Prime‐, Stress‐, and Cue‐Induced Reinstatement of Extinguished Drug‐Reinforced Responding in Rats: Cocaine as the Prototypical Drug of Abuse

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Abstract
Table of Contents
Materials
Figures
Literature Cited

Abstract

This unit describes the testing of rats in prime?, footshock?, and cue?induced reinstatement procedures. Evaluating rats in these procedures enables the assessment of treatments on behavior thought to model drug relapse precipitated by re?contact with an abused drug (prime?induced), induced by stress (footshock?induced), or by stimuli previously associated with drug administration (cue?induced). For instance, levels of reinstatement under the effects of test compound administration could be compared to levels under vehicle administration to help identify potential treatments for drug relapse, or reinstatement levels of different rat strains could be compared to identify potential genetic determinants of perseverative drug?seeking behavior. Cocaine is used as a prototypical drug of abuse, and relapse to its use serves as the model in this unit, but other self?administered drugs could readily be substituted with little modification to the procedures. Curr. Protoc. Neurosci. 61:9.39.1?9.39.40. © 2012 by John Wiley & Sons, Inc.

Keywords: drug relapse; drug abuse; cocaine

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Introduction
Strategic Planning
Basic Protocol 1: Train and Test Rats in Cocaine‐Induced Reinstatement Procedures
Support Protocol 1: Preparation of Catheter Lock/Antibiotic Solution
Support Protocol 2: Construction of a Catheter Introducer
Support Protocol 3: Construction of a Flush Syringe Assembly and Catheter Cap
Support Protocol 4: Construction of a Tapered Polyurethane Chronic Intravenous Catheter for Rats
Support Protocol 5: Self‐Administration Catheter Implantation in the Rat
Basic Protocol 2: Train and Test Rats in Cocaine‐Cue Induced Reinstatement Procedures
Basic Protocol 3: Train and Test Rats in Footshock‐Induced (Stress) Reinstatement Procedures
Commentary
Literature Cited
Figures
Tables

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Materials

Basic Protocol 1: Train and Test Rats in Cocaine‐Induced Reinstatement Procedures

Materials

Pharmaceutical‐grade cocaine HCl (National Institute on Drug Abuse, Rockville, MD)
500‐ml bags of 0.9% sterile physiological saline
30‐ml vial of 1000 U/ml heparin solution
Twelve naïve adult male Long‐Evans hooded rats per dose condition instrumented with chronic indwelling jugular catheters at least 5 days prior to start of study (see protocol 6 )
Catheter lock solution (see protocol 2 )
Standard laboratory rodent diet

Analytical balance with 1 mg accuracy for weighing drugs
20‐ml Luer‐lock sterile disposable plastic syringes
0.2‐µm membrane sterile syringe filters (25‐mm diameter)
18‐G sterile, disposable hypodermic needles
30‐ml sterilized serum vials and stoppers with aluminum crimp seals
Twelve operant conditioning chambers enclosed within sound attenuating cubicles and equipped with two retractable levers, two stimulus lights, house light, Sonalert, liquid swivel/balance arm, and drug infusion syringe pump
100‐foot roll, 0.040‐in. (1.02‐mm) i.d. Tygon microbore polyethylene tubing
Sterile, blunt 25‐G disposable hypodermic needles
Twelve catheter connection assemblies with metal spring covering (PlasticsOne, cat. no. C313CS)
Scale with 1 g accuracy and at least 500‐g capacity for weighting rats
Control and interface system consisting of Windows computer, interface, control software, and 28 v DC power supply (Med Associates or comparable)
Flush syringe assembly (see protocol 4 )
1‐ml sterile, disposable tuberculin syringes with 25‐G needles attached

Support Protocol 1: Preparation of Catheter Lock/Antibiotic Solution

Materials

Saline
10‐ml bottle heparin sodium (1000 U/ml concentration)
Glycerol USP (Fisher Scientific or similar)
3.1‐g bottle Timentin powder (ticarcillin disodium and clavulanate potassium)

10‐ and 20‐ml sterile disposable syringes
18‐ and 22‐G sterile disposable needles
100‐ml beaker
Stir plate and stir bar (optional)
Sterile syringe filter (25‐mm diameter, 0.2‐µm pore size)
60‐ml Luer lock sterile disposable syringe
50‐ml sterilized serum vial, butyl rubber stopper, and foil retainer in sterilization peel pack

Support Protocol 2: Construction of a Catheter Introducer

Materials

Safety glasses
3/8‐in. or longer 27‐G disposable needle
Rotary tool (Dremel or similar) with mandrel and abrasive cut‐off wheel
1‐ml disposable tuberculin syringes

Support Protocol 3: Construction of a Flush Syringe Assembly and Catheter Cap

Materials

Safety glasses
25‐G disposable needles
Rotary tool (Dremel or similar) with mandrel and abrasive cut‐off wheel
1‐ml disposable tuberculin syringes
Tygon tubing (5.5‐cm length, 0.040‐in. i.d.)
Self‐sealing sterilization pouch

Support Protocol 4: Construction of a Tapered Polyurethane Chronic Intravenous Catheter for Rats

Materials

Sesame oil (Acros Organic/Fisher Scientific)
Fragrance‐free liquid hand dishwashing detergent
Thin cyanoacrylate glue (Super Glue or similar)

Cardstock
20‐ or 50‐ml beaker
Hotplate
Thermometer capable of reading to 200°C or higher
3.5 French polyurethane tubing (Access Technologies)
Dumont no. 5/45° forceps (Fine Science Tools)
Safety razor blades
100‐ml or larger wide mouth sealable container
20‐ml syringes
25‐G blunt‐end needle
Wooden handled cotton swab

Support Protocol 5: Self‐Administration Catheter Implantation in the Rat

Materials

Rats
Anesthesia (see unit 9.20 )
500‐ml bag 0.9% sterile saline

Blue underpads
Temperature‐regulated animal heating pad (e.g., Gaymar Mul·T·Pad, Deltaphase Isothermal Pad or similar)
Sterilized jugular catheter (see protocol 5 )
1‐ml tuberculin syringes with 25‐G needles, sterile
Sterile surgical masks
Sterile surgical gloves
Steam‐sterilized, double‐wrapped surgical pack consisting of:
- Straight mosquito hemostats
- Curved mosquito hemostats
- 1 × 2–tooth small Adson forceps
- Fine carbide blade straight scissors
- Fine Dumont forceps
- Fine 1 × 2–tooth straight Graefe or iris forceps
- 1 × 1 gauze pads
- Wooden handle swabs
- 12 × 12–in. paper surgical drape
- No. 2 tapered Kalt suture needle
- 4‐0 braided silk or nylon suture material (two 10‐cm pieces)
- 4 × 4 gauze pads (for manipulating non‐sterile objects)
- 7.5‐mm Michel suture clips (or alternate closure materials)
- Tygon tubing (0.040‐in. i.d., 5‐cm long)
- 25‐G blunt‐end needles
- Catheter introducer (see protocol 3 )
- Catheter connection pedestal (PlasticsOne, cat. no. 313‐000BM)

Basic Protocol 2: Train and Test Rats in Cocaine‐Cue Induced Reinstatement Procedures

Materials

Pharmaceutical‐grade cocaine HCl (National Institute on Drug Abuse, Rockville, MD)
500‐ml bags of 0.9% sterile physiological saline
30‐ml vial of 1000 U/ml heparin solution
Twelve naïve adult male Long‐Evans hooded rats per dose condition instrumented with chronic indwelling jugular catheters at least 5 days prior to start of study (see protocol 5 for details of catheterization surgery)
Catheter lock solution (see protocol 2 )
Standard laboratory rodent diet

Analytical balance (1 mg accuracy)
20‐ml Luer‐lock sterile disposable plastic syringes
0.2‐µm membrane sterile syringe filters (25‐mm diameter)
Sterile 18‐G disposable hypodermic needles
30‐ml sterilized serum vials and stoppers and aluminum crimp seals
Twelve operant conditioning chambers enclosed within sound attenuating cubicles equipped with: two retractable levers, two stimulus lights, house light, Sonalert, liquid swivel/balance arm, and drug infusion syringe pump
100‐ft. roll of 0.040‐in. (1.02‐mm) i.d. Tygon microbore polyethylene tubing
Individually packaged and sterilized 25‐G blunt‐end disposable hypodermic needles
Catheter connection assemblies with metal spring covering (PlasticsOne, cat. no. C313CS)
Scale (1 g accuracy and at least 500‐g capacity for weighting rats)
Control and interface system consisting of Windows computer, interface, control software, and 28v DC power supply (Med Associates or comparable)
Flush syringe assembly (see protocol 4 )
Catheter connection/infusion tether

Basic Protocol 3: Train and Test Rats in Footshock‐Induced (Stress) Reinstatement Procedures

Materials

Pharmaceutical grade cocaine HCl (National Institute on Drug Abuse, Rockville, MD)
500‐ml bags of 0.9% sterile physiological saline
30‐ml vial of 1000 U/ml heparin solution
One 10 ml vial of 100 mg/ml ketamine HCl
Ten vials of Timentin antibiotic powder (GlaxoSmithKline)
Twelve naïve adult male Long‐Evans hooded rats per dose condition instrumented with chronic indwelling jugular catheters at least 5 days prior to start of study (see protocol 5 for details of catheterization surgery)
Catheter lock solution (see protocol 2 )
Standard laboratory rodent diet

Analytical balance (1 mg accuracy)
20‐ml Luer‐lock sterile disposable plastic syringes
0.2‐µm membrane sterile syringe filters (25‐mm diameter)
Sterile 18‐G disposable hypodermic needles
30‐ml sterilized serum vials and stoppers and aluminum crimp seals
Twelve operant conditioning chambers enclosed within sound attenuating cubicles equipped with: two retractable levers, two stimulus lights, house light, Sonalert, liquid swivel/balance arm, and drug infusion syringe pump
100‐ft. roll of 0.040‐in. (1.02‐mm) i.d. Tygon microbore polyethylene tubing
Individually packaged and sterilized 25‐G blunt‐end disposable hypodermic needles
Catheter connection assemblies with metal spring covering (PlasticsOne, cat. no. C313CS)
Scale (1 g accuracy and at least 500‐g capacity for weighting rats)
Control and interface system consisting of Windows computer, interface, control software, and 28v DC power supply (Med Associates or comparable)
Flush syringe assembly (see protocol 4 )
Catheter connection/infusion tether
Twelve current‐regulated footshock delivery devices

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Figures

Figure 9.39.1 Catheter introducer components showing unmodified 1‐ml syringe and 27‐G needle above and completed catheter introducer below.

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Figure 9.39.2 Catheter flush syringe assembly with attached Tygon tubing. Two catheter‐sealing caps are shown in the upper left.

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Figure 9.39.3 Magnification of the tapered tip of a polyurethane jugular catheter.

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Figure 9.39.4 Completed tapered polyurethane catheter on gauge card. Also shown is catheter connection post/button as assembled during surgery.

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Figure 9.39.5 Mean active lever presses during the final session of self‐administration and of extinction, and during the cocaine prime‐, cue‐, and footshock‐induced reinstatement tests in rats that had previously self‐administered cocaine. Brackets through bars indicate SEM. Intragastric injections of a test compound's vehicle (saline for prime and cue tests, and 0.25% methylcellulose for footshock tests) preceded tests by 30 min. N = 12 for all groups.

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Figure 9.39.6 (A ) Mean numbers of active lever presses during the cocaine footshock‐induced reinstatement test session as a function of haloperidol dose. Brackets through the bars indicate ±SEM. VEH = results of the vehicle‐treatment group. Asterisks indicate significantly different ( P < 0.05) from vehicle. N = 12 for each condition. (B ) Mean numbers of inactive lever presses during the cocaine footshock‐induced reinstatement test session as a function of haloperidol dose. Other details as in A.

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Figure 9.39.7 Mean active lever presses during cocaine prime‐ (A ), cue‐ (B ), and footshock‐induced (C ) reinstatement tests in rats when tested with vehicle or doses (mg/kg i.g.) of JDTic which had previously self‐administered cocaine. Brackets through bars indicate SEM. Dotted lines indicate range of mean responses on the last day of extinction. N = 12 for all groups.

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Videos

Literature Cited

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	Beardsley, P.M., Howard, J.L., Shelton, K.L., and Carroll, F.I. 2005. Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine‐seeking induced by footshock stressors vs. cocaine primes and its antidepressant‐like effects in rats. Psychopharmacology 183:118‐126.
	Beardsley, P.M., Pollard, G.T., Howard, J.L., and Carroll, F.I. 2010a. Effectiveness of analogs of the kappa opioid receptor antagonist (3R)‐7‐hydroxy‐N‐((1S)‐1‐{[(3R,4R)‐4‐(3‐hydroxyphenyl)‐3,4‐dimethyl‐1‐pipe ridinyl]methyl}‐2‐methylpropyl)‐1,2,3,4‐tetrahydro‐3‐isoquinolinecarboxami de (JDTic) to reduce U50,488‐induced diuresis and stress‐induced cocaine reinstatement in rats. Psychopharmacology (Berl.) 210:189‐198.
	Beardsley, P.M., Shelton, K.L., Hendrick, E., and Johnson, K.W. 2010b. The glial cell modulator and phosphodiesterase inhibitor, AV411 (ibudilast), attenuates prime‐ and stress‐induced methamphetamine relapse. Eur. J. Pharmacol 637:102‐108.
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Key References
	UNIT 9.20.
	This protocol describes details of an alternate catheter construction and surgical procedure, as well as procedures for establishing and stabilizing self‐administration behavior.