Name: A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration (Video) | JoVE Journal
Uploaded: 2016-01-22T13:00:00.000+00:00
Duration: 9 min 16 s
Description: Learn deep brain stimulation effects on IV methamphetamine self-administration in rodents. This method evaluates electrical therapy timing and setting for addiction treatment applications.

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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><li>Panenka, W. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Methamphetamine+use%3A+a+comprehensive+review+of+molecular%2C+preclinical+and+clinical+findings%5BTitle%5D)+AND+%22Drug+Alcohol+Depend%22%5BJournal%5D)">Methamphetamine use: a comprehensive review of molecular, preclinical and clinical findings.</a> Drug Alcohol Depend. 129, 167-179 (2013).</li>
<li>United Nations Office on Drugs and Crime. <a target="_blank" href="http://scholar.google.com/scholar?hl=en&safe=off&q=%22World+Drug+Report+2014%22">World Drug Report 2014</a>. 14, United Nations. (2014).</li>
<li>Miocinovic, S., Somayajula, S., Chitnis, S., Vitek, J. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((History%2C+applications%2C+and+mechanisms+of+deep+brain+stimulation%5BTitle%5D)+AND+%22JAMA+Neurol%22%5BJournal%5D)">History, applications, and mechanisms of deep brain stimulation.</a> JAMA Neurol. 70, 163-171 (2013).</li>
<li>Muller, U. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Deep+brain+stimulation+of+the+nucleus+accumbens+for+the+treatment+of+addiction%5BTitle%5D)+AND+%22Ann+N+Y+Acad+Sci%22%5BJournal%5D)">Deep brain stimulation of the nucleus accumbens for the treatment of addiction.</a> Ann N Y Acad Sci. 1282, 119-128 (2013).</li>
<li>Luigjes, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Deep+brain+stimulation+in+addiction%3A+a+review+of+potential+brain+targets%5BTitle%5D)+AND+%22Mol+Psychiatry%22%5BJournal%5D)">Deep brain stimulation in addiction: a review of potential brain targets.</a> Mol Psychiatry. 17, 572-583 (2012).</li>
<li>Pierce, R. C., Vassoler, F. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Deep+brain+stimulation+for+the+treatment+of+addiction%3A+basic+and+clinical+studies+and+potential+mechanisms+of+action%5BTitle%5D)+AND+%22Psychopharmacology+%28Berl%29%22%5BJournal%5D)">Deep brain stimulation for the treatment of addiction: basic and clinical studies and potential mechanisms of action.</a> Psychopharmacology (Berl). 229, 487-491 (2013).</li>
<li>Yadid, G., Gispan, I., Lax, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Lateral+habenula+deep+brain+stimulation+for+personalized+treatment+of+drug+addiction%5BTitle%5D)+AND+%22Front+Hum+Neurosci%22%5BJournal%5D)">Lateral habenula deep brain stimulation for personalized treatment of drug addiction.</a> Front Hum Neurosci. 7, 806(2013).</li>
<li>Wilden, J. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Reduced+ethanol+consumption+by+alcohol-preferring+%28P%29+rats+following+pharmacological+silencing+and+deep+brain+stimulation+of+the+nucleus+accumbens+shell%5BTitle%5D)+AND+%22J+Neurosurg%22%5BJournal%5D)">Reduced ethanol consumption by alcohol-preferring (P) rats following pharmacological silencing and deep brain stimulation of the nucleus accumbens shell.</a> J Neurosurg. 120, 997-1005 (2014).</li>
<li>Guercio, L. A., Schmidt, H. D., Pierce, R. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Deep+brain+stimulation+of+the+nucleus+accumbens+shell+attenuates+cue-induced+reinstatement+of+both+cocaine+and+sucrose+seeking+in+rats%5BTitle%5D)+AND+%22Behav+Brain+Res%22%5BJournal%5D)">Deep brain stimulation of the nucleus accumbens shell attenuates cue-induced reinstatement of both cocaine and sucrose seeking in rats.</a> Behav Brain Res. 281, 125-130 (2015).</li>
<li>Vassoler, F. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Deep+brain+stimulation+of+the+nucleus+accumbens+shell+attenuates+cocaine+priming-induced+reinstatement+of+drug+seeking+in+rats%5BTitle%5D)+AND+%22J+Neurosci%22%5BJournal%5D)">Deep brain stimulation of the nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug seeking in rats.</a> J Neurosci. 28, 8735-8739 (2008).</li>
<li>Friedman, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Electrical+stimulation+of+the+lateral+habenula+produces+enduring+inhibitory+effect+on+cocaine+seeking+behavior%5BTitle%5D)+AND+%22Neuropharmacology%22%5BJournal%5D)">Electrical stimulation of the lateral habenula produces enduring inhibitory effect on cocaine seeking behavior.</a> Neuropharmacology. 59, 452-459 (2010).</li>
<li>Gorelick, D. A., Zangen, A., George, M. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Transcranial+magnetic+stimulation+in+the+treatment+of+substance+addiction%5BTitle%5D)+AND+%22Ann+N+Y+Acad+Sci%22%5BJournal%5D)">Transcranial magnetic stimulation in the treatment of substance addiction.</a> Ann N Y Acad Sci. , (2014).</li>
<li>Zangen, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((IS+44.+Development+and+applications+of+deep+rTMS+in+depression+and+addiction+studies%5BTitle%5D)+AND+%22Clin.+Neurophysiol%22%5BJournal%5D)">IS 44. Development and applications of deep rTMS in depression and addiction studies.</a> Clin. Neurophysiol. 124, e53(2013).</li>
<li>Alba-Ferrara, L. M., Fernandez, F., de Erausquin, G. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((The+Use+of+Neuromodulation+in+the+Treatment+of+Cocaine+Dependence%5BTitle%5D)+AND+%22Addict+Disord+Their+Treat%22%5BJournal%5D)">The Use of Neuromodulation in the Treatment of Cocaine Dependence.</a> Addict Disord Their Treat. 13, 1-7 (2014).</li>
<li>Alba-Ferrara, L., Fernandez, F., Salas, R., de Erausquin, G. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Transcranial+Magnetic+Stimulation+and+Deep+Brain+Stimulation+in+the+treatment+of+alcohol+dependence%5BTitle%5D)+AND+%22Addict+Disord+Their+Treat%22%5BJournal%5D)">Transcranial Magnetic Stimulation and Deep Brain Stimulation in the treatment of alcohol dependence.</a> Addict Disord Their Treat. 13, 159-169 (2014).</li>
<li>Amiaz, R., Levy, D., Vainiger, D., Grunhaus, L., Zangen, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Repeated+high-frequency+transcranial+magnetic+stimulation+over+the+dorsolateral+prefrontal+cortex+reduces+cigarette+craving+and+consumption%5BTitle%5D)+AND+%22Addiction%22%5BJournal%5D)">Repeated high-frequency transcranial magnetic stimulation over the dorsolateral prefrontal cortex reduces cigarette craving and consumption.</a> Addiction. 104, 653-660 (2009).</li>
<li>Levy, D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Repeated+electrical+stimulation+of+reward-related+brain+regions+affects+cocaine+but+not+%27natural%27+reinforcement%5BTitle%5D)+AND+%22J+Neurosci%22%5BJournal%5D)">Repeated electrical stimulation of reward-related brain regions affects cocaine but not 'natural' reinforcement.</a> J Neurosci. 27, 14179-14189 (2007).</li>
<li>McKetin, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Does+methamphetamine+use+increase+violent+behaviour%3F+Evidence+from+a+prospective+longitudinal+study%5BTitle%5D)+AND+%22Addiction%22%5BJournal%5D)">Does methamphetamine use increase violent behaviour? Evidence from a prospective longitudinal study.</a> Addiction. 109, 798-806 (2014).</li>
<li>Ahmed, S. H., Koob, G. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Transition+from+moderate+to+excessive+drug+intake%3A+change+in+hedonic+set+point%5BTitle%5D)+AND+%22Science%22%5BJournal%5D)">Transition from moderate to excessive drug intake: change in hedonic set point.</a> Science. 282, 298-300 (1998).</li>
<li>Hamani, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Antidepressant-like+effects+of+medial+prefrontal+cortex+deep+brain+stimulation+in+rats%5BTitle%5D)+AND+%22Biol+Psychiatry%22%5BJournal%5D)">Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats.</a> Biol Psychiatry. 67, 117-124 (2010).</li>
<li>Laver, B., Diwan, M., Nobrega, J. N., Hamani, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Augmentative+therapies+do+not+potentiate+the+antidepressant-like+effects+of+deep+brain+stimulation+in+rats%5BTitle%5D)+AND+%22J+Affect+Disord%22%5BJournal%5D)">Augmentative therapies do not potentiate the antidepressant-like effects of deep brain stimulation in rats.</a> J Affect Disord. 161, 87-90 (2014).</li>
<li>Pascoli, V., Turiault, M., Luscher, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Reversal+of+cocaine-evoked+synaptic+potentiation+resets+drug-induced+adaptive+behaviour%5BTitle%5D)+AND+%22Nature%22%5BJournal%5D)">Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour.</a> Nature. 481, 71-75 (2012).</li>
<li>Gazit, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Programmed+deep+brain+stimulation+synchronizes+VTA+gamma+band+field+potential+and+alleviates+depressive-like+behavior+in+rats%5BTitle%5D)+AND+%22Neuropharmacology%22%5BJournal%5D)">Programmed deep brain stimulation synchronizes VTA gamma band field potential and alleviates depressive-like behavior in rats.</a> Neuropharmacology. 91, 135-141 (2015).</li>
<li>Mayberg, H. S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Deep+brain+stimulation+for+treatment-resistant+depression%5BTitle%5D)+AND+%22Neuron%22%5BJournal%5D)">Deep brain stimulation for treatment-resistant depression.</a> Neuron. 45, 651-660 (2005).</li>
<li>Heldmann, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Deep+brain+stimulation+of+nucleus+accumbens+region+in+alcoholism+affects+reward+processing%5BTitle%5D)+AND+%22PLoS+One%22%5BJournal%5D)">Deep brain stimulation of nucleus accumbens region in alcoholism affects reward processing.</a> PLoS One. 7, e36572(2012).</li>
<li>de Hemptinne, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Exaggerated+phase-amplitude+coupling+in+the+primary+motor+cortex+in+Parkinson+disease%5BTitle%5D)+AND+%22Proc+Natl+Acad+Sci+U+S+A%22%5BJournal%5D)">Exaggerated phase-amplitude coupling in the primary motor cortex in Parkinson disease.</a> Proc Natl Acad Sci U S A. 110, 4780-4785 (2013).</li>
<li>Segal, D. S., Kuczenski, R., O'Neil, M. L., Melega, W. P., Cho, A. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Escalating+dose+methamphetamine+pretreatment+alters+the+behavioral+and+neurochemical+profiles+associated+with+exposure+to+a+high-dose+methamphetamine+binge%5BTitle%5D)+AND+%22Neuropsychopharmacology%22%5BJournal%5D)">Escalating dose methamphetamine pretreatment alters the behavioral and neurochemical profiles associated with exposure to a high-dose methamphetamine binge.</a> Neuropsychopharmacology. 28, 1730-1740 (2003).</li>
<li>Kuczenski, R., Segal, D. S., Melega, W. P., Lacan, G., McCunney, S. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Human+methamphetamine+pharmacokinetics+simulated+in+the+rat%3A+behavioral+and+neurochemical+effects+of+a+72-h+binge%5BTitle%5D)+AND+%22Neuropsychopharmacology%22%5BJournal%5D)">Human methamphetamine pharmacokinetics simulated in the rat: behavioral and neurochemical effects of a 72-h binge.</a> Neuropsychopharmacology. 34, 2430-2441 (2009).</li>
<li>Kamei, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Repeated+methamphetamine+treatment+impairs+recognition+memory+through+a+failure+of+novelty-induced+ERK1%2F2+activation+in+the+prefrontal+cortex+of+mice%5BTitle%5D)+AND+%22Biol+Psychiatry%22%5BJournal%5D)">Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK1/2 activation in the prefrontal cortex of mice.</a> Biol Psychiatry. 59, 75-84 (2006).</li>
<li>Kitamura, O., Wee, S., Specio, S. E., Koob, G. F., Pulvirenti, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Escalation+of+methamphetamine+self-administration+in+rats%3A+a+dose-effect+function%5BTitle%5D)+AND+%22Psychopharmacology+%28Berl%29%22%5BJournal%5D)">Escalation of methamphetamine self-administration in rats: a dose-effect function.</a> Psychopharmacology (Berl). 186, 48-53 (2006).</li>
<li>Wee, S., Specio, S. E., Koob, G. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Effects+of+dose+and+session+duration+on+cocaine+self-administration+in+rats%5BTitle%5D)+AND+%22J+Pharmacol+Exp+Ther%22%5BJournal%5D)">Effects of dose and session duration on cocaine self-administration in rats.</a> J Pharmacol Exp Ther. 320, 1134-1143 (2007).</li>
<li>Rogers, J. L., De Santis, S., See, R. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Extended+methamphetamine+self-administration+enhances+reinstatement+of+drug+seeking+and+impairs+novel+object+recognition+in+rats%5BTitle%5D)+AND+%22Psychopharmacology+%28Berl%29%22%5BJournal%5D)">Extended methamphetamine self-administration enhances reinstatement of drug seeking and impairs novel object recognition in rats.</a> Psychopharmacology (Berl). 199, 615-624 (2008).</li>
<li>Kufahl, P. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Attenuation+of+methamphetamine+seeking+by+the+mGluR2%2F3+agonist+LY379268+in+rats+with+histories+of+restricted+and+escalated+self-administration%5BTitle%5D)+AND+%22Neuropharmacology%22%5BJournal%5D)">Attenuation of methamphetamine seeking by the mGluR2/3 agonist LY379268 in rats with histories of restricted and escalated self-administration.</a> Neuropharmacology. 66, 290-301 (2013).</li>
<li>Hadamitzky, M., Markou, A., Kuczenski, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Extended+access+to+methamphetamine+self-administration+affects+sensorimotor+gating+in+rats%5BTitle%5D)+AND+%22Behav+Brain+Res%22%5BJournal%5D)">Extended access to methamphetamine self-administration affects sensorimotor gating in rats.</a> Behav Brain Res. 217, 386-390 (2011).</li>
<li>Le Cozannet, R., Markou, A., Kuczenski, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Extended-access%2C+but+not+limited-access%2C+methamphetamine+self-administration+induces+behavioral+and+nucleus+accumbens+dopamine+response+changes+in+rats%5BTitle%5D)+AND+%22Eur+J+Neurosci%22%5BJournal%5D)">Extended-access, but not limited-access, methamphetamine self-administration induces behavioral and nucleus accumbens dopamine response changes in rats.</a> Eur J Neurosci. 38, 3487-3495 (2013).</li>
<li>Creed, M., Pascoli, V. J., Luscher, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Addiction+therapy.+Refining+deep+brain+stimulation+to+emulate+optogenetic+treatment+of+synaptic+pathology%5BTitle%5D)+AND+%22Science%22%5BJournal%5D)">Addiction therapy. Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology.</a> Science. 347, 659-664 (2015).</li>
</ol>

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

Although the exact mechanisms of deep brain stimulation are not fully characterized, DBS efficacy for both motor and psychiatric disorders may result from a dynamic interaction between the electrical therapy and the functioning of various subcortical and cortical brain regions over time6,22-26. While non-contingent methods of methamphetamine delivery to rodents are well-described27,28, these methods are most appropriate for discrete investigations of drug pharmacokinetics and neurochemical effects27-29. Operant IV drug self-administration, by incorporating an element of motivation for drug, is ideally suited for the study of how electrical therapies like DBS interact with pathological behaviors over time. The procedures we describe examine the effects of DBS in one environment on contingent methamphetamine use in a different environment.
There are three key steps in our IV methamphetamine self-administration paradigm: 1) Induction of rapid acquisition and escalation of drug intake during long access sessions, 2) Maintenance of a stable, high rate of drug intake during subsequent short access sessions and 3) Development of a front loading pattern of drug taking. This paradigm can be accomplished in a 2 to 3 week timeframe with 10 - 12 rats per experiment, which is both cost-effective and ideally suited to test the effects of DBS given the potentially limited lifespan of head caps in rodents using psycho-stimulants. This procedure, like other paradigms that incorporate a period of long access19,30,31 reasonably simulates some aspects of substance use disorders; it demonstrates both escalation of use and high motivation to obtain drug with early session &#8220;drug-loading,&#8221; which are important aspects of human dependence versus recreational use19,30. Rodents who have long access exposure to IV methamphetamine also demonstrate cognitive deficits32, distinct responses to pharmacological treatment33, pharmacokinetics34 and neurochemical changes35 that are more similar to humans suffering from chronic methamphetamine use disorder than rodents with only short access exposure.
Likewise there are three key steps in our deep brain stimulation procedure: 1) Habituation to the DBS environment, including the head tether connection, for one or two &#8220;mock&#8221; sessions, 2) Daily, intermittent delivery of active stimulation using a commercial system, and 3) DBS disconnection and subsequent transport to the drug setting. This paradigm is designed to mimic the process of non-invasive therapies like TMS rather than that of traditional continuous DBS. Fully implanted, programmable DBS systems like those used for common movement disorders3 will be marginally feasible in patients suffering from psycho-stimulant dependence for several aforementioned reasons. Intermittent electrical treatment strategies that do not involve high-risk surgery and aftercare, like TMS, may be better adapted to this patient population. The methods we have described will allow investigators to develop and refine treatment strategies that can modify drug-related behavior while being delivered outside of the drug environment in a restricted timeframe. There is accumulating evidence that transient intracranial electrical stimulation that is patterned after specific neurophysiological deficits23 or combined with systemic pharmacotherapy36 exert long-lasting positive effects on psychiatric and drug-related behaviors for several weeks after the treatment has ceased.
The needs for initial excellent surgical technique and for ongoing care of multiple surgical sites during intense drug-use are the main limitations of this methodology. If either the IV catheter or the DBS electrodes become non-operational and/or infected, the rat must exit the study. Jugular catheter and intracranial electrode placements under strict sterile technique are best learned from experienced investigators prior to initiating these procedures independently.
This procedure is amenable to several modifications and future investigations, including examination of: 1) alternate stimulation parameters (e.g.,-stimulation waveform, pulse width, frequency, amplitude), 2) other potential therapeutic brain targets (e.g.,-nucleus accumbens core, medial prefrontal cortex, midbrain, habenula), 3) different DBS delivery patterns (e.g.,- daily DBS delivery, weekly DBS delivery, DBS at various intervals prior to operant sessions, DBS before acquisition), and, perhaps most exciting, 4) combinations of short-duration DBS and pharmaceutical agents that imitate optogenetic stimulation of selective pathways and exert enduring behavioral modifications36.

Methamphetamine is a psychostimulant that produces an intense and prolonged euphoria due to an acute increase in synaptic monoamines, particularly dopamine. Methamphetamine dependence is an epidemic health problem with an estimated 25 to 34 million users globally and no proven treatment1,2. There is a substantial need to develop novel therapeutic strategies for methamphetamine dependence. Deep brain stimulation (DBS) is a neurosurgical procedure that uses a brain &#8220;pacemaker&#8221; to normalize disruptive neuronal firing patterns that occur in certain diseases, including Parkinson&#8217;s disease, dystonia, and essential tremor3. Recent human case reports suggest that DBS may also be an effective treatment for alcohol and drug dependence, but preclinical evidence regarding psychostimulants (e.g., cocaine, methamphetamine) is limited4-8.
Continuous deep brain stimulation, as it is currently practiced, requires exceptional cooperation from the patient and his/her family. Meticulous wound care and personal hygiene are required to protect the underlying pacemaker hardware, which is susceptible to infection even in patients who are not using intravenous drugs with resultant bacteremia. Regular follow-up of the DBS device is also necessary given the open loop design of the system; experienced physicians alter the settings of modern DBS to decrease target symptoms during routine clinic appointments3. This treatment paradigm will be limited in cocaine and methamphetamine users due to their challenging psychosocial situations. Several rodent studies have imitated this impractical paradigm by examining DBS effects when the therapy is delivered continuously during cocaine self-administration procedures in the drug-use environment9-11.
Non-invasive discontinuous techniques that do not require indwelling hardware, like transcranial magnetic stimulation (TMS), may be a better option for treatment of substance use disorders12. TMS is delivered non-invasively using an external headcoil to generate electrical fields in a particular brain target during daily, intermittent treatments. The recent advent of H coil or &#8220;deep&#8221; TMS allows deeper brain structures to be stimulated, in addition to cortical sites, expanding its potential use13,14. Both therapies are delivered discontinuously during a series of sessions in a different environment than that of primary drug use and have shown promise in both human and rodent trials for drug dependence13,15-17. The window to treat methamphetamine dependent patients will likely be during periods of sobriety such as court-mandated rehabilitation, not during street binges when they can experience violent or erratic behavior18. As such, the aim of this article is to describe the delivery of electrical stimulation that is temporally and spatially separate from the drug-use environment, which more closely approximates what is possible in humans, for the treatment of IV methamphetamine dependence.

<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

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.

Following placement of an IV jugular catheter and intracranial DBS electrodes, rodents can be successfully trained to self-administer IV methamphetamine after a brief recovery period. Figure 3 shows that rats will acquire and escalate methamphetamine self-administration after 2 days of extended-access to drug with an average of 168 ± 12 infusions per session by day 4.
Rats are then moved to a daily 2-hr schedule of operant training for two reasons: 1) to prevent methamphetamine toxicity and severe behavioral alterations with persistent, prolonged access and 2) to establish a relatively stable rate of responding that can be manipulated by various therapeutic interventions. Figure 4 shows that the average number of total infusions per short access session over the second week is 75 ± 8 and generally varies by less than 10% day-to-day. Figure 5 demonstrates that rats develop an increased motivation to take drug as shown by the emergence of a “front-loading” pattern of intake by day 6 of training as compared to day 1. Once this develops, the effect is largely sustained over subsequent sessions (data not shown).
Figure 6 shows that bilateral DBS delivered in the non-drug environment resulted in a marked decrease of operant IV methamphetamine self-administration on three of five days compared to the sham stimulated group. The nucleus accumbens shell was targeted given its known involvement in drug-consummatory behavior8 using the following stereotactic coordinates relative to bregma (AP + 1.6, DV - 8.5, ML ± 2.4). Stimulation parameters and duration were loosely based on previous published experience with DBS for the treatment of psychiatric disease8,20,21 but can be adjusted depending on the experimenter’s needs. Error bars are moderate and not all days reach significance indicating the range of responses that can be seen in behavioral assessments despite a clear treatment effect. Increasing the number of rats per experiment can help compensate for this natural variability. 11 animals were initially used for this experiment. One animal was euthanized for poor feeding post-operatively, one animal was excluded due to seizures, and one animal was excluded due to DBS electrode malfunction leaving us with a total of 8 animals (N = 4 Sham; N = 4 active DBS). In general starting with about 10 - 12 rats for each experiment will allow for its successful completion.
<img alt="LabVIEW simulation diagram, iterative data control, waveform generation, signal processing flowchart." src="/files/ftp_upload/53266/53266fig1.jpg" data-altupdatedat="1787630408000" data-alt="Figure 1">
Figure 1. Visual Programming Language. The investigator uses a visual programming language, like the example shown here, to design a program that can deliver brain stimulation to multiple animals simultaneously at user-entered parameters. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Neural signal recording diagram; electrophysiology setup; pulse amplitude, width, frequency controls." src="/files/ftp_upload/53266/53266fig2.jpg" data-altupdatedat="1787630408000" data-alt="Figure 2">
Figure 2. Visual Control Panel. Prior to the start of the experiment, the investigator specifies the desired frequency, pulse width, and amplitude on the left side of a visual control panel. Here stimulation parameters are: current intensity 200 μA; pulse width 61 msec; pulse frequency 130 Hz. Once stimulation is initiated, the waveform for the active current delivery is displayed on the right. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Infusion rate graph, time vs. session days, data trend analysis, error bars, medical study." src="/files/ftp_upload/53266/53266fig3.jpg" data-altupdatedat="1787630408000" data-alt="Figure 3">
Figure 3. Acquisition of IV Methamphetamine Self-Administration. Total operant responding (360 min) data were analyzed using a repeated-measures ANOVA with the daily session defined as the repeated measure. All analyses that were p &lt;0.05 were considered significant. Data is mean ± standard error. Total methamphetamine infusions during the daily 6-hr operant sessions over the first four days of operant training. + P &lt;0.05 compared to sessions 1 and 2. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Time vs. Infusions graph; error bars; data analysis over 5 days; scientific experiment results." src="/files/ftp_upload/53266/53266fig4.jpg" data-altupdatedat="1787630408000" data-alt="Figure 4">
Figure 4. Maintenance of IV Methamphetamine Self-Administration. Total operant responding (120 min) data were analyzed using a repeated-measures ANOVA with the daily session defined as the repeated measure. All analyses that were p &lt;0.05 were considered significant. Data is mean ± standard error. Total methamphetamine infusions during the daily 2-hr operant sessions over the second week of operant training, demonstrating stable but intense drug-taking behavior. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig4large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Drug infusion reduction over time; line graph comparing Day 1 versus Day 6 infusions." src="/files/ftp_upload/53266/53266fig5.jpg" data-altupdatedat="1787630408000" data-alt="Figure 5">
Figure 5. Development of Motivation to Take Drug. Operant responding was totaled every 15 min for the first hour and data were analyzed using a repeated-measures ANOVA with each 15-min quadrant defined as the repeated measure. All analyses that were p &lt;0.05 were considered significant. Data is mean ± standard error. A “front-loading” pattern is not present on day 1 of operant training but develops by the second week, indicating a strong motivation to take drug. + P &lt;0.05 compared to 30, 45, and 60 min, ++ P &lt;0.05 compared to 45 and 60 min, +++ P &lt;0.05 compared to 60 min. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig5large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Infusion rates comparison chart; sham vs. active DBS; treatment over 8 days; error bars included." src="/files/ftp_upload/53266/53266fig6.jpg" data-altupdatedat="1787630408000" data-alt="Figure 6">
Figure 6. DBS Effects on IV Methamphetamine Self-Administration. Total operant responding in the first hour (60 min) data were analyzed using a mixed ANOVA with a between subject variable of treatment (DBS vs Sham) and a repeated measure of daily session. All analyses that were p &lt;0.05 were considered significant. Data is mean ± standard error. Bilateral pre-operant deep brain stimulation significantly reduced the number of methamphetamine infusions over the first 60 min of operant responding on treatment days 3, 4, and 7. + P &lt;0.05 compared to sham group and baseline responding. Responding returned to baseline levels after daily treatment ended. <a href="https://www.jove.com/files/ftp_upload/53266/53266fig6large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

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.

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

The overall goal of this procedure is to evaluate the effects of deep brain stimulation that is temporally and spatially separate from the drug use environment of intravenous methamphetamine in rodents. This method can help answer key questions in addiction psychiatry, such as:can electrical stimulation of discrete brain regions decrease drug abuse, and under what circumstances is this therapy most effective? The main advantage of this technique is that the electrical therapy is delivered at a different time and in a different setting than the drug use environment.This more closely approximates what will be possible in human patients. Demonstrating this procedure will be Dr.Vinita Batra, one of our post-doctoral fellows in our laboratory, and Mr.Glenn Guerin, our head laboratory technician. Preparations for this experiment are outlined in the text protocol.To begin, load the rats into the operant chambers as quickly and calmly as possible to minimize behavioral artifacts. Flush the rat's catheter with 0.1 milliliters of 0.9%saline solution to ensure patency of the line prior to the beginning of the experiment. Next, attach a stainless steel spring leash to the guide cannula on the rodent's back.Connect the other end of the cannula to a leak-proof fluid swivel above the operant chamber. In order for the rats to rapidly learn the self-administration task, run the sessions for six hours per day over four to five consecutive days, and always around the same time of day. For each active lever press, provide one infusion of methamphetamine, followed by a 30 second timeout where the lever supplies nothing.By the end of the first week, the rodents will be adept at administering themselves methamphetamine. During the second week of training, run the rats on daily two hour sessions, Monday through Friday, to maintain and refine their IV methamphetamine self administration. Continue conducting the sessions on a fixed ratio of one, with thirty second timeouts.Stable, intense responding is reached when the total number of methamphetamine infusions across each three consecutive sessions varies by less than ten percent. Another indicator of stable intense responding occurs when the cumulative number of infusions across the first thirty minutes is greater than the cumulative number of infusions during the second thirty minutes. When the rats develop this drug loading pattern, it indicates addictive behavior, and not simply casual use.At the end of each session, prepare a syringe to flush the catheter and disconnect the leash from the rodent's back. Flush the rat's catheter with 0.1 milliliters of 0.9%saline solution containing 800 IU streptokinase to prevent blood clots. Following the flush, insert a sheath onto each guide cannula to prevent clogging.Then, return the rat to its home cage. See the text protocol on testing the patency of the catheters and how to address common problems with this experiment. Prepare ten to twelve Plexiglas boxes for this experiment.On each box, cover the outside of three walls with stiff opaque paper to prevent the rats from seeing each other. However, leave the front wall clear to view the animals during the stimulation sessions. Next, partially cover the tops of the boxes with a hard panel to prevent the rats from escaping, but still allowing air flow.On the top panel, support the commutators for the electrical connection between the rodent head cap and the stimulation system. Use a stimulation system that can deliver constant current to multiple simultaneous animals for the DBS experiments. It should include a programmable interface.With custom length cables, connect the stimulators'channel ports to the superior electronic pedestal of each commutator. Then, connect the inferior electronic pedestal of the commutator to the implanted electrode pedestal on the rodent's head cap using 16 inch cables encased in a stainless steel spring. The cable should allow free movement for the rat to every area of the enclosure without creating significant tension on the head cap.A cable that reaches to where the rat's head could go when it is on four feet is usually long enough. To program the system, use a visual programming language to specify which functions each device will perform to meet the experimental endpoints, and which data will be stored and/or projected for viewing in real time. Specify the desired frequency, pulse width, and amplitude into the visual control panel prior to the start of the experiment.Typical parameters for high frequency stimulation in rats are similar to those used in clinical human deep brain stimulation. A frequency of 130 to 180 Hertz, a pulse width of 60 to 90 milliseconds, and a current amplitude of 100 to 250 microamps. For the brain stimulation experiment, when loading the rats into the boxes, attach the stainless steel spring cable from the commutator to each electrode pedestal on the head cap.First test the impedance of each electrode using five microamps of current at 1000 Hertz for two seconds. If an electrode's impedance is equal to or less than 125 kilo Ohms, then proceed with the experiment. But if not, consider removing the animal from the experiment because the electrode's resistance may truncate the current to potentially sub-therapeutic levels.Start with one or two mock sessions to habituate the rats. Don't apply any active therapy during these sessions. Immediately following each mock session, transport the rats to the operant boxes for their daily two hour session of IV methamphetamine self administration.For the experiment, counterbalance the rats into two groups, an active stimulation cohort and a sham stimulation cohort that gets mock sessions. Perform the daily deep brain stimulation sessions for five days, for three hours a day. Observe animals carefully during a portion of each stimulation session to note if the stimulation is causing any clear alteration in behavior.Directly following every deep brain stimulation session, start the rats'daily IV methamphetamine self administration session. Following the placement of intravenous jugular catheters and intracranial deep brain stimulation electrodes, rats acquired and escalated drug self administration after two days of extended access to methamphetamine. Next, the rats were moved to a daily two hour schedule of operant training to prevent methamphetamine toxicity and to establish a stable rate of responding that could be manipulated by various therapeutic interventions.By day six of operant training, the rats developed an increased motivation to take the drug, as indicated by the emergence of a front loading pattern of intake. This pattern was largely sustained over the subsequent sessions. Following the establishment of this stabilized drug abuse pattern, deep brain stimulation was administered per the described protocol.This resulted in a marked decrease of operant IV methamphetamine self administration. Once mastered, this technique can be completed in a two to four week time frame, using about ten to twelve animals per group. This is ideally suited to test the effects of deep brain stimulation, given the limited lifespan of head caps and IV catheters in rodents using methamphetamine.This procedure may be used to investigate alternate electrical parameters, different brain targets, and novel delivery patterns, as well as combinations of electrical therapy and pharmaceutical agents that may result in long lasting behavioral modification.

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JoVE Journal

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