Name: a general method for evaluating deep brain stimulation effects on intravenous methamphetamine self-administration
Uploaded: 2016-01-22T13:00:00.000+00:00
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Description: Watch this Scientific Journal Video about A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration at JoVE.com

Supported by the 2014-2015 Neurosurgery Research and Education Foundation (NREF) award and a 2014 Grant-In-Aid Award from Louisiana State University Shreveport School of Medicine (J.A.W.). We thank S. Harold and C.M. Keller for their invaluable technical assistance and teaching.

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The authors have no competing financial interests with regards to this methodology.

Derin beyin uyarımı kesin mekanizmaları tam olarak karakterize edilmemiş olmasına rağmen, motor ve psikiyatrik bozukluklar hem DBS etkinliği elektriksel tedavisi ve zaman 6,22-26 içinde çeşitli subkortikal ve kortikal beyin bölgeleri işleyişi arasındaki dinamik etkileşimin bir sonucu olabilir. Kemirgenlere metamfetamin teslimat olmayış yöntemler 27,28 iyi tanımlanmış olsa da, bu yöntemler, ilaç farmakokinetiği ve nörokimyasal etkileri 27-29 ayrı ayrı araştırmalar için en uygun olan. Edimsel IV ilaç öz-yönetim, ilaç için bir motivasyon unsuru dahil ederek ideal DBS gibi elektrikli tedaviler zamanla patolojik davranışlar nasıl etkileşime çalışma için uygundur. Biz tanımlayan prosedürler farklı bir ortamda şarta metamfetamin kullanımı ile ilgili tek bir ortamda DBS etkilerini incelemek. Bizim IV metamfetamin kendini Administ üç temel adım vardırrasyon paradigma: Uzun erişim oturumları sırasında hızlı satın alma ve uyuşturucu alımının artması 1) İndüksiyon, daha sonraki kısa erişim oturumları sırasında ilaç alımının istikrarlı, yüksek oranda 2) Bakım ve ilaç alma bir ön yükleme desen 3) geliştirilmesi. Maliyet-etkin ve ideal psiko-uyarıcı kullanan kemirgenler baş kapaklar potansiyel sınırlı ömrü verilen DBS etkilerini test etmek uygun hem deney başına 12 sıçan, - Bu paradigma 10 2 hafta 3 zaman diliminde gerçekleştirilebilir. Uzun erişim 19,30,31 bir dönem dahil diğer paradigmaları gibi Bu prosedür, makul madde kullanım bozuklukları bazı yönlerini taklit; o eğlence kullanımı 19,30 karşı insan bağımlılığı önemli yönleri vardır erken oturum &quot;uyuşturucu yükleme,&quot; ile ilaç elde etmek için kullanım ve yüksek motivasyon hem de tırmanması göstermektedir. IV metamfetamin uzun erişim maruziyeti Kemirgenler da bilişsel açıkları 32 göstermektedirFarmakolojik tedavi 33 farmakokinetiği 34 ve nörokimyasal için farklı tepkiler sadece kısa erişim maruz kalan kemirgenlerde göre kronik metamfetamin kullanımı bozukluğu muzdarip insanlara daha benzer 35 değiştirir. Aynı şekilde bizim derin beyin stimülasyonu prosedüründe üç temel adım vardır: Bir veya iki &quot;sahte&quot; oturumları için baş urgan bağlantısı da dahil olmak üzere DBS ortama 1) Alışma, 2) Günlük, ticari bir sistem kullanarak aktif stimülasyon aralıklı teslimat, ve 3) DBS kopukluk ve ilaç ayarına sonraki ulaşım. Bu paradigma yerine geleneksel sürekli bir DBS daha TMS gibi invazif olmayan tedaviler işlemini taklit etmek için tasarlanmıştır. Tam implante ortak hareket bozuklukları 3 için kullanılanlar gibi programlanabilir DBS sistemleri çeşitli Yukarıda bahsedilen nedenlerden dolayı, psiko-uyarıcı bağımlılık şikayeti olan hastalarda, marjinal mümkün olacaktır. IntermittenDaha iyi bu hasta grubunda adapte edilebilir TMS gibi yüksek riskli ameliyat ve tedavi sonrası içermeyen elektrikli tedavi stratejileri, t. Biz tarif ettiğim yöntemler araştırmacılar geliştirmek ve kısıtlı bir zaman diliminde ilaç ortamı dışında teslim edilirken uyuşturucu davranışını değiştirebilirsiniz tedavi stratejilerini geliştirmek için izin verecektir. Biriken kanıtlar vardır belirli nörofizyolojik açıklarının 23 sonra desenli ya da tedavi kesildikten sonra sistemik ilaç 36 uygulamayın birkaç hafta psikiyatrik ve uyuşturucuyla ilgili davranışlar üzerinde olumlu etkileri uzun ömürlü ile birleştirilir geçici intrakranial elektrik stimülasyonu. İlk Mükemmel cerrahi teknik ve yoğun ilaç kullanımı sırasında birden cerrahi sitelerin sürekli bakımı için ihtiyaç bu metodolojinin temel sınırlamalar vardır. IV kateter veya DBS elektrotlar ya olmayan operasyonel ve / veya enfekte hale gelirse, sıçan gerekirçalışma çıkın. Sıkı steril tekniği altında boyun kateter ve intrakranial elektrot yerleşimleri iyi bağımsız bu işlemleri başlatmadan önce, deneyimli müfettişler öğrenilir. . Uyarım dalga, darbe genişliği, frekans, genlik), 2) Diğer potansiyel tedavi beyin hedefleri (örneğin, - - nukleus akkumbenlere 1) alternatif stimülasyon parametreleri (örneğin:. Bu prosedür incelenmesi dahil olmak üzere birçok değişiklikler ve gelecekteki araştırmaların, mükellef olan Çekirdek, medial prefrontal korteks, orta beyin, habenula), 3) farklı DBS teslim desenleri (örneğin, -., günlük DBS teslimat, haftalık DBS teslimat, DBS önce en heyecan verici belki de operant oturumları, DBS edinim öncesi), ve çeşitli aralıklarla, 4) kısa süreli DBS kombinasyonları ve seçici yolların optogenetic uyarılması taklit ve davranışsal değişiklikler 36 kalıcı sarf ilaç ajanlar.

Metamfetamin nedeniyle sinaptik monoaminler akut artış, özellikle dopamin yoğun ve uzun süreli öfori üreten bir psikostimulandır. Metamfetamin bağımlılığı dünyada tahminen 25 milyon 34 kullanıcı ve kanıtlanmış bir tedavi 1,2 ile bir salgın sağlık sorunudur. Metamfetamin bağımlılığı için yeni tedavi stratejileri geliştirmek için önemli bir ihtiyaç vardır. Derin beyin stimülasyonu (DBS) beyin &quot;kalp pili&quot; Parkinson hastalığı, distoni ve esansiyel tremor 3 olmak üzere bazı hastalıkların meydana yıkıcı nöronal ateşleme desenleri, normalleştirmek için kullandığı bir nöroşirürji işlemdir. Son insan olgu sunumları DBS da alkol ve uyuşturucu bağımlılığı için etkili bir tedavi olabilir, ama psikostimülanlar ilişkin klinik öncesi kanıt (örn., Kokain, metamfetamin) 4-8 sınırlı olduğunu göstermektedir. Sürekli derin beyin stimülasyonu, bu currentl olduğu gibiy uygulanan hasta ve onun / onun ailesinden olağanüstü işbirliğini gerektirir. Titiz yara bakımı ve kişisel hijyen, hatta sonuçtaki bakteriyemi ile intravenöz ilaç kullanmayan hastalarda enfeksiyona duyarlı olan altta yatan kalp pili donanım korumak için gereklidir. DBS Cihazın düzenli takip sisteminin açık döngü tasarımı verilen gereklidir; Deneyimli hekimler rutin klinik randevuları 3 sırasında hedef semptomları azaltmak için, modern DBS ayarlarını değiştirmek. Bu tedavi paradigma nedeniyle zorlu psikososyal durumlara kokain ve metamfetamin kullanıcıları sınırlı olacaktır. Birkaç kemirgen çalışmaları tedavinin ilaç kullanım ortamında 9-11 kokain öz-yönetim prosedürleri sırasında sürekli olarak teslim edildiğinde DBS etkilerini inceleyerek bu pratik paradigma taklit var. Transkranial yolla gibi, kalıcı donanım gerektirmeyen süreksiz teknikler Non-invazivmanyetik stimülasyon (TMS), madde kullanım bozuklukları 12 tedavisi için daha iyi bir seçenek olabilir. TMS non-invaziv günlük sırasında belirli bir beyin hedefi elektrik alanları, aralıklı tedaviler oluşturmak için harici headcoil kullanılarak teslim edilir. H bobin ya da &quot;derin&quot; TMS potansiyel kullanımını 13,14 genişletilmesi, kortikal sitelere ek olarak, derin beyin yapıları teşvik edilmesini sağlar son gelişi. Her iki tedaviler birincil ilaç kullanımı daha farklı bir ortamda bir dizi oturum sırasında kesintili teslim edilir ve uyuşturucu bağımlılığı 13,15-17 insan ve kemirgen denemeleri hem de söz göstermiştir. Onlar şiddet veya hatalı davranış 18 yaşayabilirsiniz zaman metamfetamin bağımlı hastaları tedavi etmek için pencere muhtemelen sokak binges sırasında değil, böyle bir mahkeme-zorunlu rehabilitasyon gibi itidal dönemlerinde olacaktır. Bunun gibi, bu makalenin amacı zamansal olan elektriksel stimülasyon teslim tanımlamaktırve mekansal olarak daha yakından IV metamfetamin bağımlılığı tedavisi için insanlarda mümkün olanı yaklaşık olarak ilaç kullanım ortamına, ayrılır.

<table><tbody><tr><td>Rodent operant chambers</td><td>Med Associates, Inc</td><td>ENV-008CT</td><td>Med Associates Inc. PO Box 319 St. Albans, Vermont 05478 USA Phone: (802) 527-2343</td></tr><tr><td>Kopf Small Animal Stereotaxic Instrument with Digital Display Console</td><td>Kopf Instruments</td><td>Model 940</td><td>Kopf Phone: 1-877-352-3275 Fax: 1-818-352-3275 Email: sales@kopfinstruments.net</td></tr><tr><td>Z-Series 3-DSP Bioamp Processor</td><td>Tucker Davis Technologies</td><td>RZ5D</td><td>Tucker-Davis Technologies&amp;nbsp;11930 Research Circle Alachua, FL 32615&amp;nbsp;USA Ph: 386-462-9622&amp;nbsp;www.tdt.com</td></tr><tr><td>Z-Series 32-Channel Stimulator</td><td>Tucker Davis Technologies</td><td>IZ2-32</td><td>Software is accompanied by a manual that discusses how to program experiments using the OpenEx platform, which can be accessed here: http://www.tdt.com/files/manuals/OpenEx_User_Guide.pdf</td></tr><tr><td>48 Volt LI-ION Battery Pack for IZ2 Stimulator</td><td>Tucker Davis Technologies</td><td>LZ48-200</td><td></td></tr><tr><td>32-Channel Splitter Box for PZ5</td><td>Tucker Davis Technologies</td><td>S-BOX_PZ5</td><td></td></tr><tr><td>OpenEx Ext Software Package for Multi-Channel Neural Recording</td><td>Tucker Davis Technologies</td><td>OpenEx</td><td></td></tr><tr><td>Platinum-iridium stimulating electrodes</td><td>Plastics One Inc</td><td>MS303/8-B/SPC ELECT PT 2C TW .005&quot;</td><td>Plastics One Inc P.O.Box 21465, S.W. Roanoke, VA 24018, PH 540-772-7950</td></tr><tr><td>2-channel cables between stimulator and commutator</td><td>Plastics One Inc</td><td>305-441/2 W/ Spring</td><td></td></tr><tr><td>2-channel cables between commutator and electrode pedestal</td><td>Plastics One Inc</td><td>305-305 W/ Spring</td><td></td></tr><tr><td>4-channel commutators</td><td>Plastics One Inc</td><td>SL2+2C and SL2+SC/SB</td><td></td></tr></tbody></table>

a general method for evaluating deep brain stimulation effects on intravenous methamphetamine self-administration

Substance use disorders, particularly to methamphetamine, are devastating, relapsing diseases that disproportionally affect young people. There is a need for novel, effective and practical treatment strategies that are validated in animal models. Neuromodulation, including deep brain stimulation (DBS) therapy, refers to the use of electricity to influence pathological neuronal activity and has shown promise for psychiatric disorders, including drug dependence. DBS in clinical practice involves the continuous delivery of stimulation into brain structures using an implantable pacemaker-like system that is programmed externally by a physician to alleviate symptoms. This treatment will be limited in methamphetamine users due to challenging psychosocial situations. Electrical treatments that can be delivered intermittently, non-invasively and remotely from the drug-use setting will be more realistic. This article describes the delivery of intracranial electrical stimulation that is temporally and spatially separate from the drug-use environment for the treatment of IV methamphetamine dependence. Methamphetamine dependence is rapidly developed in rodents using an operant paradigm of intravenous (IV) self-administration that incorporates a period of extended access to drug and demonstrates both escalation of use and high motivation to obtain drug.

IV juguler kateter ve intrakranial DBS elektrot yerleştirme sonrasında, kemirgenler başarıyla kısa bir iyileşme süresinden sonra kendiliğinden administer IV metamfetamin için eğitilmiş olabilir. Sıçanlar kazanmak ve genişletilmiş erişim 2 gün sonra metamfetamin öz-yönetim yükselmek olacaktır 3 gösterir Şekil 4 gün ile oturum başına 168 ± 12 infüzyon ortalama ilaç. 1) metamfetamin toksisite ve kalıcı, uzun süreli erişim ile ciddi davranış değişiklikleri önlemek ve 2) bu yanıt nispeten istikrarlı bir oran kurmak için çeşitli tarafından manipüle edilebilir: Sıçanlar sonra iki nedenden dolayı edimsel eğitim günlük 2 saatlik programa taşınır Terapötik müdahaleler. Şekil 4, ikinci hafta içinde kısa erişim seans başına toplam infüzyon ortalama sayısı 75 ± 8 olduğunu gösterir ve genellikle% 10&#39;dan az güne-gün değişir. Şekil 5 bu sıçanlar devel gösteriyorop güne kıyasla eğitim 6 gün kadar alımının bir &quot;önden yüklemeli&quot; desen ortaya çıkması ile gösterildiği gibi ilaç almak için artan bir motivasyon 1. Bu geliştirir sonra, etkisi büyük ölçüde sonraki oturumlarda üzerinde sürdürülen (veriler gösterilmemiştir) . Şekil 6, çift yönlü DBS sham uyarılmış grubuna göre üç ila beş gün ile operant IV metamfetamin kendi kendine uygulama belirgin bir azalma ile sonuçlandı ilaçsız bir ortamda getirdiğini göstermektedir. (- 8.5 ML 2.4 ± AP + 1.6, DV) çekirdek kabuğu bregma göre koordinatları aşağıdaki stereotaktik kullanarak ilaç consummatory davranış 8 yılında bilinen katılımı verildi hedefli edildi akkumbens. Uyarım parametreleri ve süresi gevşek psikiyatrik hastalık 8,20,21 tedavisinde DBS daha önce yayınlanmış deneyime dayalı ama deneycinin ihtiyaçlarına bağlı olarak ayarlanabilir. Hata çubukları ılımlı ve tüm gün rea vardırnet bir tedavi etkisine rağmen davranışsal değerlendirmeler görülebilir yanıtların yelpazesini gösteren ch önemi. Deneme başına farelerin sayısının artırılması bu doğal değişkenliği telafi yardımcı olabilir. 11 hayvan başlangıçta bu deney için kullanıldı. Bir hayvan nedeniyle nöbet kötü beslenme postoperatif bir hayvan dışlandı için ötenazi edildi ve bir hayvan 8 hayvanların toplam bizi terk nedeniyle DBS elektrot arızaya çıkarılmıştır (N = 4 aktif DBS N = 4 Sham). Onun başarılı bir şekilde tamamlanması için izin verecek her bir deney için 12 sıçan - Genel yaklaşık 10 ile başlayan. <img alt="figür 1" src="/files/ftp_upload/53266/53266fig1.jpg" /> Şekil 1. Görsel Programlama Dili. Araştırmacı birden anima beyin uyarımı sağlayabilir bir program tasarımı, burada gösterilen örnekte olduğu gibi bir görsel programlama dilini kullanırls eşzamanlı kullanıcı tarafından girilen parametrelere de. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig1large.jpg" target="_blank">Bu rakamın büyük halini görmek için lütfen buraya tıklayınız.</a> <img alt="Şekil 2," src="/files/ftp_upload/53266/53266fig2.jpg" /> Şekil 2. Görsel Kontrol Paneli. Deneyin başlamasından önce, araştırmacı görsel kontrol panelinin sol tarafında istenen frekansı, darbe genişliği ve genliği belirtir. İşte stimülasyon parametreleri: akım şiddeti 200 uA; nabız 61 msn genişliği; darbe frekansı 130 Hz. Stimülasyon, aktif akım teslimat için dalga sağ tarafta görüntülenir başlatılır sonra. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig2large.jpg" target="_blank">Bu rakamın büyük halini görmek için lütfen buraya tıklayınız.</a> IV Metamfetamin Öz İdaresi Şekil 3. kazanılması. Yanıt Toplam operant (360 dakika) veri tekrarlanan tedbir olarak tanımlanan günlük oturumu ile bir tekrarlanan-önlemler ANOVA kullanılarak analiz edildi. S idi Tüm analizler &lt;0.05 anlamlı kabul edildi. Veriler ortalama ± standart hatadır. Edimsel eğitimin ilk dört gün boyunca günde 6 saatlik edimsel oturumlarda toplam metamfetamin infüzyon. + P &lt;0.05 seans 1 ile karşılaştırıldığında ve 2. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig3large.jpg" target="_blank">bu rakamın büyük halini görmek için lütfen buraya tıklayınız.</a> <img alt="Şekil 4," src="/files/ftp_upload/53266/53266fig4.jpg" /> Şekil 4.IV Metamfetamin Öz İdaresi Bakım. Toplam operant yanıt (120 dakika) veri tekrarlanan tedbir olarak tanımlanan günlük oturumu ile bir tekrarlanan-önlemler ANOVA kullanılarak analiz edildi. S idi Tüm analizler &lt;0.05 anlamlı kabul edildi. Veriler ortalama ± standart hatadır. Kararlı fakat yoğun ilaç alma davranışı gösteren edimsel eğitim, ikinci hafta günde 2 saat edimsel oturumları sırasında toplam metamfetamin infüzyon. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig4large.jpg" target="_blank">Bu rakamın büyük halini görmek için lütfen buraya tıklayınız.</a> <img alt="Şekil 5," src="/files/ftp_upload/53266/53266fig5.jpg" /> Şekil Motivasyon 5. Kalkınma Drug Take. Edimsel ilk bir saat için her 15 dakikada ulaştı edildi yanıt vermenin ve veri analiz edildi kullanarak tekrarlanan-meANOVA tekrarlanan tedbir olarak tanımlanan her 15 dk kadranda ile asures. S idi Tüm analizler &lt;0.05 anlamlı kabul edildi. Veriler ortalama ± standart hatadır. Bir &quot;ön yüklemeli&quot; desen edimsel eğitimin 1 gün mevcut değil ilaç almak için güçlü bir motivasyon gösteren ikinci haftasına göre gelişir. + P &lt;0.05 oranla 60 dakika ile karşılaştırıldığında 45 ve 60 dakika, +++ P &lt;0.05 oranla 30, 45, ve 60 dakika ++ P &lt;0.05. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig5large.jpg" target="_blank">Bu rakamın büyük halini görmek için lütfen buraya tıklayınız.</a> <img alt="Şekil 6," src="/files/ftp_upload/53266/53266fig6.jpg" /> Şekil 6. IV Metamfetamin Öz İdaresi DBS Etkileri. Ilk bir saat içinde yanıt Toplam edimsel (60 dk) verileri bir betwe ile karışık bir ANOVA kullanılarak analiz edildiTedavinin konusu değişkenin (Sham vs DBS) ve günlük seans bir tekrarlanan ölçü tr. S idi Tüm analizler &lt;0.05 anlamlı kabul edildi. Veriler ortalama ± standart hatadır. İkili öncesi edimsel derin beyin stimülasyonu ölçüde tedavi günlerde 3, 4 yanıt edimsel ilk 60 dakika içinde metamfetamin infüzyon sayısını azalttı ve Sham grubuna ve başlangıca yanıt kıyasla 7. + p &lt;0.05. Sona günlük tedaviden sonra bazal düzeylere geri cevaplamayı. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig6large.jpg" target="_blank">Bu rakamın büyük halini görmek için lütfen buraya tıklayınız.</a>

Watch this Scientific Journal Video about A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration at JoVE.com

A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration

This article describes the delivery of intracranial electrical stimulation that is temporally and spatially separate from the drug-use environment for the treatment of IV methamphetamine dependence.

İntravenöz Metamfetamin Self-İdaresi Derin Beyin Stimülasyonu Etkileri değerlendirilmesi için Genel Bir Yöntem

Substance use disorders, particularly to methamphetamine, are devastating, relapsing diseases that disproportionally affect young people.  There is a need ...

a-general-method-for-evaluating-deep-brain-stimulation-effects-on

Research

JoVE Journal

Behavior

15.1K Görüntüleme.  Louisiana State University. This article describes the delivery of intracranial electrical stimulation that is temporally and spatially separate from the drug-use environment for the treatment of IV methamphetamine dependence.

Video: A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration

Novel Apparatus and Method for Drug Reinforcement

Animal models of reinforcement have proven to be useful for understanding the neurobiological mechanisms underlying drug addiction. Operant drug self-administration and conditioned place preference (CPP) procedures are expansively used in animal research to model various components of drug reinforcement, consumption, and addiction in humans. For this study, we used a novel approach to studying drug reinforcement in rats by combining traditional CPP and self-administration methodologies. We assembled an apparatus using two Med Associate operant chambers, sensory stimuli, and a Plexiglas-constructed neutral zone. These modifications allowed our experiments to encompass motivational aspects of drug intake through self-administration and drug-free assessment of drug/cue conditioning strength with the CPP test. In our experiments, rats self-administered cocaine (0.75 mg/kg/inj, i.v.) during either four (e.g., the "short-term") or eight (e.g., the "long-term") alternating-day sessions in an operant environment containing distinctive sensory cues (e.g., olfactory and visual). On the alternate days, in the other (differently-cued) operant environment, saline was available for self-infusion (0.1 ml, i.v.). Twenty-four hours after the last self-administration/cue-pairing session, a CPP test was conducted. Consistent with typical CPP findings, there was a significant preference for the chamber associated with cocaine self-administration. In addition, in animals undergoing the long-term experiment, a significant positive correlation between CPP magnitude and the number of cocaine-reinforced lever responses. In conclusion, this apparatus and approach is time and cost effective, can be used to examine a wide array of topics pertaining to drug abuse, and provides more flexibility in experimental design than CPP or self-administration methods alone.

Operant drug self-administration and conditioned place preference (CPP) procedures are expansively used in research to model various components of drug reinforcement, consumption, and addiction in humans. In this report, we combined traditional CPP and self-administration methods as a novel approach to studying drug reinforcement and addiction in rats.

İlaç Takviye için yeni cihaz ve Yöntem

Animal models of reinforcement have proven to be useful for understanding the neurobiological mechanisms underlying drug addiction.  Operant drug ...

Nörobilim

A Novel Approach to Assess Motor Outcome of Deep Brain Stimulation Effects in the Hemiparkinsonian Rat: Staircase and Cylinder Test

Deep brain stimulation of the subthalamic nucleus is an effective treatment option for Parkinson&#39;s disease. In our lab we established a protocol to screen different neurostimulation patterns in hemiparkinsonian (unilateral lesioned) rats. It consists of creating a unilateral Parkinson&#39;s lesion by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle, implanting chronic stimulation electrodes into the subthalamic nucleus and evaluating motor outcomes at the end of 24 hr periods of cable-bound external neurostimulation. The stimulation was conducted with constant current stimulation. The amplitude was set 20% below the individual threshold for side effects. The motor outcome evaluation was done by the assessment of spontaneous paw use in the cylinder test according to Shallert and by the assessment of skilled reaching in the staircase test according to Montoya. This protocol describes in detail the training in the staircase box, the cylinder test, as well as the use of both in hemiparkinsonian rats. The use of both tests is necessary, because the staircase test seems to be more sensitive for fine motor skill impairment and exhibits greater sensitivity to change during neurostimulation. The combination of the unilateral Parkinson model and the two behavioral tests allows the assessment of different stimulation parameters in a standardized way.

Deep brain stimulation (DBS) is an effective treatment option for Parkinson's disease. We established a study design to screen novel stimulation paradigms in rats. The protocol describes the use of the staircase test and cylinder test for motor outcome assessment in DBS treated hemiparkinsonian rats.

Merdiven ve Silindir Testi: Yeni Bir Yaklaşım Hemiparkinsonian Rat Derin beyin stimülasyonu Etkileri Motor Sonuçlarını Değerlendirmek için

Deep brain stimulation of the subthalamic nucleus is an effective treatment option for Parkinson&#39;s disease. In our lab we established a protocol to ...

Davranış

Methods for Intravenous Self Administration in a Mouse Model

Animal models have been developed to study the reinforcing effects of drugs, including the intravenous self-administration (IVSA) paradigm. The advantages of using an IVSA paradigm to study the reinforcing properties of drugs of abuse such as cocaine include the fact that the drug is self-administered instead of experimenter-administered, the schedule of reinforcement can be altered, and accurate measurement of the quantities of drug consumed as well as the timing and pattern of IV injections can be obtained. Furthermore, the intravenous route of administration avoids potential confounds related to first pass metabolism or taste, and produces rapid increases in blood and brain drug levels. As outlined in this video, intravenous self-administration can be obtained without prior food restriction or prior drug training following careful catheter placement during surgery and meticulous daily catheter flushing and maintenance. Experimental procedures outlined in this paper include a description of animal housing and acclimation methods, operant training using sweetened milk solutions, and catheter implantation surgery.

The intravenous self-administration (IVSA) paradigm is considered to be the gold standard in examining the reinforcing properties of drugs of abuse in rodents. This manuscript outlines the experimental procedures and surgical techniques necessary to obtain reliable IVSA data. In particular, meticulous catheter implantation and maintenance are highlighted.

Bir Fare Modelinde İntravenöz Öz Yönetim Yöntemleri

Animal models have been developed to study the reinforcing effects of drugs, including the intravenous self-administration (IVSA) paradigm. The advantages ...

Microdialysis of Ethanol During Operant Ethanol Self-administration and Ethanol Determination by Gas Chromatography

Operant self-administration methods are commonly used to study the behavioral and pharmacological effects of many drugs of abuse, including ethanol. However, ethanol is typically self-administered orally, rather than intravenously like many other drugs of abuse. The pharmacokinetics of orally administered drugs are more complex than intravenously administered drugs. Because understanding the relationship between the pharmacological and behavioral effects of ethanol requires knowledge of the time course of ethanol reaching the brain during and after drinking, we use in vivo microdialysis and gas chromatography with flame ionization detection to monitor brain dialysate ethanol concentrations over time. 
Combined microdialysis-behavioral experiments involve the use of several techniques. In this article, stereotaxic surgery, behavioral training and microdialysis, which can be adapted to test a multitude of self-administration and neurochemical centered hypotheses, are included only to illustrate how they relate to the subsequent phases of sample collection and dialysate ethanol analysis. Dialysate ethanol concentration analysis via gas chromatography with flame-ionization detection, which is specific to ethanol studies, is described in detail. Data produced by these methods reveal the pattern of ethanol reaching the brain during the self-administration procedure, and when paired with neurochemical analysis of the same dialysate samples, allows conclusions to be made regarding the pharmacological and behavioral effects of ethanol.

A method to determine the time course of ethanol concentration in the brains of rats during operant ethanol self-administration is described. Gas chromatography with flame ionization detection is used to quantify ethanol in the dialysate samples, because it has the sensitivity required for the small volumes that are generated.

Gaz kromatografisi ile operant etanol kendi kendine uygulama ve etanol belirleme sırasında etanol mikrodivaliz

Operant self-administration methods are commonly used to study the behavioral and pharmacological effects of many drugs of abuse, including ethanol.  ...

A Procedure for Implanting Organized Arrays of Microwires for Single-unit Recordings in Awake, Behaving Animals

In vivo electrophysiological recordings in the awake, behaving animal provide a powerful method for understanding neural signaling at the single-cell level. The technique allows experimenters to examine temporally and regionally specific firing patterns in order to correlate recorded action potentials with ongoing behavior. Moreover, single-unit recordings can be combined with a plethora of other techniques in order to produce comprehensive explanations of neural function. In this article, we describe the anesthesia and preparation for microwire implantation. Subsequently, we enumerate the necessary equipment and surgical steps to accurately insert a microwire array into a target structure. Lastly, we briefly describe the equipment used to record from each individual electrode in the array. The fixed microwire arrays described are well-suited for chronic implantation and allow for longitudinal recordings of neural data in almost any behavioral preparation. We discuss tracing electrode tracks to triangulate microwire positions as well as ways to combine microwire implantation with immunohistochemical techniques in order to increase the anatomical specificity of recorded results.

Implanting organized arrays of microwires for use in single-unit electrophysiological recordings presents a number of technical challenges.&#160;Methods for performing this technique and the equipment necessary are described.&#160;Also, the beneficial use of organized microwire arrays to record from distinct neural subregions with high spatial selectivity is discussed.

Hayvanlar davranmak, Awake Tek-birim Recordings Microwires Organize Dizileri implantasyon için Usulü

In vivo electrophysiological recordings in the awake, behaving animal provide a powerful method for understanding neural signaling at the single-cell ...

Deep Brain Stimulation with Simultaneous fMRI in Rodents

In order to visualize the global and downstream neuronal responses to deep brain stimulation (DBS) at various targets, we have developed a protocol for using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) to image rodents with simultaneous DBS. DBS fMRI presents a number of technical challenges, including accuracy of electrode implantation, MR artifacts created by the electrode, choice of anesthesia and paralytic to minimize any neuronal effects while simultaneously eliminating animal motion, and maintenance of physiological parameters, deviation from which can confound the BOLD signal.&#160;Our laboratory has developed a set of procedures that are capable of overcoming most of these possible issues. For electrical stimulation, a homemade tungsten bipolar microelectrode is used, inserted stereotactically at the stimulation site in the anesthetized subject. In preparation for imaging, rodents are fixed on a plastic headpiece and transferred to the magnet bore. For sedation and paralysis during scanning, a cocktail of dexmedetomidine and pancuronium is continuously infused, along with a minimal dose of isoflurane; this preparation minimizes the BOLD ceiling effect of volatile anesthetics. In this example experiment, stimulation of the subthalamic nucleus (STN) produces BOLD responses which are observed primarily in ipsilateral cortical regions, centered in motor cortex. Simultaneous DBS and fMRI allows the unambiguous modulation of neural circuits dependent on stimulation location and stimulation parameters, and permits observation of neuronal modulations free of regional bias. This technique may be used to explore the downstream effects of modulating neural circuitry at nearly any brain region, with implications for both experimental and clinical DBS.

This protocol describes a standard method for simultaneous functional magnetic resonance imaging and deep brain stimulation in the rodent. The combined use of these experimental tools allows for the exploration of global downstream activity in response to electrical stimulation at virtually any brain target.

Kemirgenler Eşzamanlı fMRI ile derin beyin stimülasyonu

In order to visualize the global and downstream neuronal responses to deep brain stimulation (DBS) at various targets, we have developed a protocol for ...

Microelectrode Guided Implantation of Electrodes into the Subthalamic Nucleus of Rats for Long-term Deep Brain Stimulation

Deep brain stimulation (DBS) is a widely used and effective therapy for several neurologic disorders, such as idiopathic Parkinson&#8217;s disease, dystonia or tremor. DBS is based on the delivery of electrical stimuli to specific deep anatomic structures of the central nervous system. However, the mechanisms underlying the effect of DBS remain enigmatic. This has led to an interest in investigating the impact of DBS in animal models, especially in rats. As DBS is a long-term therapy, research should be focused on molecular-genetic changes of neural circuits that occur several weeks after DBS. Long-term DBS in rats is challenging because the rats move around in their cage, which causes problems in keeping in place the wire leading from the head of the animal to the stimulator. Furthermore, target structures for stimulation in the rat brain are small and therefore electrodes cannot easily be placed at the required position. Thus, a set-up for long-lasting stimulation of rats using platinum/iridium electrodes with an impedance of about 1 M&#937; was developed for this study. An electrode with these specifications allows for not only adequate stimulation but also recording of deep brain structures to identify the target area for DBS. In our set-up, an electrode with a plug for the wire was embedded in dental cement with four anchoring screws secured onto the skull. The wire from the plug to the stimulator was protected by a stainless-steel spring. A swivel was connected to the circuit to prevent the wire from becoming tangled. Overall, this stimulation set-up offers a high degree of free mobility for the rat and enables the head plug, as well as the wire connection between the plug and the stimulator, to retain long-lasting strength.

A method for implanting electrodes into the subthalamic nucleus (STN) of rats is described. Better localization of the STN was achieved by using a microrecording system. Furthermore, a stimulation set-up is presented that is characterized by long-lasting connections between the head of the animal and the stimulator.

Mikroelektrod Uzun vadeli Derin Beyin Stimülasyonu için Sıçan Subtalamik Nucleus içine elektrotlar implantasyonu Rehberli

Deep brain stimulation (DBS) is a widely used and effective therapy for several neurologic disorders, such as idiopathic Parkinson&#8217;s disease, ...

A Protocol for Measuring Cue Reactivity in a Rat Model of Cocaine Use Disorder

Cocaine use disorder (CUD) follows a trajectory of repetitive self-administration during which previously neutral stimuli gain incentive value. Cue reactivity, the sensitivity to cues previously linked with the drug-taking experience, plays a prominent role in human craving during abstinence. Cue reactivity can be assessed as the attentional orientation toward drug-associated cues that is measurable as appetitive approach behavior in both preclinical and human studies. Herein describes an assessment of cue reactivity in rats trained to self-administer cocaine. Cocaine self-administration is paired with the presentation of discrete cues that act as conditioned reinforcers (i.e., house light, stimulus light, infusion pump sounds). Following a period of abstinence, lever presses in the cocaine self-administration context accompanied by the discrete cues previously paired with cocaine infusion are measured as cue reactivity. This model is useful to explore neurobiological mechanisms underlying cue reactivity processes as well as to assess pharmacotherapies to suppress cue reactivity and therefore, modify relapse vulnerability. Advantages of the model include its translational relevance, and its face and predictive validities.&#160;The primary limitation of the model is that the cue reactivity task can only be performed infrequently and must only be used in short duration (e.g., 1 hour), otherwise rats will begin to extinguish the pairing of the discrete cues with the cocaine stimulus. The model is extendable to any positively reinforcing stimulus paired with discrete cues; though particularly applicable to drugs of abuse, this model may hold future applications in fields such as obesity, where palatable food rewards can act as positively reinforcing stimuli.

Cue reactivity is conceptualized as sensitivity to cues linked with drug-taking experiences that contribute to craving and relapse in abstinent humans. Cue reactivity is modeled in rats by measuring attentional orientation toward drug-associated cues that results in appetitive approach behavior in a cue reactivity test following self-administration and forced abstinence.

Cue reaktivite kokain kullanımı bozukluğu bir sıçan modelinde ölçmek için bir protokol

Cocaine use disorder (CUD) follows a trajectory of repetitive self-administration during which previously neutral stimuli gain incentive value. Cue ...

An Invasive Method for the Activation of the Mouse Dentate Gyrus by High-frequency Stimulation

Electrical high-frequency stimulation (HFS), using implanted electrodes targeting various brain regions, has been proven as an effective treatment for various neurological and psychiatric disorders. HFS in the deep region of the brain, also named deep-brain stimulation (DBS), is becoming increasingly important in clinical trials. Recent progress in the field of high-frequency DBS (HF-DBS) surgery has begun to spread the possibility of utilizing this invasive technique to other situations, such as treatment for major depression disorder (MDD), obsessive-compulsive disorder (OCD), and so on. 
Despite these expanding indications, the underlying mechanisms of the beneficial effects of HF-DBS remain enigmatic. To address this question, one approach is to use implanted electrodes that sparsely activate distributed subpopulations of neurons by HFS. It has been reported that HFS in the anterior nucleus of the thalamus could be used for the treatment of refractory epilepsy in the clinic. The underlying mechanisms might be related to the increased neurogenesis and altered neuronal activity. Therefore, we are interested in exploring the physiological alterations by the detection of neuronal activity as well as neurogenesis in the mouse dentate gyrus (DG) before and after HFS treatment. 
In this manuscript, we describe methodologies for HFS to target the activation of the DG in mice, directly or indirectly and in an acute or chronic manner. In addition, we describe a detailed protocol for the preparation of brain slices for c-fos and Notch1 immunofluorescent staining to monitor the neuronal activity and signaling activation and for bromodeoxyuridine (BrdU) labeling to determine the neurogenesis after the HF-DBS induction. The activation of the neuronal activity and neurogenesis after the HF-DBS treatment provides direct neurobiological evidence and potential therapeutic benefits. Particularly, this methodology can be modified and applied to target other interested brain regions such as the basal ganglia and subthalamic regions for specific brain disorders in the clinic.

This protocol shows how to set up a reliable HFS method in mice. Neurons throughout the hippocampal dentate gyrus are electrically stimulated by HFS directly and indirectly in vivo. Neuronal activity and molecular signaling are examined by c-fos and Notch1 immunofluorescent staining, respectively; neurogenesis is quantified by bromodeoxyuridine labeling assay.

Yüksek frekanslı stimülasyon tarafından fare dentat Gyrus aktivasyonu için invaziv bir yöntem

Electrical high-frequency stimulation (HFS), using implanted electrodes targeting various brain regions, has been proven as an effective treatment for ...

Combined Infusion and Stimulation with Fast-Scan Cyclic Voltammetry (CIS-FSCV) to Assess Ventral Tegmental Area Receptor Regulation of Phasic Dopamine

Phasic dopamine (DA) release from the ventral tegmental area (VTA) to the nucleus accumbens plays a pivotal role in reward processing and reinforcement learning. Understanding how the diverse neuronal inputs into the VTA control phasic DA release can provide a better picture of the circuitry that controls reward processing and reinforcement learning. Here, we describe a method that combines intra-VTA cannula infusions of pharmacological agonists and antagonists with stimulation-evoked phasic DA release (combined infusion and stimulation, or CIS) as measured by in vivo fast-scan cyclic voltammetry (FSCV). Using CIS-FSCV in anesthetized rats, a phasic DA response can be evoked by electrically stimulating the VTA with a bipolar electrode fitted with a cannula while recording in the nucleus accumbens core. Pharmacological agonists or antagonists can be infused directly at the stimulation site to investigate specific VTA receptors&#39; roles in driving phasic DA release. A major benefit of CIS-FSCV is that VTA receptor function can be studied in vivo, building on in vitro studies.

Combined Infusion and Stimulation with Fast-Scan Cyclic Voltammetry CIS-FSCV to Assess Ventral Tegmental Area Receptor Regulation of Phasic Dopamine

The goal of this protocol is to directly manipulate ventral tegmental area receptors to study their contribution to subsecond dopamine release.

Phasic Dopamin'in Ventral Tegmental Alan Reseptör Reseptör Reseptör Düzenlemesini Değerlendirmek için Hızlı Taramalı Döngüsel Voltammetri (CIS-FSCV) ile Kombine infüzyon ve stimülasyon

Phasic dopamine (DA) release from the ventral tegmental area (VTA) to the nucleus accumbens plays a pivotal role in reward processing and reinforcement ...