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.

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

脳深部刺激の正確なメカニズムは完全には特徴付けされていないが、モーターおよび精神障害の両方のためのDBSの有効性は、電気治療と時間6,22-26にわたる様々な皮質下と皮質の脳領域の機能間の動的相互作用に起因する可能性があります。げっ歯類にメタンフェタミン配信の非偶発的な方法は27,28を十分に記載されているが、これらの方法は、薬物動態及び神経化学的効果27〜29の個別の調査のために最も適切です。オペラントの静注薬物自己投与、薬剤のための動機の要素を組み込むことによって、DBSなどの電気治療は時間をかけて病理学的行動との対話方法の研究に最適です。私たちが説明した手順は、異なる環境での偶発的なメタンフェタミンの使用上の1つの環境でのDBSの効果を調べます。 私たちのIVメタンフェタミン自己administにおける3つの重要なステップがあります配給パラダイム：長いアクセスセッション中に薬物摂取の迅速な取得とエスカレーションの1）の誘導、その後の短いアクセスセッション中に薬物摂取の安定した、高レートの2）保守および薬物服用のフロントローディングパターンの3）開発。費用対効果と心理覚せい剤を使用して、げっ歯類でヘッドキャップの潜在限られた寿命を与え、DBSの効果をテストするために理想的に適して両方である、1回の実験当たり12匹のラット - このパラダイムは10で2〜3週間の時間枠で達成することができます。長いアクセス19,30,31の期間を組み込む他のパラダイムのようなこの手順は、合理的に、物質使用障害のいくつかの側面をシミュレートします。それは、レクリエーション利用19,30対人間の依存性の重要な側面である初期のセッション「薬物ローディング、「で、薬物を取得するために使用し、高いモチベーションの両方の拡大を示しています。 IVのメタンフェタミンへの長いアクセス・エクスポージャーを持っているげっ歯類も認知障害32を実証、薬物療法33、薬物動態34 ​​および神経化学的に明確な回答は短いアクセス暴露とげっ歯類よりも慢性メタンフェタミン使用障害を患っているヒトに類似している35を変更します 。 同様に、私たちの脳深部刺激手順における3つの重要なステップがある：一つまたは二つの「モック」セッションのヘッドテザー接続、を含むDBS環境への1）馴化、2）毎日、商用システムを使用してアクティブな刺激の断続的な配信、 3）薬物設定にDBSの切断とその後の輸送を。このパラダイムは、むしろ従来の連続的なDBSよりもTMSのような非侵襲性の治療の過程を模倣するように設計されています。完全に移植され、一般的な運動障害3のために使用されるもののようなプログラム可能なDBSシステムには、いくつかの前述の理由で精神刺激薬依存に苦しむ患者にわずかに可能になります。 Intermitten高リスク手術やアフターケアを伴わない電気治療戦略をT、TMSのように、よりよいこの患者集団に適合させることができます。私たちが説明した方法は、研究者が開発し、制限された時間枠内での薬物環境の外で配信されながら薬物関連の動作を変更することができ、治療戦略を絞り込むことができます。治療が終わった後、36は数週間のために精神科と薬物関連行動の長期的なプラスの効果を発揮全身薬物療法と組み合わせて、特定の神経生理学的欠損23または後にパターン化された過渡頭蓋電気刺激その蓄積の証拠があります。 初期の優れた手術手技のための激しい薬物使用中に複数の手術部位の継続的なケアのニーズが、この方法の主な制限があります。 IVカテーテルまたはDBS電極のどちらかが非動作および/または感染した場合、ラットを行う必要があり調査を終了します。厳格な無菌技術の下で頸静脈カテーテルおよび頭蓋内電極配置は最高の独立これらの手順を開始する前に、経験豊富な研究者から学習されます。 この手順は、の検査を含むいくつかの変更および将来の研究に適している：1）代替刺激パラメータ（例えば、 -刺激波形、パルス幅、周波数、振幅）、2）他の潜在的な治療の脳の標的（ 例えば 、 -側坐核。オペラントセッションの前に様々な間隔で毎日DBS配信、毎週DBS配信、DBS、買収前DBS）、そして、おそらく最もエキサイティングな、 -コア、内側前頭前皮質、中脳、手綱）、3）異なるDBSの配信パターン（例えば、。 4）短期DBSと選択経路のoptogenetic刺激を模倣し、行動修正36に耐え発揮する薬剤の組み合わせを。

メタンフェタミンが原因シナプスモノアミンの急性増加、特にドーパミンに強く、長時間の幸福感を生み出す精神刺激薬です。メタンフェタミン依存性が世界的に推定25万34人のユーザーと無実績のある治療1,2と流行の健康問題です。メタンフェタミン依存性のための新たな治療戦略を開発するための実質的な必要性があります。脳深部刺激（DBS）はパーキンソン病、ジストニア、及び本態性振戦3を含む特定の疾患に発生する破壊的なニューロンの発火パターンを、正規化するために脳「ペースメーカー」を使用して神経外科処置です。最近のヒトの症例報告は、DBSはまた、アルコールや薬物依存の有効な治療法かもしれないが、精神刺激薬に関する前臨床証拠が（ 例えば 、コカイン、メタンフェタミン）は4-8を制限されていることを示唆しています。 それはcurrentlであるように、連続的な脳深部刺激yは、練習患者および彼/彼女の家族からの例外的な協力が必要です。細心の創傷ケアおよび個人衛生があっても、得られた菌血症と静脈内の薬を使用していない患者では、感染を受けやすい基盤となるペースメーカーのハードウェアを保護するために必要とされています。 DBS装置の定期的なフォローアップは、システムの開ループ設計所与も必要です。経験豊富な医師は、日常診療の予定3中にターゲット症状を減少させるために近代的なDBSの設定を変更します。この治療パラダイムは、その挑戦的な心理社会的状況に起因するコカインやメタンフェタミンのユーザーに制限されます。いくつかのげっ歯類の研究では、治療は、薬物使用環境9-11でコカイン自己投与手順の間に連続的に送達されたときに、DBSの効果を調べることによって、この非現実的なパラダイムを模倣しています。 経頭蓋のように、留置ハードウェアを必要としない不連続な技術の非侵襲的磁気刺激（TMS）は、物質使用障害12の治療のためのより良い選択肢かもしれません。 TMSは、毎日、断続的な治療中に特定の脳のターゲット内の電界を発生させるために外部headcoilを用いた非侵襲的に配信されます。 Hコイルまたは「深い」TMSの最近の出現は、その潜在的な使用13,14を拡大し 、皮質のサイトに加えて、より深い脳の構造が刺激されることを可能にします。どちらの治療法は、一次薬物使用とは異なる環境での一連のセッションの間に不連続に配信され、薬物依存13,15-17のためのヒトおよびげっ歯類試験で有望であることを示しています。彼らは暴力や不安定な動作18を体験することができたときにメタンフェタミン依存症患者を治療するためのウィンドウは、おそらくストリート過食中ではない、そのような裁判所の指示によるリハビリなど飲酒の期間中になります。このように、この記事の目的は、一時的であり、電気刺激の送達を記載することです空間的により密接IVのメタンフェタミン依存の治療のために、ヒトにおいて可能であるものを近似する薬剤の使用環境から分離します。

<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の頸静脈カテーテルおよび頭蓋内のDBS電極の配置に続いて、齧歯類が正常に短い回復期間後に自己投与の静脈メタンフェタミンに訓練することができる。 図3は、ラットはに拡張アクセスの2日後にメタンフェタミン自己投与を獲得し、エスカレートすることを示しています4日目までに、セッションごとに168±12注入の平均を有する薬物。 1）メタンフェタミン毒性および永続的な、長期のアクセスを伴う重度の行動の変化を防止し、2）その応答の比較的安定した速度を確立するために、様々なによって操作することができます：ラットは、2つの理由からオペラント訓練の毎日2時間のスケジュールに移動します治療的介入。 図4第二週以上の短いアクセスセッションあたりの全注入の平均数は75±8であり、一般的に10％未満の日々を変化することを示している。 図5は、そのラットのdevelのを示していますオペアンプの日に比べて、トレーニングの6日目まで吸入の「フロントローディング」のパターンの出現によって示されるように、薬剤を取るために増加した動機1.これが発達すると、効果が大きく、その後のセッションで維持される（データは示していません） 。 図6は 、二国間のDBSは、偽刺激群と比較して、3 5の日にオペラントIVのメタンフェタミン自己投与の著しい減少をもたらした非薬物環境で配信することを示しています。 （ - 8.5、MLは2.4±AP + 1.6、DV）核は、シェルは以下の定位を使用して、薬物完了行動8での既知の関与はブレグマからの相対座標を与えられた目標とした側坐核します。刺激パラメータおよび期間は緩く精神疾患8,20,21の治療のためのDBSと以前公開された経験に基づいていたが、実験者のニーズに応じて調整することができます。エラーバーは、すべての日のREA適度ではありません明確な治療効果にもかかわらず、行動評価に見られる応答の範囲を示す、CH意義。実験あたりのラットの数を増やすと、この自然変動を補うことができます。 11匹の動物は、最初に、この実験に用いました。 （; N = 4アクティブDBS N = 4シャム）ワン動物が手術後に食欲不振のために安楽死させ、1動物が原因で発作を除外した、1動物は、8匹の動物の合計で私たちを残しによるDBS電極の誤動作に除外されました。その正常に完了を可能にする、各実験のために12匹 - 一般的には約10から始まります。 <img alt="図1" src="/files/ftp_upload/53266/53266fig1.jpg" /> 図1. ビジュアルプログラミング言語。研究者は、複数のアニマに脳刺激を提供することができますプログラムを設計するために、ここに示す例のように、視覚的なプログラミング言語を使用していますLS同時に、ユーザーが入力したパラメータで。 <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53266/53266fig1large.jpg" target="_blank">この図の拡大版をご覧になるにはこちらをクリックしてください。</a> <img alt="図2" src="/files/ftp_upload/53266/53266fig2.jpg" /> 図2. ビジュアルコントロールパネル。実験の開始に先立ち、研究者は、ビジュアルコントロールパネルの左側にある所望の周波数、パルス幅、および振幅を指定します。ここで刺激パラメータは以下のとおりです。電流強度200μA。パルス幅61ミリ秒。パルス周波数130ヘルツ。刺激が開始されると、アクティブ電流送達するための波形が右側に表示されている。 <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53266/53266fig2large.jpg" target="_blank">この図の拡大版をご覧になるにはこちらをクリックしてください。</a> IVメタンフェタミン自己管理の 図3. 獲得。合計オペラント応答（360分）のデータを反復測定として定義され、毎日のセッションを反復測定ANOVAを用いて分析しました。 p &lt;0.05であったすべての分析は、有意であるとみなしました。データは平均±標準誤差です。オペラント訓練の最初の4日間毎日6時間のオペラントセッション中総メタンフェタミン注入。+ P &lt;0.05セッション1と2に比べて<a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53266/53266fig3large.jpg" target="_blank">、この図の拡大版をご覧になるにはこちらをクリックしてください。</a> <img alt="図4" src="/files/ftp_upload/53266/53266fig4.jpg" /> 図4。IVメタンフェタミン自己管理のメンテナンス。合計オペラント応答（120分）のデータは、反復測定として定義され、毎日のセッションでの反復測定ANOVAを用いて分析しました。 p &lt;0.05であったすべての分析は、有意であるとみなしました。データは平均±標準誤差です。安定したが、強烈な服薬行動を実証オペラント訓練、第2週にわたり毎日2時間のオペラントセッション中総メタンフェタミン注入。 <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53266/53266fig4large.jpg" target="_blank">この図の拡大版をご覧になるにはこちらをクリックしてください。</a> <img alt="図5" src="/files/ftp_upload/53266/53266fig5.jpg" /> 薬を服用するための動機の 図5. 開発応答オペラントは、最初の一時間とデータのための15分毎に繰り返し、私を使用して分析した集計されましたANOVAは、反復測定のように定義された各15分象限でasures。 p &lt;0.05であったすべての分析は、有意であるとみなしました。データは平均±標準誤差です。 「フロントローディング」のパターンがオペラント訓練の1日目には存在しないが、薬を服用する強い意欲を示し、第二週によって開発しています。 + P &lt;0.05は、60分に比べて45〜60分に比べて30、45、および60分、++ P &lt;0.05、+++ P &lt;0.05と比較する。 <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53266/53266fig5large.jpg" target="_blank">この図の拡大版をご覧になるにはこちらをクリックしてください。</a> <img alt="図6" src="/files/ftp_upload/53266/53266fig6.jpg" /> 図6. IVメタンフェタミン自己投与のDBS影響。最初の一時間で応答総オペラントは（60分）のデータがbetweで混合ANOVAを用いて分析しました治療の対象変数（シャム対 DBS）、毎日のセッションの反復測定が備わっています。 p &lt;0.05であったすべての分析は、有意であるとみなしました。データは平均±標準誤差です。二国間事前オペラント脳深部刺激が大幅に処置日3、4で応答オペラントの最初の60分間にわたってメタンフェタミン注入の数を減少し、偽群およびベースライン応答に比べ7 + P &lt;0.05。終了毎日の治療後のベースラインレベルに戻った応答。 <a href="https://www-jove-com.bdigitaluss.remotexs.co/files/ftp_upload/53266/53266fig6large.jpg" target="_blank">この図の拡大版をご覧になるにはこちらをクリックしてください。</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.

静脈内メタンフェタミン自己管理に脳深部刺激効果を評価するための一般的な方法

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

Universidad San Sebastian

Research

JoVE Journal

Behavior

15.1K ビュー.  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.

ビデオ: 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.

薬物の強化のための新規装置および方法

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

神経科学

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.

Hemiparkinsonianラットにおける脳深部刺激効果のモーターの成果を評価するための新しいアプローチ：階段室とシリンダーテスト

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 ...

行動学

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.

マウスモデルにおける静脈内自己投与方法

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.

ガスクロマトグラフィーによるオペラントエタノール自己投与とエタノール判別中エタノールのマイクロダイアリシス

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.

動物を振る舞う、覚醒中のシングルユニット記録のためにマイクロワイヤの組織化された配列を移植するための手順

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.

げっ歯類での同時のfMRIと脳深部刺激

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.

微小電極は、長期的な脳深部刺激のためのラットの視床下核に電極の移植ガイド付き

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.

コカイン使用障害のモデルラットにおけるキュー反応を測定するためのプロトコル

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.

高周波刺激によるマウスの海馬歯状回の活性化のための侵襲的な方法

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.

高速スキャン環状ボルタンメトリー(CIS-FSCV)による注入と刺激を組み合わせて、パジカルドーパミンの腹側テグメンタル領域受容体調節を評価する

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