Orexin/hypocretin is necessary for context-driven cocaine-seeking

Orexin/hypocretin signaling at the orexin 1 receptor (OX1R) has recently been implicated in addiction and relapse. We examined the role of the orexin system in cocaine-seeking elicited by a drug-associated context following abstinence or extinction from chronic cocaine self-administration. Male Sprague–Dawley rats self-administered cocaine in 2-h sessions for 10 days, followed by extinction training or extended abstinence in the home cage. The OX1R antagonist SB-334867 (SB; 10, 20, or 30 mg/kg, i.p.) was administered prior to re-exposure to the cocaine self-administration environment. We found that pretreatment with SB significantly attenuated cocaine-seeking when rats were placed back into the self-administration environment following either 1 day or 2 weeks of abstinence (no extinction), or following extinction of cocaine-seeking in an alternative environment (distinct from the training environment). These results indicate that orexin signaling at OX1R is critical for conditioned cocaine-seeking elicited by a drug-associated context, following either extinction or abstinence.