Differential Characteristics of Ketamine Self-Administration in the Olfactory Bulbectomy Model of Depression in Male Rats

Ketamine has been extensively studied for its antidepressant potential, with promising results in both preclinical and clinical studies. However, concerns regarding its abuse liabilities greatly limit its potential to become an approved treatment for depression. Therefore, a better understanding the risks and benefits of ketamine use in depression is needed. This study aimed to assess the characteristics of operant intravenous (IV) ketamine self-administration and relapse-like behavior in the olfactory bulbectomy (OBX) model of depression in male rats. Twenty-five male Wistar rats were divided randomly into 2 groups; in 1 group the bilateral olfactory bulbectomy was performed, whereas the other group was sham-operated. Intravenous self-administration of ketamine (.5 mg/kg/infusion) was conducted under a fixed ratio 1 schedule of reinforcement. After reaching stable drug intakes, rats then underwent a 14-day period of forced abstinence followed by a drug-free relapse-like session. The forced swim test was conducted before the commencement of the self-administration protocol and on the 1st day of abstinence. Consistent with findings in previous studies on other substances, OBX animals showed increased operant IV ketamine self-administration. In contrast, ketamine-seeking behavior in the OBX group did not differ from sham-operated animals during the relapse-like session, whereas previous studies on other psychostimulants like methamphetamine and cocaine reported increases. Our findings suggest substantially different underlying neuroadaptations between chronic ketamine and psychostimulant exposure.