Rate of Onset as a Determinant of Abuse Potential Assessment Using Intracranial Self‐Stimulation in Rats

Abstract

Background Intracranial self-stimulation (ICSS) is one procedure that has been used to evaluate abuse potential of drugs, and as with more commonly used drug self-administration procedures, ICSS is especially sensitive to drugs that activate the mesolimbic dopamine system. Drug self-administration studies have shown that abuse potential can also be influenced by temporal parameters, and especially rate of onset; however, the degree to which rate of onset influences abuse-potential metrics in ICSS procedures has not been systematically examined. To address this issue, this study evaluated three dopamine transporter (DAT) inhibitors that have different onset rates and were shown previously to maintain different peak break points in rhesus monkeys responding under a progressive-ratio schedule (cocaine > WIN35428 > RTI-31 for both rate of onset and break point). In ICSS, abuse potential is generally indicated when a drug increases low rates of responding maintained by low levels of brain stimulation, a phenomenon called “ICSS facilitation”. We hypothesized that these three DAT inhibitors would facilitate ICSS different time courses, but the degree to which rate of onset might influence peak facilitation was unknown. Methods Adult male and female Sprague-Dawley rats (n = 5-7 per drug) were surgically implanted with permanent stainless-steel electrodes targeting the medial forebrain bundle and trained to respond on a lever to receive electrical brain stimulation. Behavioral sessions were organized in components consisting of ten one-minute frequency trials over a range of brain-stimulation frequencies (56-158 Hz), such that a full curve relating brain-stimulation frequency to response rate could be determined every 10 min. On test days, three baseline ICSS components were followed first by intraperitoneal drug injection and then immediately by 12 consecutive test components (120 min). Additional pairs of test components were initiated at 300 and 1440 minutes post-injection. The drugs and dose ranges tested were as follows: cocaine HCl (1.0 - 10 mg/kg), WIN35428 (0.10 – 0.32 mg/kg), and RTI-31 (0.032 – 0.10 mg/kg). All drugs were tested up to doses that produced peak levels of ICSS facilitation; higher doses disrupted responding and produced stereotypies. Results Under baseline conditions, brain stimulation maintained a frequency-dependent increase in reinforcement rates. All three drugs dose-dependently and robustly facilitated ICSS, shifting ICSS frequency-rate curves to the left and increasing the total number of stimulations per component when data were collapsed across all frequencies. Consistent with previous studies, the rate of onset for ICSS facilitation was fastest for cocaine, slower for WIN35428, and slowest for RTI-31. Cocaine also had the shortest duration of action and the lowest potency, whereas RTI-31 had the longest duration of action and highest potency. However, despite these differences in time course and potency, peak ICSS facilitation was not statistically different across drugs. Conclusions These results suggest that ICSS studies should evaluate rate of onset as well as peak ICSS facilitation in reaching conclusions about overall abuse potential of a test drug.