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Helpful Hints: Self-Administration in Mice
The technique of self-administration is an extremely useful model of human drug-seeking behavior. It is also the gold standard test for assessing the potential abuse liability of new pharmaceutical compounds in a pre-clinical setting.
The self-administration model consists of an operant behavior setup in which a drug is available, usually via intravenous route, as a reinforcer of some behavioral response. It is used primarily to predict abuse liability, but also in evaluating treatments for drug addiction. The model is used effectively in laboratories utilizing rats and non-human primates. However, the maintenance of chronic intravenous self-administration has been historically more difficult in mice, despite the abundant interest in and availability of transgenic mice.
Some laboratories have come up with their own “homemade” methods of getting good self-administration in mice. Recently, we checked in with Drs. Andrew Lawrence and Robyn Brown at the Florey Neuroscience Institute at the University of Melbourne, who were generous enough to give us some extra details on the surgical approach utilized in the Lawrence laboratory.
Note: A complete, step-by-step guide is also available for download here.
First, Drs. Lawrence and Brown prepare a 22 gauge needle by bending it in a “U” shape that is at a right angle to the Luer hub as shown in Figure 1. The end of the needle should be blunted by filing off the sharp point (Figure 1).
The home-made catheters use 3.5 cm of Silastic® tubing which is treated with limonene to soften it. The softened end of the catheter is then pushed over the U-shaped needle as shown in Figure 2. Silicone is then applied to the joint of the Silastic® tubing and the needle.
To insert the jugular catheter, the mouse is anesthetized with isoflurane (1.5-2%), and an incision is made along the midline of the skull. Then, the animal is turned over and an incision is made below the neck, halfway between the midline and the forelimb. Using blunt dissection, the jugular vein is isolated and the catheter tubing is fed through the head incision to the jugular vein. Two pieces of suture are then fed underneath the vein, one above and one below the insertion point, and loosely tied allowing for cannulation. The catheter is then inserted 1 cm into the jugular vein using a stereoscope and anchored with a suture.
Next, the animal is turned over and the bottom of the U-shaped needle is affixed to the skull with instant adhesive, followed by dental acrylic (Figure 4). A solid base of dental acrylic is built up to keep the catheter firmly in place (Figure 5).
Allow 3-4 days for recovery, flushing the catheter twice daily to maintain patency. Mice can then be maintained in self-administration experiments for 3-4 weeks.
For self-administration experiments, the jugular cannula is connected to a swivel, which is then connected to a syringe in an infusion pump. After surgery and between uses, the port is sealed with a removable plug.
For complete printable instructions on this procedure, download the PDF here. Please refer to the In Your Lab article for helpful hints about how to maintain catheter patency using a daily flushing protocol, and how to determine if the iv catheter is patent.
Brown RM, Lawrence AJ (2012). Intravenous Self-Administration of Drugs of Abuse in Mice. MedLines Newsletter Summer 2012
Brown RM, Stagnitti MR, Duncan JR, Lawrence AJ (2012). The mGlu5 receptor antagonist MTEP attenuates opiate self-administration and cue-induced opiate-seeking behavior in mice. Drug Alcohol Depend Jun 1;123(1-2):264-8.
Brown RM, Short JL, Cowen MS, Ledent C, Lawrence AJ (2009). A differential role for the adenosine A2A receptor in opiate reinforcement versus opiate-seeking behavior. Neuropsychopharmacology 34: 844-856.
Cahir E, Pillidge K, Drago J, Lawrence AJ (2011). The necessity of alpha4* nicotinic receptors in nicotine-driven behaviors: dissociation between reinforcing and motor effects of nicotine. Neuropsychopharmacology 36(7): 1505-1517.
Madsen H, Brown RM, Short JL, Lawrence AJ (2012). Investigation of the neuroanatomical substrates of reward-seeking following protracted abstinence in mice. J. Physiol., May 1;590(Pt 10):2427-42.