Systemic Oxytocin Attenuates Methylphenidate Self‐Administration and Potentiates Its Effects on Dopamine in the Nucleus Accumbens Shell in Rats

Abstract

Clinical and preclinical reports have shown that the hypothalamic neurohormone oxytocin plays a role in social bonding, a behavior that is also controlled by the neurotransmitter dopamine. Dopamine also plays an important role in both natural and pathologic behaviors related to reward and reinforcement, including substance use disorders. Dopamine is especially relevant for psychostimulant used is orders, and early reports have shown that oxytocin treatments might interfere with psychostimulant behavioral effects. Several recent studies have focused on oxytocin effects in models of reward or drug abuse in order to understand whether this neuropeptide interferes with pathological compulsive behaviors. Thus, oxytocin has been tested as a potential therapy for alcohol and psychostimulant use disorders. In the present study, the effects of oxytocin were assessed in Sprague‐Dawley rats: 1) trained to self‐administer methylphenidate intravenously (1 mg/kg, fixed ratio 5) during single daily 1‐hr sessions, 2) implanted with microdialysis probes to assess methylphenidate(0.1–1 mg/kg, i.v.) effects on extracellular levels of dopamine in the nucleus accumbens, a brain area related to reward and reinforced behavior, and 3)placed in infrared activity monitors to measure behavioral activation.Injections of oxytocin (0.1–2mg/kg, i.p.) 10 min before the sessions dose‐dependently decreased maximal self‐administration of methylphenidate (0.03–1.0 mg/kg/injection, i.v.). Though, oxytocin (0.2–2 mg/kg, i.p.) had little to no significant effects on extracellular levels of dopamine in the accumbens shell, oxytocin dose‐dependently enhanced the dopamine levels stimulated by intravenous methylphenidate (0.1–1 mg/kg, i.v.). Notably, this enhancement of dopamine levels did not result in stimulation of behavioral activities at levels higher than those produced by methylphenidate alone.The present results suggest that oxytocin attenuates the psychostimulant‐like reinforcing effects of methylphenidate, likely acting through altered dopamine neurotransmission in the terminals of the mesolimbic system. Thus, these results confirm and extend the potential translational therapeutic value of oxytocin for psychostimulant use disorders.Support or Funding InformationResearch Funded by:NIDA‐IRP, NIH/DHHS; Bench‐to‐Bedside Grant by the OBSSR/NIH; Intramural Grant ZIAAA000218‐01 (CPN Section) DICBR/NIAAA/NIH/DHHS.