National Institutes of Health
Direct evidence of cerebrospinal fluid penetrance of oxytocin after intranasal and intravenous administration and effect of systemic oxytocin administration on methylphenidate-induced changes in accumbal dopamine levels and methylphenidate self-administration
Background: Diffusion of peptides such as Oxytocin (OT), when delivered intravenously (IV), across the blood brain barrier is restricted. Intranasal (IN) delivery of OT is based on the notion that IN delivery bypasses the BBB. Animal studies report elevated cerebrospinal fluid (CSF) OT levels after IN or IV OT administration. However, actual CSF penetrance of IV or IN delivered OT has not been demonstrated. Additionally, OT alters behaviors related to the administration of drugs of abuse via centrally mediated pathways, however its mechanisms of action are not fully elucidated. Here, we present a set of experiments (Exp) where we investigated: 1) CSF penetrance of labelled OT; 2) the effect of OT on methylphenidate (MPH)-induced increase of dopamine (DA) levels in the nucleus accumbens shell (AcbSh); and 3) the effect of OT on MPH self-administration (SA).
Method: Exp 1. We developed a LC-MS/MS assay to measure administered [deuterated (D5)] OT and endogenous [nondeuterated (D0)] OT in CSF and plasma. D5 OT was administered IN and IV to rhesus macaques (N=6). D5 and D0 OT in plasma and CSF were measured over 60 minutes post-IV and IN administration of 80 IU of D5OT. Exp 2. DA levels were measured via microdialysis in the AcbSh in male rats (N=10) who were pretreated with either OT (0 mg/Kg, 1 mg/kg, 2 mg/kg) 10 minutes before IV MPH injections (0.1, 0.32 and 1.0 mg/kg at 0, 30 and 60 min, respectively). Exp 3. Rats (N=7) were trained to self-administer MPH at doses of 0.01, 0.03, 0.1 and 0.3 mg/kg/inf. Animals were pre-treated with intraperitoneal OT or vehicle, 20 min prior to MPH SA sessions at doses of 0.1, 0.25, 0.5, 1 and 2 mg/kg. Food SA was used as a control condition.
Results: Exp 1. The LC-MS/MS assay measured D5 and D0 OT with high sensitivity (level of detection and quantification of 10 pg/ml) and specificity. Cmax (±SD) D5 OT CSF levels were 636±457 and 82±117 pg/ml after IV and IN D5 OT administration, respectively. There was no significant effect of D5 OT administration on D0 OT levels. Exp 2. MPH injections resulted in a dose-dependent increase in basal DA levels and pretreatment with 2 mg/kg OT resulted in a significantly greater DA stimulation as compared to 1 mg/kg OT and vehicle (p’s<0.05) . OT per se did not affect basal DA levels. Exp 3. Pretreatment with 0.25, 0.5, 1 and 2 mg/kg OT resulted in an overall decrease in responses across all doses of MPH while 0.1 mg/kg OT did not alter responses as compared to baseline and vehicle. 0.5, 1 and 2 mg/kg OT also caused a decrease in food SA, while 0.1 and 0.25 mg/kg OT did not have any effect.
Conclusion: The LC-MS/MS assay measures D5 OT in the CSF after IN and IV administration. There is no evidence of a “feed-forward” effect of exogenous OT administration on endogenous OT levels. The IN route does not appear to be a “privileged pathway” for OT delivery over the time course here studied. Systemic OT administration dose-dependently potentiates AcbSh MPH-stimulated DA levels. Most rodent studies to date show a decrease in psychostimulants SA with pretreatment with OT; our microdialysis results suggest that OT would cause a shift to the left in the MPH dose response. However, results from the MPH SA experiment indicate a shift downwards following OT pretreatment, with no dose-dependent effect of OT. Together, these results indicate that OT is involved in the DAergic processes related to drug use and that treatment with OT induces changes with respect to SA behavior.