Oxytocin receptors mediate oxytocin potentiation of methylphenidate‐induced stimulation of accumbens dopamine in rats

Abstract

While the illicit use and misuse of stimulants like cocaine and methylphenidate (MP) has increased, there remains no FDA-approved treatments for psychostimulant use disorders (PSUD). Oxytocin (OT) has shown promise as a potential pharmacotherapy for PSUD. Dopamine (DA) neurotransmission plays a significant role in PSUD. We have recently shown that OT blunts the reinforcing effects of MP but, surprisingly, enhanced MP-induced stimulation of DA levels. Such effects have been suggested as a result of activation of OT receptors or, alternatively, could be mediated by direct actions of OT on MP blockade of the DA transporter. Here, we employed fast scan cyclic voltammetry (FSCV) to investigate the effects of systemic OT on MP-induced changes in the dynamics of DA, phasic release and uptake, in the nucleus accumbens shell (NAS) of Sprague-Dawley rats. We also tested the systemic effects of an antagonist of OT receptors, atosiban, to counteract the OT enhancement of dopaminergic effects of MP under microdialysis procedures in the NAS in rats. Administration of OT alone (2 mg/kg; i.p.) did not significantly modify evoked NAS DA dynamics measured by FSCV, and when administered 10 min before MP (0.1, 0.3, 1.0 mg/kg; i.v.), OT did not potentiate MP-induced increases in phasic DA release and did not alter DA clearance rate, suggesting no direct interactions of OT with the MP-induced blockade of DA uptake. Also, OT alone did not elicit significant changes in tonic, extracellular NAS DA levels measured by microdialysis. However, consistent with previous studies, we observed that OT pretreatments (2 mg/kg; i.p.) potentiated MP-induced (0.1, 0.3, 1.0 mg/kg; i.v.) efflux of extracellular NAS DA levels. This effect was abolished when rats were pretreated with atosiban (2 mg/kg; i.p.), suggesting that OT receptors mediate this OT action. Overall, our results suggest that OT receptors mediated OT potentiation of MP-induced stimulation of extracellular NAS DA levels, likely driven by modulation of DA receptor signaling pathways, without affecting MP blockade of DAT.

An FSCV Study on the Effects of Targeted Typical and Atypical DAT Inhibition on Dopamine Dynamics in the Nucleus Accumbens Shell of Male and Female Mice

“…A standard sample size of 5 was selected based on a previously published post-hoc power analysis. 54 Experimental data were collected every 5 min as follows: four control evoked DA files (stable with less than 15% variability in signal), pharmacological agent was administered, and data collection continued for 2 h postdrug. Drug treatments (cocaine, R-modafinil, JJC8-088, JJC8-091) at doses of 3, 10, or 32 mg/kg were arbitrarily assigned, and only one treatment was administered to each animal for the purpose of these studies.…”

“…Experimentally naı̈ve mice were arbitrarily assigned to a treatment, and only one experiment was performed on each animal. A standard sample size of 5 was selected based on a previously published post-hoc power analysis . Experimental data were collected every 5 min as follows: four control evoked DA files (stable with less than 15% variability in signal), pharmacological agent was administered, and data collection continued for 2 h postdrug.…”

Dual DAT and sigma receptor inhibitors attenuate cocaine effects on nucleus accumbens dopamine dynamics in rats

“…Probes with an effective dialyzing surface of 1.8–2.0 mm were implanted into the NAS [uncorrected coordinates AP = +2.0 mm, ML = 1.0 mm in reference to bregma; DV = 7.9 mm from the dura (Paxinos & Watson, 2006)] as described in previous publications (Tanda et al, 2005, 2007). A silastic catheter was implanted into the external jugular vein during the same surgical procedure also previously described (Garcés‐Ramírez et al, 2011; Hersey, Bacon, et al, 2023; Tanda et al, 2008). The right external jugular vein was exposed by a skin incision followed by blunt dissection in which the vein was isolated from connective tissue.…”

“…An Ag/AgCl reference electrode was implanted in the contralateral side of the brain. Carbon fiber microelectrodes were fabricated as previously described (Hersey, Bacon, et al, 2023).…”

Interactions of calmodulin kinase II with the dopamine transporter facilitate cocaine-induced enhancement of evoked dopamine release

“…For animal studies included in this work, no formal randomization protocol was applied but animals were arbitrarily allocated into each drug treatment group. A sample size minimum of four animals was selected based on previously performed power analyses on similar studies [ 38 ]. Animals were excluded if the data set collected was incomplete or the data were statistically significant outliers from the mean.…”