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Improvements in self-administration studies based on changes in skin button type and surgical technique
Journal of Pharmacological and Toxicological Methods 75 (2015) 130–134
Contents lists available at ScienceDirect
Journal of Pharmacological and Toxicological Methods journal homepage: www.elsevier.com/locate/jpharmtox
Brief communication
Improvements in self-administration studies based on changes in skin button type and surgical technique Lindsey M. Gilbert, Mario P. Sgro, Deah L. Modlin, Nathaniel J. Wheat, Mary J. Kallman ⁎ Covance Laboratories, 671 S. Meridian Rd., Greenfield, IN, USA
a r t i c l e
i n f o
Article history: Received 13 February 2015 Received in revised form 22 April 2015 Accepted 13 May 2015 Available online 19 May 2015 Keywords: Catheter Longevity Methods Patency Rat Self-administration Skin button Surgical technique
a b s t r a c t Introduction: These studies, ranging in duration from 3 to 8 months, evaluated the patency and longevity of the intravenous (IV) self-administration surgical model in male Sprague Dawley rats. Surgeries were categorized and assessed based on the number of catheter and/or skin button repairs required per animal across four separate self-administration studies. Design improvements in skin button types and changes in surgical procedures were chronologically tracked and assessed. Methods: Animals were evaluated under a self-administration paradigm in which they were trained to respond for a food reward under a fixed ratio schedule (FR5 or FR10). Animals were then surgically prepared with a femoral catheter and skin button port. Following recovery, animals were returned to food-maintained responding for at least 5 sessions and subsequently trained to respond for injections of a reinforcing drug. Once drug training criteria was established, the effects of vehicle or varying doses of test articles were evaluated. Animals were tested in operant chambers one hour each day 5 days a week and the length of each study was recorded. Differences in the number of repairs per study as well as the total number of repairs were tabulated. Results: Study length was directly correlated to the mean number of repairs occurring per study, with study length increasing as the total number of repairs increased. The majority of repairs were skin button-related issues. Multiple combinations of skin button types and surgical techniques were implemented across time to evaluate model efficiency and decrease overall cycle time per study. Initial combinations produced a greater number of repairs on a per study basis. However, the skin button type and surgical technique combination that resulted in the fewest number of total repairs used a lateral incision with a dorsal biopsy punch. Discussion: The combination of improvements in skin button type and surgical techniques drastically decreased the number of surgical repairs required per study, increasing efficiency and thereby decreasing the overall cycle time for study completion. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Drug self-administration is a well-established method for evaluating potential abuse liability of therapeutic agents (Childs, Shoaib, & Stolerman, 2006; Griffiths & Balster, 1979; LeSage, Stafford, & Glowa, 2000; Weeks, 1962). Based on the complexity of the study design, a self-administration study may last up to 6–8 months. Skin button failures or catheter patency issues are common reasons for study prolongation. An animal with a skin button or catheter malfunction may require surgical repair multiple times throughout the course of a study. With each surgical repair, the animal must be allowed a recovery period before being placed back on study. This delays the animal's progression through the study, thereby increasing the length of time to complete the study with a sufficient cohort
⁎ Corresponding author.
http://dx.doi.org/10.1016/j.vascn.2015.05.006 1056-8719/© 2015 Elsevier Inc. All rights reserved.
for analysis. To reduce cycle time for self-administration studies, improvements in skin button type and surgical techniques were implemented over time at Covance Laboratories, Greenfield. The number of surgical repairs and the length of each study were evaluated across four studies to characterize the effectiveness of these improvements in skin button type and the surgical technique used in our selfadministration model.
2. Methods 2.1. Statement of use and care of animals All experiments were conducted in accordance with the guidelines from the Guide for the Care and Use of Laboratory Animals, Eighth Edition (Committee for the Update of the Guide for the Care and Use of Laboratory Animals, Institute for Laboratory Animal Research, National
L.M. Gilbert et al. / Journal of Pharmacological and Toxicological Methods 75 (2015) 130–134
Research Council, The National Academies Press, 2011) and approved by the Covance Laboratories Institutional Animal Care and Use Committee. 2.2. Subjects Male Sprague–Dawley rats were acclimated to the vivarium for at least 3 days prior to study initiation. Animals were individually housed in suspended shoebox cages with bedding under standard conditions for animal care. Animals were fed a restricted diet of 10–12 g of Harlan Teklad Global Diets-Rodent 2014 (Harlan, Indianapolis, IN) until lever pressing behavior was established. Animals were then maintained on 15–20 g of food per day throughout the remainder of the study. Greenfield city water was provided ad libitum. The housing room photoperiod was maintained on a 12 h light:12 h dark cycle. Room temperature was between 72 ± 3 °F and relative humidity was between 30 and 70%. 2.3. Self-administration procedures 2.3.1. Food training Animals were trained to press a lever to obtain food reinforcement under a fixed ratio response schedule up to 5 days. The response requirement is gradually increased over sessions from an FR1 to an FR5 (Midazolam) or FR10 (Cocaine) depending on the training drug used on study. Response criteria prior to an increase from an FR1 to an FR3 were reached when an animal received a minimum of 50 earned food reinforcements during the first training session and a minimum of 90 earned food reinforcements during the second session. Response criteria for subsequent increases in the FR schedule were reached when earned food reinforcements were between 90 and 100 pellets for two consecutive sessions. Stable responding at an FR5 or FR10 was reached when earned food reinforcements were between 90 and 100 pellets for three consecutive sessions. After reaching successful training criteria, each animal was surgically prepared with an indwelling femoral catheter and skin button prior to drug substitution. For dose calculation purposes, body weights were collected daily, except weekends, throughout the length of the study. 2.3.2. Surgery All animals were implanted with a chronic indwelling femoral tapered catheter (3 French: Part No. RVF-01, SAI-Infusion Technologies; Lake Villa, IL). The catheter was inserted into a femoral vein and secured to the vessel with a silk suture. The catheter was passed subcutaneously through a trocar to an incision posterior to the scapulae and attached under the skin to a skin button. The skin button was secured in place with Ethilon® sutures. After completion of surgery, the catheter and skin button were filled with taurolidine citrate as a locking solution. The locking solution is composed of 1.35% taurolidine and 2.61% citrate and has broad spectrum antimicrobial activity. Rats also initially received Convenia prior to their first surgery. For any subsequent surgery, animals received Convenia or Baytril prior to the procedure. If animals were given Baytril, they received treatment for 4 consecutive days following surgery. All Baytril doses were administered after a given test session. Animals also received pain medication (typically Buprenex) prior to surgery. All animals were allowed to recover for a minimum of 7 days before initiating self-administration testing. 2.3.3. Self-administration Following surgical recovery, animals were returned to food maintained responding for a minimum of 5 sessions to re-establish lever pressing behavior. Once successful criteria were achieved, drug injections replaced food representations under a fixed ratio schedule. Animals were then trained to respond to a training drug (cocaine or midazolam) with known reinforcing properties. These studies were
131
evaluated using a within-subjects design where every animal was assessed at every dose of compound. All animals were tested with training drug, vehicle, or test article for 60 min a day for up to 5 days. Once stability was established for the training drug, a dose response curve of the training drug, typically 3–4 doses, was evaluated. Following the dose response curve, animals were maintained on vehicle for up to 5 days. Following vehicle extinction, a dose response curve of the test article, typically 4–5 doses, was evaluated. 2.4. Skin button types Four different skin button types (SAI-Infusion Technologies; Lake Villa, IL) were used (Fig. 1). The skin button part numbers were designated as follows: • • • •
Part No. SBD-LA: Luer adapter button with felt base (Fig. 1a) Part No. SBD-CLH: Pinch tether button with nylon base (Fig. 1b) Part No. SBD-CLD: Pinch tether button with Dacron® base (Fig. 1c) Part No. SBD-CL1: Pinch tether button with felt base (Fig. 1d)
In the event that catheters or skin buttons lost patency or otherwise became dysfunctional, they were surgically repaired or replaced to the extent possible. Following any surgical repair or replacement procedure, animals were allowed 7 days of recovery before being placed back into the study schedule. Animals that required a surgical repair during evaluation were allowed to return to the training dose or the dose they were self-administering prior to surgery. Data from four studies were evaluated for patency and longevity based on the surgical model (Fig. 2) and skin button type used. Study 1 had 26 animals on study and all animals were implanted with an SBD-LA button. The skin button was placed via a cranial–caudal dorsal incision above the scapulae on the midline (Fig. 2a). Twenty-two animals were implanted with an SBD-CLH button for Study 2. The skin button was placed via a cranial–caudal dorsal incision above the scapulae on the midline (Fig. 2a). Study 3 had 29 animals on study and all animals were implanted with an SBD-CLD button. A cranial–caudal incision was made on the lateral surface (off midline) and a dorsal biopsy punch (on midline) was placed between the scapulae to allow for skin button placement (Fig. 2b). Thirty-nine animals were implanted with an SBD-CL1 button for Study 4. A cranial–caudal incision was made on the lateral surface (off midline) and a dorsal biopsy punch (on midline) was placed between the scapulae to allow for skin button placement (Fig. 2b). The length of each study, the skin button type, the number of repairs due to catheter versus button malfunctions per study, the total number of repairs, and the surgical technique implemented were all assessed to evaluate the patency and longevity of the IV self-administration surgical model. 3. Results For Study 1 (7 months, SBD-LA button, dorsal incision), 71% of total repairs were skin button related (27 of the 38 total repairs). The remaining 11 repairs (29%) were due to catheter malfunctions. Eighteen of the 26 animals on study went back to surgery for repairs. Using a new skin button (SBD-CLH) for Study 2 (8 months, dorsal incision) resulted in an approximate 53% increase in total repairs, with 88% (51 of 58) of the repairs due to skin button failure. The remaining 7 repairs (12%) were due to catheter malfunction. Of the 22 animals on study 20 of them went back to surgery for repairs. A third skin button (SBD-CLD) used for Study 3 (8 months), as well as a new surgical technique (lateral incision with dorsal biopsy punch), resulted in more repairs than the previous two studies. A total of 82 repairs were required for this study. Twenty-eight of the 29 animals on study went back to surgery for repairs. Skin button repairs
132
L.M. Gilbert et al. / Journal of Pharmacological and Toxicological Methods 75 (2015) 130–134
a) SBD-LA
b) SBD-CLH
Leur adapter button with felt base
Pinch tether button with nylon base
d) SBD-CL1
c) SBD-CLD Pinch tether button with Dacron® base
Pinch tether button with felt base
Fig. 1. Skin button types utilized.
a
b
Cranial-caudal dorsal incision above the scapulae on the midline
Cranial-caudal incision on the lateral surface (off midline) and a dorsal biopsy punch (on midline) above the scapulae
Fig. 2. Illustration of surgical techniques utilized.
L.M. Gilbert et al. / Journal of Pharmacological and Toxicological Methods 75 (2015) 130–134
133
Fig. 3. Mean number of repairs per study.
accounted for approximately 70% (57 of 82) of this total and catheter issues accounted for the remaining 30% of repairs. A fourth skin button (SBD-CL1) implanted using a lateral incision with a dorsal biopsy punch for Study 4 (3 months) resulted in no skin button repairs and only 3 catheter repairs throughout the length of the study. In total, 3 animals of the 39 on study went back to surgery for repairs. As seen in Fig. 3, study length was directly correlated to the mean number of repairs occurring per study. Study length increased as the total number of repairs increased. Additionally, the majority of required repairs were due to skin button-related malfunctions (Fig. 4). Multiple combinations of skin button types and surgical techniques were implemented across time. Initial combinations evaluated in Studies 1, 2 and 3 produced a greater number of repairs on a per study basis. However, the skin button type and surgical technique combination utilized in Study 4 (SBD-CL1; lateral incision with a dorsal biopsy punch) resulted in the fewest number of total repairs (Fig. 5). (See Fig. 4.) The impact on health status and behavior of the animals was minimal because animals were given one week to recover after surgery
and subsequently returned to the training drug. Animals were then required to pass protocol-driven criteria while on the training drug to demonstrate that stable self-administration behavior was established prior to further evaluation. 4. Discussion As a result of improvements to the self-administration model through testing and evaluating multiple combinations of skin buttons and surgical techniques, the number of surgical repairs occurring per study significantly decreased. This decrease in surgical repairs per study resulted in a concomitant decrease in the length of time required to complete a self-administration study. The felt base of the button is less irritating to the tissue and therefore the body won't reject it. The pinch tether top allows for less manipulation when tethering and untethering an animal. This decreases the structural stress to the button and to the animal overall. In keeping with the Institutional Animal Care and Use Committee's 3R Policy of “Reduction, Refinement, Replacement”, these refinements
Fig. 4. Mean number of button or catheter repairs per study.
134
L.M. Gilbert et al. / Journal of Pharmacological and Toxicological Methods 75 (2015) 130–134
Fig. 5. Chronological representation of total repairs per study.
to the self-administration model improved animal welfare by reducing the number of surgeries required per animal. Moreover, these improvements to the self-administration surgical model increased study efficiency and reduced overall cycle time to study completion. References Childs, E., Shoaib, M., & Stolerman, I. P. (2006). Cocaine self-administration in rats with histories of cocaine exposure and discrimination. Psychopharmacology, 186, 168–176.
Griffiths, R. R., & Balster, R. L. (1979). Opioids: Similarity between evaluation of subjective effects and animal self-administration results. Clinical Pharmacology and Therapuetics, 25, 611–617. LeSage, M. G., Stafford, D., & Glowa, J. R. (2000). Abuse liability of the anesthetic propofol: self-administration of propofol in rats under fixed-ratio schedules of drug delivery. Psychopharmacology, 153, 148–154. Weeks, J. R. (1962). Experimental morphine addiction: method for automatic intravenous injections in unrestrained rats. Science, 138, 143–144.
Contents lists available at ScienceDirect
Journal of Pharmacological and Toxicological Methods journal homepage: www.elsevier.com/locate/jpharmtox
Brief communication
Improvements in self-administration studies based on changes in skin button type and surgical technique Lindsey M. Gilbert, Mario P. Sgro, Deah L. Modlin, Nathaniel J. Wheat, Mary J. Kallman ⁎ Covance Laboratories, 671 S. Meridian Rd., Greenfield, IN, USA
a r t i c l e
i n f o
Article history: Received 13 February 2015 Received in revised form 22 April 2015 Accepted 13 May 2015 Available online 19 May 2015 Keywords: Catheter Longevity Methods Patency Rat Self-administration Skin button Surgical technique
a b s t r a c t Introduction: These studies, ranging in duration from 3 to 8 months, evaluated the patency and longevity of the intravenous (IV) self-administration surgical model in male Sprague Dawley rats. Surgeries were categorized and assessed based on the number of catheter and/or skin button repairs required per animal across four separate self-administration studies. Design improvements in skin button types and changes in surgical procedures were chronologically tracked and assessed. Methods: Animals were evaluated under a self-administration paradigm in which they were trained to respond for a food reward under a fixed ratio schedule (FR5 or FR10). Animals were then surgically prepared with a femoral catheter and skin button port. Following recovery, animals were returned to food-maintained responding for at least 5 sessions and subsequently trained to respond for injections of a reinforcing drug. Once drug training criteria was established, the effects of vehicle or varying doses of test articles were evaluated. Animals were tested in operant chambers one hour each day 5 days a week and the length of each study was recorded. Differences in the number of repairs per study as well as the total number of repairs were tabulated. Results: Study length was directly correlated to the mean number of repairs occurring per study, with study length increasing as the total number of repairs increased. The majority of repairs were skin button-related issues. Multiple combinations of skin button types and surgical techniques were implemented across time to evaluate model efficiency and decrease overall cycle time per study. Initial combinations produced a greater number of repairs on a per study basis. However, the skin button type and surgical technique combination that resulted in the fewest number of total repairs used a lateral incision with a dorsal biopsy punch. Discussion: The combination of improvements in skin button type and surgical techniques drastically decreased the number of surgical repairs required per study, increasing efficiency and thereby decreasing the overall cycle time for study completion. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Drug self-administration is a well-established method for evaluating potential abuse liability of therapeutic agents (Childs, Shoaib, & Stolerman, 2006; Griffiths & Balster, 1979; LeSage, Stafford, & Glowa, 2000; Weeks, 1962). Based on the complexity of the study design, a self-administration study may last up to 6–8 months. Skin button failures or catheter patency issues are common reasons for study prolongation. An animal with a skin button or catheter malfunction may require surgical repair multiple times throughout the course of a study. With each surgical repair, the animal must be allowed a recovery period before being placed back on study. This delays the animal's progression through the study, thereby increasing the length of time to complete the study with a sufficient cohort
⁎ Corresponding author.
http://dx.doi.org/10.1016/j.vascn.2015.05.006 1056-8719/© 2015 Elsevier Inc. All rights reserved.
for analysis. To reduce cycle time for self-administration studies, improvements in skin button type and surgical techniques were implemented over time at Covance Laboratories, Greenfield. The number of surgical repairs and the length of each study were evaluated across four studies to characterize the effectiveness of these improvements in skin button type and the surgical technique used in our selfadministration model.
2. Methods 2.1. Statement of use and care of animals All experiments were conducted in accordance with the guidelines from the Guide for the Care and Use of Laboratory Animals, Eighth Edition (Committee for the Update of the Guide for the Care and Use of Laboratory Animals, Institute for Laboratory Animal Research, National
L.M. Gilbert et al. / Journal of Pharmacological and Toxicological Methods 75 (2015) 130–134
Research Council, The National Academies Press, 2011) and approved by the Covance Laboratories Institutional Animal Care and Use Committee. 2.2. Subjects Male Sprague–Dawley rats were acclimated to the vivarium for at least 3 days prior to study initiation. Animals were individually housed in suspended shoebox cages with bedding under standard conditions for animal care. Animals were fed a restricted diet of 10–12 g of Harlan Teklad Global Diets-Rodent 2014 (Harlan, Indianapolis, IN) until lever pressing behavior was established. Animals were then maintained on 15–20 g of food per day throughout the remainder of the study. Greenfield city water was provided ad libitum. The housing room photoperiod was maintained on a 12 h light:12 h dark cycle. Room temperature was between 72 ± 3 °F and relative humidity was between 30 and 70%. 2.3. Self-administration procedures 2.3.1. Food training Animals were trained to press a lever to obtain food reinforcement under a fixed ratio response schedule up to 5 days. The response requirement is gradually increased over sessions from an FR1 to an FR5 (Midazolam) or FR10 (Cocaine) depending on the training drug used on study. Response criteria prior to an increase from an FR1 to an FR3 were reached when an animal received a minimum of 50 earned food reinforcements during the first training session and a minimum of 90 earned food reinforcements during the second session. Response criteria for subsequent increases in the FR schedule were reached when earned food reinforcements were between 90 and 100 pellets for two consecutive sessions. Stable responding at an FR5 or FR10 was reached when earned food reinforcements were between 90 and 100 pellets for three consecutive sessions. After reaching successful training criteria, each animal was surgically prepared with an indwelling femoral catheter and skin button prior to drug substitution. For dose calculation purposes, body weights were collected daily, except weekends, throughout the length of the study. 2.3.2. Surgery All animals were implanted with a chronic indwelling femoral tapered catheter (3 French: Part No. RVF-01, SAI-Infusion Technologies; Lake Villa, IL). The catheter was inserted into a femoral vein and secured to the vessel with a silk suture. The catheter was passed subcutaneously through a trocar to an incision posterior to the scapulae and attached under the skin to a skin button. The skin button was secured in place with Ethilon® sutures. After completion of surgery, the catheter and skin button were filled with taurolidine citrate as a locking solution. The locking solution is composed of 1.35% taurolidine and 2.61% citrate and has broad spectrum antimicrobial activity. Rats also initially received Convenia prior to their first surgery. For any subsequent surgery, animals received Convenia or Baytril prior to the procedure. If animals were given Baytril, they received treatment for 4 consecutive days following surgery. All Baytril doses were administered after a given test session. Animals also received pain medication (typically Buprenex) prior to surgery. All animals were allowed to recover for a minimum of 7 days before initiating self-administration testing. 2.3.3. Self-administration Following surgical recovery, animals were returned to food maintained responding for a minimum of 5 sessions to re-establish lever pressing behavior. Once successful criteria were achieved, drug injections replaced food representations under a fixed ratio schedule. Animals were then trained to respond to a training drug (cocaine or midazolam) with known reinforcing properties. These studies were
131
evaluated using a within-subjects design where every animal was assessed at every dose of compound. All animals were tested with training drug, vehicle, or test article for 60 min a day for up to 5 days. Once stability was established for the training drug, a dose response curve of the training drug, typically 3–4 doses, was evaluated. Following the dose response curve, animals were maintained on vehicle for up to 5 days. Following vehicle extinction, a dose response curve of the test article, typically 4–5 doses, was evaluated. 2.4. Skin button types Four different skin button types (SAI-Infusion Technologies; Lake Villa, IL) were used (Fig. 1). The skin button part numbers were designated as follows: • • • •
Part No. SBD-LA: Luer adapter button with felt base (Fig. 1a) Part No. SBD-CLH: Pinch tether button with nylon base (Fig. 1b) Part No. SBD-CLD: Pinch tether button with Dacron® base (Fig. 1c) Part No. SBD-CL1: Pinch tether button with felt base (Fig. 1d)
In the event that catheters or skin buttons lost patency or otherwise became dysfunctional, they were surgically repaired or replaced to the extent possible. Following any surgical repair or replacement procedure, animals were allowed 7 days of recovery before being placed back into the study schedule. Animals that required a surgical repair during evaluation were allowed to return to the training dose or the dose they were self-administering prior to surgery. Data from four studies were evaluated for patency and longevity based on the surgical model (Fig. 2) and skin button type used. Study 1 had 26 animals on study and all animals were implanted with an SBD-LA button. The skin button was placed via a cranial–caudal dorsal incision above the scapulae on the midline (Fig. 2a). Twenty-two animals were implanted with an SBD-CLH button for Study 2. The skin button was placed via a cranial–caudal dorsal incision above the scapulae on the midline (Fig. 2a). Study 3 had 29 animals on study and all animals were implanted with an SBD-CLD button. A cranial–caudal incision was made on the lateral surface (off midline) and a dorsal biopsy punch (on midline) was placed between the scapulae to allow for skin button placement (Fig. 2b). Thirty-nine animals were implanted with an SBD-CL1 button for Study 4. A cranial–caudal incision was made on the lateral surface (off midline) and a dorsal biopsy punch (on midline) was placed between the scapulae to allow for skin button placement (Fig. 2b). The length of each study, the skin button type, the number of repairs due to catheter versus button malfunctions per study, the total number of repairs, and the surgical technique implemented were all assessed to evaluate the patency and longevity of the IV self-administration surgical model. 3. Results For Study 1 (7 months, SBD-LA button, dorsal incision), 71% of total repairs were skin button related (27 of the 38 total repairs). The remaining 11 repairs (29%) were due to catheter malfunctions. Eighteen of the 26 animals on study went back to surgery for repairs. Using a new skin button (SBD-CLH) for Study 2 (8 months, dorsal incision) resulted in an approximate 53% increase in total repairs, with 88% (51 of 58) of the repairs due to skin button failure. The remaining 7 repairs (12%) were due to catheter malfunction. Of the 22 animals on study 20 of them went back to surgery for repairs. A third skin button (SBD-CLD) used for Study 3 (8 months), as well as a new surgical technique (lateral incision with dorsal biopsy punch), resulted in more repairs than the previous two studies. A total of 82 repairs were required for this study. Twenty-eight of the 29 animals on study went back to surgery for repairs. Skin button repairs
132
L.M. Gilbert et al. / Journal of Pharmacological and Toxicological Methods 75 (2015) 130–134
a) SBD-LA
b) SBD-CLH
Leur adapter button with felt base
Pinch tether button with nylon base
d) SBD-CL1
c) SBD-CLD Pinch tether button with Dacron® base
Pinch tether button with felt base
Fig. 1. Skin button types utilized.
a
b
Cranial-caudal dorsal incision above the scapulae on the midline
Cranial-caudal incision on the lateral surface (off midline) and a dorsal biopsy punch (on midline) above the scapulae
Fig. 2. Illustration of surgical techniques utilized.
L.M. Gilbert et al. / Journal of Pharmacological and Toxicological Methods 75 (2015) 130–134
133
Fig. 3. Mean number of repairs per study.
accounted for approximately 70% (57 of 82) of this total and catheter issues accounted for the remaining 30% of repairs. A fourth skin button (SBD-CL1) implanted using a lateral incision with a dorsal biopsy punch for Study 4 (3 months) resulted in no skin button repairs and only 3 catheter repairs throughout the length of the study. In total, 3 animals of the 39 on study went back to surgery for repairs. As seen in Fig. 3, study length was directly correlated to the mean number of repairs occurring per study. Study length increased as the total number of repairs increased. Additionally, the majority of required repairs were due to skin button-related malfunctions (Fig. 4). Multiple combinations of skin button types and surgical techniques were implemented across time. Initial combinations evaluated in Studies 1, 2 and 3 produced a greater number of repairs on a per study basis. However, the skin button type and surgical technique combination utilized in Study 4 (SBD-CL1; lateral incision with a dorsal biopsy punch) resulted in the fewest number of total repairs (Fig. 5). (See Fig. 4.) The impact on health status and behavior of the animals was minimal because animals were given one week to recover after surgery
and subsequently returned to the training drug. Animals were then required to pass protocol-driven criteria while on the training drug to demonstrate that stable self-administration behavior was established prior to further evaluation. 4. Discussion As a result of improvements to the self-administration model through testing and evaluating multiple combinations of skin buttons and surgical techniques, the number of surgical repairs occurring per study significantly decreased. This decrease in surgical repairs per study resulted in a concomitant decrease in the length of time required to complete a self-administration study. The felt base of the button is less irritating to the tissue and therefore the body won't reject it. The pinch tether top allows for less manipulation when tethering and untethering an animal. This decreases the structural stress to the button and to the animal overall. In keeping with the Institutional Animal Care and Use Committee's 3R Policy of “Reduction, Refinement, Replacement”, these refinements
Fig. 4. Mean number of button or catheter repairs per study.
134
L.M. Gilbert et al. / Journal of Pharmacological and Toxicological Methods 75 (2015) 130–134
Fig. 5. Chronological representation of total repairs per study.
to the self-administration model improved animal welfare by reducing the number of surgeries required per animal. Moreover, these improvements to the self-administration surgical model increased study efficiency and reduced overall cycle time to study completion. References Childs, E., Shoaib, M., & Stolerman, I. P. (2006). Cocaine self-administration in rats with histories of cocaine exposure and discrimination. Psychopharmacology, 186, 168–176.
Griffiths, R. R., & Balster, R. L. (1979). Opioids: Similarity between evaluation of subjective effects and animal self-administration results. Clinical Pharmacology and Therapuetics, 25, 611–617. LeSage, M. G., Stafford, D., & Glowa, J. R. (2000). Abuse liability of the anesthetic propofol: self-administration of propofol in rats under fixed-ratio schedules of drug delivery. Psychopharmacology, 153, 148–154. Weeks, J. R. (1962). Experimental morphine addiction: method for automatic intravenous injections in unrestrained rats. Science, 138, 143–144.