Name: a general method for evaluating deep brain stimulation effects on intravenous methamphetamine self-administration
Uploaded: 2016-01-22T13:00:00
Duration: 9 min 16 s
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.

<ol>
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N., Hamani, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Augmentative+therapies+do+not+potentiate+the+antidepressant-like+effects+of+deep+brain+stimulation+in+rats.">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/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reversal+of+cocaine-evoked+synaptic+potentiation+resets+drug-induced+adaptive+behaviour.">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/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Programmed+deep+brain+stimulation+synchronizes+VTA+gamma+band+field+potential+and+alleviates+depressive-like+behavior+in+rats.">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/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Deep+brain+stimulation+for+treatment-resistant+depression.">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/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Deep+brain+stimulation+of+nucleus+accumbens+region+in+alcoholism+affects+reward+processing.">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/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Exaggerated+phase-amplitude+coupling+in+the+primary+motor+cortex+in+Parkinson+disease.">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/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Escalating+dose+methamphetamine+pretreatment+alters+the+behavioral+and+neurochemical+profiles+associated+with+exposure+to+a+high-dose+methamphetamine+binge.">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. 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F., Pulvirenti, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Escalation+of+methamphetamine+self-administration+in+rats:+a+dose-effect+function.">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/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+dose+and+session+duration+on+cocaine+self-administration+in+rats.">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/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Extended+methamphetamine+self-administration+enhances+reinstatement+of+drug+seeking+and+impairs+novel+object+recognition+in+rats.">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/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Attenuation+of+methamphetamine+seeking+by+the+mGluR2/3+agonist+LY379268+in+rats+with+histories+of+restricted+and+escalated+self-administration.">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/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Extended+access+to+methamphetamine+self-administration+affects+sensorimotor+gating+in+rats.">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/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Extended-access,+but+not+limited-access,+methamphetamine+self-administration+induces+behavioral+and+nucleus+accumbens+dopamine+response+changes+in+rats.">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. 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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&#160;11930 Research Circle Alachua, FL 32615&#160;USA Ph: 386-462-9622&#160;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&#34;</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.

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 &#177;&#160;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 &#177; 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 &#8220;front-loading&#8221; 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&#160;&#177;&#160;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&#8217;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="Figure 1" src="/files/ftp_upload/53266/53266fig1.jpg" />
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="Figure 2" src="/files/ftp_upload/53266/53266fig2.jpg" />
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 &#956;A; 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="Figure 3" src="/files/ftp_upload/53266/53266fig3.jpg" />
Figure 3. Acquisition of IV Methamphetamine Self-Administration. Total operant responding (360&#160;min) data were analyzed using a repeated-measures ANOVA with the daily session defined as the repeated measure. All analyses that were&#160;p&#160;&#60;0.05 were considered significant. Data is mean &#177; standard error. Total methamphetamine infusions during the daily 6-hr operant sessions over the first four days of operant training. + P &#60;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="Figure 4" src="/files/ftp_upload/53266/53266fig4.jpg" />
Figure 4. Maintenance of IV Methamphetamine Self-Administration. Total operant responding (120&#160;min) data were analyzed using a repeated-measures ANOVA with the daily session defined as the repeated measure. All analyses that were&#160;p&#160;&#60;0.05 were considered significant. Data is mean &#177; 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="Figure 5" src="/files/ftp_upload/53266/53266fig5.jpg" />
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&#160;p&#160;&#60;0.05 were considered significant. Data is mean &#177;&#160;standard error. A &#8220;front-loading&#8221; pattern is not present on day 1 of operant training but develops by the second week, indicating a strong motivation to take drug. + P &#60;0.05 compared to 30, 45, and 60 min, ++ P &#60;0.05 compared to 45 and 60 min, +++ P &#60;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="Figure 6" src="/files/ftp_upload/53266/53266fig6.jpg" />
Figure 6. DBS Effects on IV Methamphetamine Self-Administration. Total operant responding in the first hour (60&#160;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&#160;p &#60;0.05 were considered significant. Data is mean &#177; 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 &#60;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>

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.

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

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