Oxytocin attenuates demand for cocaine in female rats

There are substantial sex differences in substance use disorders (SUDs), and a key feature of SUD is pathologically high economic demand for drug. The hypothalamic neuropeptide oxytocin (OXT) is heavily implicated in the modern treatment of SUDs. Using a within-session threshold behavioral economics (BE) procedure, we quantified demand elasticity (a, inverse motivation) and free consumption (Q₀) in male and female rats to investigate the effect of OXT on cocaine demand. Results showed that OXT decreased motivation for cocaine; an effect greater during the high-demand phase (diestrus, low progesterone, P₄) vs low demand phases (proestrus, high P₄). We confirmed our prior findings that P₄ attenuates cocaine demand in female rats and that chronic cocaine self-administration disrupts estrus cyclicity. Following each injection, OXT at either 0.1mg/kg or 0.3mg/kg restored estrous cycling in intact females with prior cocaine experience for one week and remained effective with up to 4 weeks of injections. Fos reactivity in OXT+ neurons was greater when rats were in proestrus compared to diestrus and significantly correlated to motivation and circulating levels of P₄. Finally, using ovariectomized females with P₄ replacement, we show that P₄'s demand attenuating effects are reversed by atosiban (1.0 mg/kg, IP), an OXT antagonist. These data show an interaction between oxytocin and progesterone in female rats that may underlie differences in cocaine demand between sexes. Additionally, we show critical periods for using OXT as a treatment to reduce cocaine demand in females. Our results indicate novel therapeutic treatments for SUDs must be tailored to hormonal states.