Effects of cocaine on sodium dependent dopamine uptake in rat striatal synaptosomes

Abstract

Initial velocity of uptake of dopamine (DA) has been measured in the presence of 1 microM cocaine as a function of both [DA] and [Na]. Although DA uptake is overwhelmingly dependent on sodium, it appears that a small amount of DA uptake takes place in the absence of sodium. This contrasts with a previous study of the sodium dependence of uptake without cocaine (referred to below as control), in which uptake was found to be 100% sodium dependent. The data were fitted to several rapid equilibrium models and the minimal best fit model identified. The interaction of transporter (C), DA (S), and Na+ (Na) in this present model is identical to the reaction scheme found previously to fit control data (no cocaine). Whereas the control model required translocation only as CNa2S, in the presence of cocaine (I), two additional translocated species are required to fit the data (CS and CNaS). Another previous study of the interaction of carrier and cocaine at a constant [Na]0 predicted that cocaine interacts with a transporter site other than the DA binding site and that uptake takes place as CS and CSI. The present results are consistent with the assumption that the CS and CNaS forms of the present model are actually CSI and CNaSI, since they are required to fit a model of the sodium dependence in the presence of cocaine, but are not required in the absence of cocaine.

A Multisubstrate Kinetic Mechanism of Dopamine Transport in the Nucleus Accumbens and Its Inhibition by Cocaine

“…Thus, cocaine should produce different effects on dopaminergic chemical neurotransmission in the two areas. In the striatum the cocaine-dependent alterations in the kinetic activity of the dopamine transporter are dependent on the extracellular levels of doparnine (McElvain and Schenk, 1992;Wheeler et a!., 1994), whereas in the NAcc they are not (Missa!e et a!., 1985; present study). In addition, the K, for inhibition of transporter activity is smaller in the NAcc than the striatum, in qualitative agreement with the results of Cass et al (1993).…”

Modeling of the Interaction of Na+ and K+ with theBinding of Dopamine and [3H]WIN 35,428 to the Human Dopamine Transporter

“…This would be similar to the recently observed Na + independence of serotonin transport by the Ser 545 Ala mutant of the SERT, which is postulated to be in the activated conformation for serotonin binding so that Li + can replace Na + in the translocation step (Sur et al, 1997). The results on cocaine inhibition of DAT‐mediated leak currents in 0 Na + medium (Sonders et al, 1997) suggest a site different from the Na + site advanced by McElvain and Schenk (1992) and Wheeler et al (1994) for the inhibition of DAT function by cocaine. Normally, Na + binding is required for DA translocation.…”

RTI-76, an isothiocyanate derivative of a phenyltropane cocaine analog, as a tool for irreversibly inactivating dopamine transporter function in vitro

“…Although inhibition of dopamine uptake by cocaine via the neuronal dopamine transporter in the striatum and nucleus accumbens has been reported to be of a non-or uncompetitive type (Missale et al 1985;McElvain and Schenk 1992;Wheeler et al 1994;Povlock and Schenk 1997), most studies indicate a competitive mechanism (Richelson and Pfenning 1984;Andersen 1989;Cao et al 1989;Krueger 1990;Jones et al 1995;Xu et al 1995;Reith et al 1996a;Garris et al 1998;Wu et al 1998;Eshleman et al 1999). If indeed the mechanism is competitive, there is likely to be a one-to-one relationship between cocaine binding sites and dopamine recognition sites, i.e.…”