oge nkwụsị ọgwụ na-eme nhọrọ na synapses na D1-receptor-na-egosipụta MSN, ọ bụghị na synapses na D2-receptor-na-egosipụta MSNs (Pascoli et al., 2012). N'oge na-adịbeghị anya, achọpụtara na ike synapti a na synapses na D1-receptor-na-egosipụta MSN dabere na nhazi nke D1R/GluN1 complexes (Cahill et al., 2014). Na-egbochi njikọ D1R/GluN1, ka ị na-echekwa D1R n'otu n'otu na nrịbama dabere na NMDAR, gbochiri ọrụ ERK, nke achọrọ maka ike synapti.

Plastic synapti dị na etiti prefrontal cortex

Ebumnuche ọzọ nke amụma DA sitere na VTA bụ medial prefrontal cortex (mPFC). Neurons pyramidal nke mPFC na-enweta amụma glutamatergic site n'ọtụtụ mpaghara ụbụrụ dị iche iche, gụnyere nucleus basolateral nke amygdala (BLA), ma ziga amụma glutamatergic na VTA, NAc na laghachi na BLA (Gabbott et al., 2005; Nzughari na Nri, 2007; Van den Oever et al., 2010). Ejikọtara ihe riri ahụ na mbelata ọrụ neuronal PFC basal, ma ọ bụ “hypofrontality” (Volkow et al., 2003), nke nwekwara ike ịhụ na oke mgbe nchịkwa cocaine ugboro ugboro (Sun na Rebec, 2006). Enwere ike kewaa mPFC n'ime azụ azụ (gụnyere PL) yana akụkụ ventral (gụnyere cortex infralimbic) nwere njirimara anatomical na arụ ọrụ dị iche iche (Van den Oever et al., 2012). Anatomically, a na-eche na mPFC dorsal na-ebutekarị NAc isi, ebe ventral mPFC na-eziga amụma na shei NAc (Heidbreder na Groenewegen, 2003). A na-echekwa na dorsal na ventral mPFC na-arụ ọrụ dị iche iche na riri ahụ. A na-eche na ọrụ dị na dorsal mPFC ga-amalite ịchọ ọgwụ na ọ dị oke mkpa maka nlọghachi azụ na-achọ ọgwụ (Gipson et al., 2013b). N'aka nke ọzọ, ọrụ dị na ventral mPFC nwere ike igbochi nzaghachi ịchọ ọgwụ (Peters et al., 2008; LaLumiere et al., 2012). N'ozuzu, a na-eche na mPFC ga-arụ ọrụ dị mkpa na njikwa omume nlọghachi azụ.

Naanị ọmụmụ ole na ole na-enyocha plasticity synapti nke ọgwụ na mPFC ka emerela. Ya mere, anyị nwere naanị ntakịrị ihe ọmụma gbasara ọrụ synaptic plasticity butere ọgwụ na mPFC. In vitro ọmụmụ egosila na nicotine nwere ike ịbawanye ọnụ ụzọ maka ntinye nke ike na-adabere na oge na-adabere na glutamatergic synapses na mouse mPFC Layer V pyramidal neurons site n'ịkwalite ntinye GABAergic na neurons ndị a (Couey et al., 2007). N'ụzọ dị iche, ụbọchị 5 ka ewepụrụ site na ikpughe cocaine na-adịghị agbanwe agbanwe ugboro ugboro (ịgba ọgwụ asaa kwa ụbọchị), ntinye nke LTP mere ka ọ dị mfe na synapses na-akpali akpali n'elu rat mPFC Layer V pyramidal neurons n'ihi mbelata ntinye GABA (Lu et al., 2010). Nke a bụ ihe na-akpata ụbụrụ neurotrophic (BDNF) na-ebute mbelata ngosipụta elu nke GABA._A ndị na-anabata ya na mPFC, na-eduga na nkwụsị nke mgbochi GABAergic. Ọ bụ ezie na enyochaghị mkpa omume nke plasticity a kwalitere nke ọma, enwere ụfọdụ ihe akaebe na-apụtaghị ìhè na nkwado nke ntinye LTP na mPFC nwere ike itinye aka na nhụta omume mgbe mwepụ cocaine gasịrị (Lu et al., 2010).

N'agbanyeghị mbelata mPFC LTP site na ngwa ngwa nke nicotine, ntinye ike nke synaptic na mPFC na-akwado site na nicotine mwepụ, dị ka cocaine. N'oge na ozugbo na-esote na vivo ọgwụgwọ nicotine, ike glutamatergic synaptic ike belatara na mPFC nke oke ndị nọ n'afọ iri na ụma, ebe LTP a mụbara nke ukwuu na mPFC nke oke oke 5 izu mgbe ha nwetasịrị ọgwụgwọ nicotine n'oge uto (Goriounova na Mansvelder, 2012). Mmetụta bidirectional nke ikpughe nicotine n'oge uto na ike synapti nwere ike bụrụ onye ogbugbo site na mgbanwe bidirectional na ọkwa synapti nke inhibitory metabotropic glutamate receptor 2 (mGluR2). Na-esochi ikpughe nicotine n'oge uto, ọkwa protein nke mGluR2 na mPFC synaptic membranes na-abawanye n'ụbọchị mbụ nke mwepụ, mana belatara izu 5 ka ekpughere nicotine (Counotte et al., 2011). N'iji mGluR2 agonists, enwere ike igbochi nkwalite nicotine nke ike synapti, ebe mGluR2 antagonists kwadoro ike synapti (Goriounova na Mansvelder, 2012).

O yikarịrị ka ọ ga-ebute nkwụsị nke obere oge nke ntinye LTP site na mmụba na-adịru nwa oge na nkwupụta nke nAChR nwere α4 na β2 subunits na mPFC ozugbo ikpughe nicotine n'oge uto, nke bụ usoro n'azụ mmachi GABAergic emelitere nke na-akpata nke a. ngọngọ nke LTP (countte et al., 2012). N'ụzọ na-akpali mmasị, mmụba na nkwupụta nke nAChR nwere α4 na β2 subunits na oke mPFC bụ naanị mgbe mkpughe nicotine n'oge uto, ọ bụghị mgbe ikpughe nicotine n'oge okenye (Counotte et al., 2012). N'otu aka ahụ, ọmụmụ nke Goriounova na Mansvelder (2012) gosipụtara ọdịiche dị n'etiti mmetụta nke nicotine ikpughe n'oge uto na n'oge ntozu. Ikpughe Nicotine n'oge ntozu edugaghị na mgbanwe na-adịgide adịgide na LTP. N'ikwekọ na nke a, ikpughe nicotine na-eto eto, ma ọ bụghị ikpughe nicotine postadolescent, na-eduga n'ịbelata ọrụ nlebara anya na mmụba na omume mkpali 5 izu mgbe ọgwụgwọ na oke (Counotte et al., 2009, 2011). Ngosipụta Nicotine n'oge uto na-ebute mbelata na-adịgide adịgide na ọkwa mGluR2 synapti yana nkwalite ike ogologo oge dabere na oke mPFC nke nwere ike bute mbelata ọgụgụ isi n'oge okenye. N'ozuzu, ọmụmụ ihe ndị a na-egosi na oge uto bụ oge dị egwu nke adịghị ike maka mmetụta nicotine na-adịte aka na PFC.

Mgbe ewepụsịrị ogologo oge, a hụrụ mgbanwe na nkesa subunit glutamate n'ọtụtụ ọmụmụ. Dịka ọmụmaatụ, mmụba nke GluA2/3, GluA4, na GluN2B na mPFC ka akọwara mgbe izu abụọ nke abstinence na nchịkwa onwe onye cocaine (Tang et al., 2004). Agbanyeghị, enweghị mmetụta dị ogologo oge na ngosipụta nke membrane synapti nke glutamate receptor subunits na mPFC ka achọpụtara mgbe nchịkwa onwe nke heroin gasịrị (Van den Oever et al., 2008). Ọ ga-ekwe omume na mgbanwe na nkesa subunit glutamate receptor subunit mgbe mwepu ogologo oge ga-ebilite naanị mgbe ị nwetachara ọgwụ. Ihe ọmụmụ Ben-Shahar et al kwadoro nke a. (2009), onye ọzọ chọtara mmụba GluN2B mgbe izu 2 nke abstinence gasịrị, mana ọ bụ naanị na oke ndị agbatịla ohere ịnweta cocaine kwa ụbọchị (Ben-Shahar et al., 2009).

Ebe a na-eche na mPFC na-arụ ọrụ dị mkpa na nlọghachi azụ na-achọ ọgwụ, a nyochakwara ya ma synaptic plasticity na-eme na mPFC n'oge nlọghachi azụ na-achọ ọgwụ. Nkpugheghachi na njirimara ndị metụtara heroin ka izu 3 nke ịhapụ nchịkwa onwe onye nke heroin kpalitere ịda mbà n'obi ngwa ngwa na mPFC nke oke (Van den Oever et al., 2008). Mwapụta nke akpụkpọ ahụ synapti nke AMPAR subunits GluA2 na GluA3 dị na mPFC belatara, na nkwupụta nke protein clathrin-coat AP2m1, nke na-etinye aka na endocytosis na-adabere na clathrin, mụbara. Nke a na-egosi na mkpugheghachi na atụmatụ metụtara heroin butere clathrin-mediated endocytosis nke GluA2/GluA3 AMPARs. Ọzọkwa, a na-ahụ mbelata AMPAR/NMDAR yana mmụba nrụzi n'ime neurons mPFC pyramidal, na-akwado ọnọdụ endocytosis nke GluA2 nwere AMPAR. N'ime nyocha ndị a, emebeghị nkewa n'etiti mPFC azụ na ventral mPFC. Ya mere, amabeghị ma ịda mbà n'obi synapti na-akpata na-eme na mPFC dum ma ọ bụ naanị n'otu mpaghara. Agbanyeghị, mmetụta omume nke igbochi endocytosis nke GluA2 nwere AMPAR ka enyochara iche maka mpaghara mPFC abụọ. N'ụzọ na-akpali mmasị, igbochi GluA2 endocytosis kpọmkwem na ventral mPFC na-eme ka nlọghachi azụ azụ na heroin na-achọ, ebe na-egbochi GluA2 endocytosis na dorsal mPFC emeghị (Van den Oever et al., 2008). Nke a na-egosi na endocytosis ngwa ngwa nke GluA2 nwere AMPARs yana ịda mbà n'obi synapti na-akpata na ventral mPFC dị oke mkpa maka nlọghachi azụ na-achọ heroin. Nke a dabara n'echiche na ventral mPFC na-egosipụta njikwa mgbochi n'ịchọ ọgwụ. N'ihe niile, enwere ike icheta na ịda mbà n'obi synaptik na-akpata na ventral mPFC na-emebi njikwa mgbochi n'ịchọ ọgwụ, si otú a na-eme ka nlọghachi azụ na ịchọ heroin.

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