Evaluation of the abuse liability of gabapentin and duloxetine in male and female rats using two approaches: intravenous self-administration and conditioned place preference

Q. Chang¹, E.A. Dugan¹, W. Min¹, H. Buechler¹, P. V. Severino¹, D. A. Nicholson¹, S.A. Woller², W. Lacsina¹, S. Iyengar², T. Hanania^1
1PsychoGenics, Paramus NJ; ²NINDS/NIH 6001. Executive Boulevard, Rockville, MD 20852

In collaboration with the NIH HEAL Initiative Preclinical Screening Platform for Pain (PSPP), we evaluated the abuse liability properties of gabapentin and duloxetine in the intravenous self-administration (SA) and conditioned place preference (CPP) tests in male and female SD rats. SA took place in operant chambers where rats pressed a lever that delivered the test compound through a jugular vein catheter. An independent group design with n=10-12 was used. Rats were allowed to self-administer saline or vehicle (6% DSMO for duloxetine study), oxycodone (0.06 mg/kg/infusion, as positive control for both studies), gabapentin (0.3, 1 and 3 mg/kg/infusion) or duloxetine (0.3, 1 and 3 mg/kg/infusion) on an FR3 schedule. Acquisition training lasted 20 days. The results indicated that oxycodone 0.06 mg/kg/infusion possessed strong abuse liability, gabapentin did not show signs of abuse potential, and the groups with higher doses of duloxetine had significantly fewer infusion compared to the vehicle group. This suggests duloxetine may have aversive effects in the SA model. In the CPP study, an independent group design (N=14-16) was used. In the gabapentin study, there were five groups (saline, oxycodone 3 mg/kg, and gabapentin 3, 10 and 30 mg/kg); in the duloxetine study, there were also five groups (saline, oxycodone 3 mg/kg, and duloxetine 10, 30 and 100 mg/kg.) Compounds were administered orally (5 ml/kg and 0 minute pretreatment, except saline and oxycodone, which were i.p. dosed with 1 ml/kg and 0 min pretreatment). Perceptive cues were applied to create a distinctive texture and visual features for the two compartments.  A 10-day protocol was used and the study was videotaped. Rats were treated with saline on days 2, 4, 6 and 8, and with either oxycodone or gabapentin / duloxetine on days 3, 5, 7, 9.  Animals were confined in the “drug compartment” or “saline compartment” immediately after administration for 20 minutes. Compared to saline, oxycodone induced significant CPP. None of the gabapentin or duloxetine groups showed bias between the two compartments. These studies confirmed the validity of both assays in screening the potential abuse liability as part of the NIH HEAL Initiative’s PSPP program towards discovering novel non-addictive analgesics.