Cocaine self-administration in dopamine-transporter knockout mice

Abstract

The plasma membrane dopamine transporter (DAT) is responsible for clearing dopamine from the synapse. Cocaine blockade of DAT leads to increased extracellular dopamine, an effect widely considered to be the primary cause of the reinforcing and addictive properties of cocaine. In this study we tested whether these properties are limited to the dopaminergic system in mice lacking DAT. In the absence of DAT, these mice exhibit high levels of extracellular dopamine, but paradoxically still self-administer cocaine. Mapping of the sites of cocaine binding and neuronal activation suggests an involvement of serotonergic brain regions in this response. These results demonstrate that the interaction of cocaine with targets other than DAT, possibly the serotonin transporter, can initiate and sustain cocaine self-administration in these mice.

Parallel Loss of Hippocampal LTD and Cognitive Flexibility in a Genetic Model of Hyperdopaminergia

“…Moreover, they do not exhibit a general defect in learning. In a self-administration paradigm, where food is used as a reinforcer, DAT-KO mice are able to learn an operant behavior within the same training sessions as controls (Rocha et al, 1998). Similarly, KO mice are able to discriminate olfactory stimuli, and show no deficits in associative learning as tested in the place preference test (Sora et al, 1998;Rodriguiz et al, 2004).…”

The effects of cocaine on regional brain glucose metabolism is attenuated in dopamine transporter knockout mice

“…However, in interpreting the hyperdopaminergic state in DAT −/− mice one needs to consider potential compensatory responses in other neurotransmitter systems (i.e. NE or 5HT), which may have an impact on brain glucose metabolism (Rocha et al, 1998). Indeed, disulfiram, which is an inhibitor of the NE biosynthetic enzyme dopamine betahydroxylase, has demonstrated promising efficacy in the treatment of cocaine dependence in preliminary clinical trials (Weinshenker and Schroeder, 2007) and 5HT receptor-specific pharmacological compounds have been shown to reduce addictive properties of cocaine (Bubar and Cunningham, 2006).…”

“…Microdialysis studies have reported significantly greater extracellular DA in DAT −/− mice than in DAT +/+ mice in the striatum and nucleus accumbens with estimates that the lifetime extracellular DA in DAT −/− mice is 300 times greater than in DAT +/+ littermates (Gainetdinov and Caron, 2003). Contrary to expected, while DAT −/− mice are resistant to cocaine's locomotor effects (Giros et al, 1996) they are sensitive to its rewarding effects (Rocha et al, 1998;Sora et al, 2001;Sora et al, 1998). Although these results led some to question the role of DAT in cocaine's reinforcing effects, the recent findings that cocaine's rewarding effects were abolished in transgenic mice with cocaine-insensitive DAT demonstrate the necessary role of DAT in cocaine's rewarding effects (Chen et al, 2006).…”

Extinction of Cocaine Self-Administration Produces a Differential Time-Related Regulation of Proenkephalin Gene Expression in Rat Brain

“…This behavioral effect is produced primarily by inhibition of dopamine uptake, thereby increasing extracellular concentrations of released dopamine (Ritz et al 1987; for a review see Kuhar et al 1991;Spanagel and Weiss 1999). However, a recent study using mice lacking dopamine transporter proposed other mechanisms, such as increases in serotonin transmission, may mediate the reinforcing effects of cocaine (Rocha et al 1998).…”

“…This behavioral effect is produced primarily by inhibition of dopamine uptake, thereby increasing extracellular concentrations of released dopamine (Ritz et al 1987; for a review see Kuhar et al 1991;Spanagel and Weiss 1999). However, a recent study using mice lacking dopamine transporter proposed other mechanisms, such as increases in serotonin transmission, may mediate the reinforcing effects of cocaine (Rocha et al 1998).Several studies have shown that cocaine also affects the expression of opioid peptides and opioid receptors. For example, chronic cocaine administration leads to increases in circulating ␤ -endorphin levels (Moldow and Fischman 1987), striatal preprodynorphin mRNA levels (Hurd et al 1992;Daunais et al 1993;Daunais and McGinty, 1995;Spangler et al 1993Spangler et al , 1996Spangler et al , 1997, and striatonigral dynorphin content (Sivam 1989;Smiley et al 1990) in rats and to decreases in preproenkephalin mRNA levels in rhesus monkeys (Daunais et al 1997) and humans (Hurd and Herkenham 1993).…”