Local Administration of Oxytocin in The Nucleus Accumbens Shell Affects The Neurochemical Effects of Methylphenidate Related to Its Reinforcing Effects.

Abstract

IntroductionDopamine (DA) transmission in mesolimbic areas is intimately involved in the mediation of natural‐ and drug‐reinforcing behavioral effects. However, oxytocin has been shown to interfere with psychostimulant‐induced behavioral effects, the mechanism for which is unknown. We have recently shown that systemic, peripheral oxytocin (10 min pretreatment) dose‐dependently decreased intravenous (i.v.) methylphenidate self‐administration behavior. Moreover, oxytocin did not significantly affect extracellular levels of DA in the nucleus accumbens shell (NAS), while it dose‐dependently enhanced methylphenidate‐stimulated extracellular NAS DA levels.MethodsIn order to better understand which brain area might be involved in the effects of oxytocin on neurochemistry related to reinforcing actions of methylphenidate, we implanted Sprague Dawley rats with microdialysis probes to assess methylphenidate's (0.1–1 mg/kg, i.v.) effects on levels of DA in the NAS and nucleus accumbens core (NAC); in the NAS, oxytocin was administered through the microdialysis probe by reverse dialysis, while systemic injections of oxytocin were administered to rats implanted with probes in the NAC. Intranasal administration of oxytocin was also tested in order to replicate the data obtained by its systemic peripheral administration before MPH doses from 0.1–1.0 mg/kg (i.v.).ResultsOxytocin did not elicit any change in dialysate DA levels when delivered either systemically in the NAC or intranasally or locally by reverse dialysis in the NAS, up to 2 hrs from the start of its administration. These effects confirm our previous data obtained after systemic oxytocin administration in the NAS. Similarly, dose‐dependent enhancements of i.v. methylphenidate‐stimulated DA levels were obtained when oxytocin was delivered intranasally or locally into the NAS, but no significant effects were obtained in the NAC. These results clearly indicate that these oxytocin actions are mediated by oxytocin receptors located in the NAS but not in the NAC. Our ongoing voltammetry studies will evaluate if oxytocin effects on methylphenidate are the results of changes in DA uptake or release.ConclusionsTogether with our previous studies, the present results suggest that oxytocin pretreatments might attenuate the psychostimulant‐like effects of methylphenidate, likely through changes in DA neurotransmission in the NAS, terminal area of the mesolimbic DA system, but not in the NAC. Thus, our results confirm and extend the potential translational value of oxytocin as a pharmacotherapy for psychostimulant use disorders.Support or Funding InformationResearch Funded by: MDP‐NIDA‐IRP, NIH/DHHS; Bench‐to‐Bedside Grant by the OBSSR/NIH; Intramural Grant ZIA AA000218‐01 (CPN Section) DICBR/NIAAA/NIH/DHHSThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.