Deep Brain Stimulation as a Treatment for Drug Addiction in a Rat Model

Begin with a rat model of drug addiction inside an operant chamber.

The rat has an implanted intravenous catheter to self-administer drugs by pressing a lever.

Lever pressing is more frequent at the start of sessions, indicating compulsive drug-seeking behavior.

The drug stimulates the mesolimbic pathway, increasing dopamine release in the nucleus accumbens, a region linked to reward and addiction.

Elevated dopamine levels stimulate neurons, reinforcing pleasurable effects and drug-seeking behavior.

The rat is implanted with bilaterally placed electrodes in the nucleus accumbens for deep brain stimulation (DBS).

Transfer the rat to a stimulation apparatus and connect the electrodes to the system.

Deliver high-frequency pulses to inactivate hyperactive neurons in the nucleus accumbens, reducing the drug's reinforcing effects.

Return the rat to the operant chamber to observe changes in drug-seeking behavior.

DBS effectively decreases the frequency of drug infusions, demonstrating its potential to suppress addiction-related behaviors.

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 Plexi-glass 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.