Methamphetamine produces behavioral flexibility deficits that are attenuated by COX-2 inhibition in both male and female rats.

Methamphetamine (METH) Use Disorder (MUD) and METH-related overdose deaths continue to rise in the United States and elsewhere. Patients with MUD experience cognitive inflexibility, which conveys a vulnerability to continued addictive behaviors and relapse. Neuroinflammation is present in both brain tissue and serum following METH use and appears to play a role in cognitive deficits. The current study sought to investigate the ability of an anti-inflammatory cyclooxygenase-2 (COX-2) inhibitor, parecoxib (PXB), to attenuate METH-induced deficits in behavioral flexibility in male and female rats. Rats were given binge-like access (96 hrs/week/3 weeks) to METH via intravenous self-administration (IVSA) at 0.05 mg/kg/infusion, or saline as a control. Behavioral flexibility was assessed using the Attentional Set Shifting Task (ASST) prior to and three weeks following the cessation of drug access, with PXB administered for the last 7 days of abstinence. Difference scores for ASST performance were calculated (post drug/treatment - baseline) and compared between groups: saline-saline, saline-PXB, METH-saline, METH-PXB. Rats that self-administered METH required more trials to reach criterion in the extradimensional shift (ED) part of ASST than they did prior to METH, indicating a deficit in attentional set shifting in both sexes following METH. Strikingly, rats treated with PXB following METH IVSA performed similarly to controls, suggesting an attenuation of behavioral deficits. Sex differences in the simple discrimination (SD) part of the task were also observed, with METH-saline females exhibiting deficits that were attenuated by PXB. These findings reinforce the argument that pharmacologically targeting neuroimmune responses to METH may facilitate recovery from MUD.