Cocaine reward models: Conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice

Abstract

Cocaine and methylphenidate block uptake by neuronal plasma membrane transporters for dopamine, serotonin, and norepinephrine. Cocaine also blocks voltagegated sodium channels, a property not shared by methylphenidate. Several lines of evidence have suggested that cocaine blockade of the dopamine transporter (DAT), perhaps with additional contributions from serotonin transporter (5-HTT) recognition, was key to its rewarding actions. We now report that knockout mice without DAT and mice without 5-HTT establish cocaine-conditioned place preferences. Each strain displays cocaine-conditioned place preference in this major mouse model for assessing drug reward, while methylphenidate-conditioned place preference is also maintained in DAT knockout mice. These results have substantial implications for understanding cocaine actions and for strategies to produce anticocaine medications.Cocaine use is a principal drug abuse problem in the United States and other countries, contributing to substantial morbidity and mortality among the millions of individuals who use it each year (1). No current medication provides effective treatment for cocaine dependence (2). These facts give particular importance to defining the sites for cocaine reward in the brain so that they can be more accurately targeted by potential therapeutic agents.Several lines of evidence have provided support for a role of the dopamine transporter (DAT) as a primary site for cocaine reward. Structure-activity studies document good correlations between psychostimulant properties in tests of reward and their abilities to block DAT; poorer correlations are noted with their potencies in blocking other transporters (3, 4). Dopaminergic lesions blunt cocaine influences in model systems that test reward (5-7). Psychostimulants enhance dopamine release from dopaminergic circuits (8). Transgenic mice that overexpress DAT display enhanced cocaine-conditioned place preference (G.R.U., et al., unpublished observations). Finally, ''indifference'' to cocaine has been inferred from the reduced cocaine-stimulated locomotion recently described in mice that lack DAT (9, 10).There are also limitations to postulated direct relationships between DAT blockade and psychostimulant-induced reward. Among these are the failure of several compounds that potently inhibit dopamine uptake, including mazindol, to display substantial abuse liability in humans or animal model studies (11-13). Because mazindol potently inhibits dopamine and norepinephrine transport, but only weakly inhibits serotonin transport, this difference from cocaine could conceivably contribute to a distinct profile on tests of reward (14-16). These and other more indirect lines of evidence support the idea that cocaine's inhibition of serotonin uptake could also provide an alternative and plausible molecular site for contributions to cocaine reward (17)(18)(19).To test the dopamine-or serotonin-transporter dependence of cocaine reward, we have constructed DAT knockout mice and assessed cocaine-conditioned plac...

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

“…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). Here, we show that their spatial navigation and motivation are spared: DAT-KO mice actively search for the platform, climb on it as soon as they find it, and do not exhibit any floating behavior.…”

Behavioral Electrophysiology of Psychostimulants

“…For example, the euphoria induced by cocaine in experienced users is resistant to DA receptor blockade (Sherer et al, 1989), and mice lacking the DA transporter show both self-administration behavior and conditioned place preference to cocaine (Rocha et al, 1998;Sora et al, 1998). It is interesting, therefore, that iontophoresis of cocaine in alert rats inhibits striatal neurons, but unlike amphetamine iontophoresis, this inhibitory response is not blocked by DA receptor antagonists .…”

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

“…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).…”