Elsevier

Neuroscience

Volume 155, Issue 1, 31 July 2008, Pages 250-257
Neuroscience

Neuropharmacology
Short-acting cocaine and long-acting GBR-12909 both elicit rapid dopamine uptake inhibition following intravenous delivery

https://doi.org/10.1016/j.neuroscience.2008.05.022Get rights and content

Abstract

The rewarding effects of cocaine have been reported to occur within seconds of administration. Extensive evidence suggests that these actions involve the ability of cocaine to inhibit the dopamine (DA) transporter. We recently showed that 1.5 mg/kg i.v. cocaine inhibits DA uptake within 5 s. Despite this evidence, there remains a lack of consensus regarding how quickly i.v. cocaine and other DA uptake inhibitors elicit DA uptake inhibition. The current studies sought to better characterize the onset of cocaine-induced DA uptake inhibition and to compare these effects to those obtained with the high-affinity, long-acting DA transporter inhibitor, GBR-12909 (1-(2-bis(4-fluorphenyl)-methoxy)-ethyl)-4-(3-phenyl-propyl)piperazine). Using in vivo fast scan cyclic voltammetry, we showed that i.v. cocaine (0.75, 1.5, and 3.0 mg/kg) significantly inhibited DA uptake in the nucleus accumbens of anesthetized rats within 5 s. DA uptake inhibition peaked at 30 s and returned to baseline levels in approximately 1 h. The effects of cocaine were dose-dependent, with the 3.0 mg/kg dose producing greater uptake inhibition at the early time points and exhibiting a longer latency to return to baseline. Further, the blood–brain barrier impermeant cocaine-methiodide had no effect on DA uptake or peak height, indicating that the generalized peripheral effects of cocaine do not contribute to the CNS alterations measured here. Finally, we show that GBR-12909 (0.75, 1.5, and 3.0 mg/kg) also significantly inhibited DA uptake within 5 s post-injection, although the peak effect and return to baseline were markedly delayed compared with cocaine, particularly at the highest dose. Combined, these observations indicate that the central effects of dopamine uptake inhibitors occur extremely rapidly following i.v. drug delivery.

Section snippets

Animals

Adult male Sprague–Dawley rats (300–350 g) were housed two per cage on a 12-h light/dark cycle with food and water available ad libitum. All protocols and animal care procedures were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80–23, revised 1996), and approved by the Institutional Animal Care and Use Committee at Wake Forest University Health Sciences. All efforts to minimize the number and suffering of animals

Cocaine produced rapid-onset DA uptake inhibition

To assess the rapidity of cocaine's actions on the DAT, the effects of cocaine on electrically evoked DA uptake and peak height were measured within the NAc of rats receiving a 2 s, i.v. bolus of cocaine (0.75 mg/kg n=8, 1.5 mg/kg n=8, and 3.0 mg/kg n=8) or saline (0.6 ml/kg n=6). Prior to saline or drug administration, electrically evoked DA uptake and peak height parameters were stable and remained at baseline levels following saline injections (uptake, F(1,29)=0.86, P<0.36; peak height, F

Discussion

The current studies demonstrate that i.v. cocaine elicits robust, dose-dependent DA uptake inhibition within 5 s of injection. Maximal levels of uptake inhibition were observed within 30 s of injection and returned to baseline levels in approximately 1 h. This effect of cocaine on DA uptake followed a similar time course to the brain levels of cocaine measured by PET imaging in humans and baboons (Fowler et al 1989, Fowler et al 1998).

Previous neurochemical studies have indicated that i.p.

Acknowledgments

We would like to thank Dr. Evgeny A. Budygin and Joanne K. Konstantopoulos for their expert technical and theoretical advice. This study was supported by P50 DA06634-16 (D.C.S.R.) and R01 DA021325 (S.R.J).

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