Examination of the behavioral effects of ketamine in Sprague‐Dawley and Wistar Kyoto rats

Abstract

Ketamine represents a breakthrough therapy for patients with major depressive disorder (MDD). Unfortunately use‐limiting effects such as sedation, cognitive impairment and risk for abuse negatively impact ketamine’s therapeutic utility. What remains unexplored is the relative vulnerability of MDD patients to ketamine’s adverse effects. Thus, we evaluated the effects of ketamine on locomotor activation and the acquisition of intravenous (IV) ketamine self‐administration. These studies were performed in Sprague‐Dawley (SD) rats, a “normal” control strain and Wistar Kyoto (WKY) rats, an inbred strain which demonstrate stress vulnerability and mimics behavioral and physiological aspects of MDD in humans. Male and female rats from each strain were administered saline or a dose of ketamine (3‐ 56 mg/kg, IP) and locomotor activity was recorded for 30 min. Following 2‐4 months during which rats were handled but underwent no experimental procedures, they were surgically implanted with chronic IV catheters. Subjects were then given access to 0.3 mg/kg/infusion IV ketamine under a fixed ratio (FR) 1 schedule during 21 daily 1‐hr sessions. Acquisition criteria required subjects to respond for >15 infusions during 3 consecutive sessions, with responding on the inactive lever < 70% of that on the active lever. To determine the potential impact of learning disparities between strains, separate groups of SD and WKY rats were also assessed for acquisition of food maintained responding under the same schedule of reinforcement. Ketamine produced a biphasic dose‐dependent effect on activity in both strains with intermediate doses producing an increase in locomotion and higher doses suppressing activity. WKY rats displayed significantly less activity than SD rats under vehicle conditions, as well as following ketamine treatments. Ketamine significantly increased distance traveled at 3, 10 and 30 mg/kg in SD rats and at 3 and 10 mg/kg in WKY rats. While distance traveled by WKY rats was lower across all ketamine doses, data normalization relative to vehicle control revealed that ketamine produced a similar level of effect in both strains. Approximately 75% of SD rats acquired ketamine self‐administration within a 21‐day window under our testing conditions; whereas, less than 20% of the WKY rats acquired the behavior. Subsequent exploration of responding for higher and lower ketamine concentrations failed to engender self‐administration behavior in WKY rats. Using active training techniques to promote responding and drug exposure ultimately resulted in approximately 75% of the WKY rats self‐administering ketamine under FR1 conditions versus 100% of the SD rats. In contrast, all subjects from both strains learned to respond for food pellets within 4 sessions. Overall, consistent with previous work, our studies show that WKY rats have lower baseline activity levels. However ketamine‐induced locomotor activation was proportionate to those for our control strain. Similarly, both strains readily acquired and responded for food under a FR schedule suggesting an equivalent capacity to learn an operant task for a natural reinforcer. Yet, obvious differences emerged when operant responding was reinforced with IV ketamine suggesting that ketamine produces lower reinforcing effects in WKY rats relative to SD. Alternatively it is possible that WKY rats are more sensitive to ketamine’s aversive effects.