Aims Limited vs extended drug exposure has been proposed as one of the key factors in determining the risk of relapse, which is the primary characteristic of addiction behaviors. The current studies were designed to explore the related behavioral effects and neuronal alterations in the insular cortex (IC), an important brain region involved in addiction. Methods Experiments started with rats at the age of 35 days, a typical adolescent stage when initial drug exposure occurs often in humans. The drug‐seeking/taking behaviors, and membrane properties and intrinsic excitability of IC pyramidal neurons were measured on withdrawal day (WD) 1 and WD 45‐48 after limited vs extended cocaine intravenous self‐administration (IVSA). Results We found higher cocaine‐taking behaviors at the late withdrawal period after limited vs extended cocaine IVSA. We also found minor but significant effects of limited but not extended cocaine exposure on the kinetics and amplitude of action potentials on WD 45, in IC pyramidal neurons. Conclusion Our results indicate potential high risks of relapse in young rats with limited but not extended drug exposure, although the adaptations detected in the IC may not be sufficient to explain the neural changes of higher drug‐taking behaviors induced by limited cocaine IVSA.
Effects of Limited vs Extended Cocaine Exposure: A, Timeline of cocaine‐seeking and cocaine‐taking test with specified age of days at each stage. Rats were trained by limited (upper line) or extended (lower line) cocaine intravenous self‐administration (IVSA) procedures. P, postnatal days. B, Cocaine‐taking behaviors tested by multiple dose of cocaine (ie, 0.1, 0.3, 1.0, 3.0 mg/kg per infusion) on withdrawal days (WD) 46‐48 after IVSA. C, cocaine (0.1 mg/kg per infusion)‐taking behaviors of individual rats are represented by the circles in the columns. D, Sample trace of action potential from the pyramidal neurons in the IC 1 day (left) and 45 days (right) after limited saline (denoted “S”)/ cocaine (denoted “C”) IVSA training. E, Summarized data showing that, relative to the saline controls, limited cocaine treatment significantly prolonged the rise time of action potential 45 days but not 1 day after IVSA training.