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

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 intravenous (i.v.) cocaine inhibits DA uptake within 5 sec. 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, 1-(2-bis(4-fluorphenyl)-methoxy)-ethyl)-4-(3-phenyl-propyl)piperazine (GBR-12909). 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 sec. DA uptake inhibition peaked at 30 sec and returned to baseline levels in approximately one hour. The effects of cocaine were dosedependent, 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 impermiant cocainemethiodide 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 sec postinjection, although the peak effect and return to baseline were markedly delayed compared to 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.Keywords nucleus accumbens; onset; cocaine methiodide; fast scan cyclic voltammetry; ratThe subjective effects of cocaine have been reported to begin within seconds of administration (Seecof and Tennant 1986;Evans et al., 1996;Zernig et al., 2003). Although it is well established that cocaine increases extracellular dopamine (DA) via inhibitory actions on the DA transporter (DAT), it remains unclear whether there is a direct relationship between DAT blockade and the rapid subjective reinforcing affects of cocaine (Koob and Bloom, 1988;Kuhar et al., 1991;Wise et al., 1995;Volkow et al., 1997). Slow and long-acting DAT inhibition has been associated with poor reinforcing effects, while rapid and short-acting DAT inhibition has Correspondence: Sara R. Jones, Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157, Office:336-716-8533, Fax: 336-716-8501, E-mail: srjones@wfubmc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting...

Reinforcing Doses of Intravenous Cocaine Produce Only Modest Dopamine Uptake Inhibition

“…We calculated DA uptake inhibition by measuring tau at baseline and comparing this to tau following cocaine delivery. Similar to our previous reports 28 , examination of the time course of cocaine effects indicated that peak uptake inhibition was reached between 30 and 60 sec post-injection (Supplementary Table I). We used the peak uptake inhibition value for all subsequent analyses.…”

“…Thus, one possibility is that differences in DA uptake inhibition and DAT occupancy may be a result of changes in DAT inhibition that occur within the first 5 min after cocaine injections. This is an unlikely explanation, however, because although DA uptake inhibition peaks within 30–60 seconds post injection, the decrease in uptake inhibition that occurs over the first 5 min post-injection is not significant 28, 33, 47 . The modest change in DA uptake inhibition across the first 5 min post-injection, thus, cannot account for the large discrepancy observed between reports of DAT occupancy and the levels of functional uptake inhibition observed in the current studies.…”

Dopamine Uptake Inhibitors but Not Dopamine Releasers Induce Greater Increases in Motor Behavior and Extracellular Dopamine in Adolescent Rats Than in Adult Male Rats

“…There is good correlation between the effects of cocaine on electrically stimulated dopamine efflux in anesthetized rats and spontaneous release and uptake events in awake rats (Greco and Garris, 2003;Españ a et al, 2008). Michaelis-Menten parameters for uptake are not different in anesthetized and awake rats .…”

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

“…Several other ligands such as GBR-12909, PTT [2β-propanoyl-3β-(4-tolyl)-tropane], and RTI (Research Triangle Institute) compounds (3-phenyltropane analogs) have been previously thought to be 'slow-onset long-acting' DAT inhibitors (Howell and Wilcox, 2001;Rothman et al, 2008). However, in vivo microdialysis and fast-cyclic voltammetry studies suggest that they are actually fast-onset (Espana et al, 2008) and have only slightly longer durations of action than cocaine (2-3 h vs 1-2 h) with respect to enhanced extracellular nucleus accumbens (NAc) DA (Baumann et al, 1994;Budygin et al, 2000;Kimmel et al, 2008;Kimmel et al, 2007;Nakachi et al, 1995). These data suggest that such DAT inhibitors may have similar addictive potential as cocaine.…”