Research ReportOne hour, but not six hours, of daily access to self-administered cocaine results in elevated levels of the dopamine transporter
Introduction
Every year, about three million Americans use cocaine at least once, many of them teenagers. Of these, roughly 6% will become addicted in the span of 2 years (Banken, 2004, Chen and Kandel, 2002, O’Brien and Anthony, 2005, Sloboda, 2002). While our knowledge regarding the neuronal substrates that support cocaine self-administration and the neuroadaptations that accompany limited use of cocaine has advanced tremendously in the last few decades, the changes that mediate the transition from limited, controlled cocaine administration to escalated, uncontrolled cocaine administration are still largely unknown. In order to study these changes, we adopted a model in which rats are given either brief daily access to cocaine and show stable pattern of cocaine administration, or extended daily access to cocaine and show an escalated pattern of cocaine self-administration (Ahmed and Koob, 1998, Ben-Shahar et al., 2004). We reasoned that looking at the differences between these two groups, and comparing them to control animals that receive access to saline alone, will advance our knowledge about the neuroadaptations that mediate the transition from drug naïve (our saline control animals) to recreational drug use (the brief 1 h/day access group), and from recreational drug use to addiction (the extended 6 h/day access condition).
We previously found that after 14 days of withdrawal, rats from the brief access group showed a sensitized locomotor response and elevated c-Fos reactivity to self-administered cocaine challenge. In contrast, extended daily access to cocaine did not produce such sensitized responses, but rather induced locomotor and immunoreactive c-Fos responses to the self-administered cocaine challenge that were not different from those of saline control animals (Ben-Shahar et al., 2004). These results support the notion that the brief and extended access conditions result in qualitatively different neuroadaptations and that the transition to addiction likely involves changes in brain function that either counteract, or are simply different from, those associated with recreational drug use. The current project sought to continue exploring the differences and changes in brain function that are associated with these two conditions of drug access.
Cocaine binds to catecholamine transporters and to muscarinic and sigma receptors in the central nervous system. However, it was shown that cocaine's ability to bind to the dopaminergic transporter (DAT) is critical for its reinforcing effects (Ritz et al., 1987, Ritz et al., 1988). Similarly, in human cocaine addicts, it was found that cocaine induced-euphoria was correlated with levels of DAT occupancy by cocaine (Volkow et al., 1996a, Volkow et al., 1996b, Volkow et al., 1997). We therefore chose to monitor changes in the function of the DAT as reflected by changes in binding, in order to further examine the neuroadaptations that mediate the transition from recreational to escalated compulsive drug use. More specifically, in the current project, we monitored levels of the DAT in saline control (Sal group), brief 1-h access (Coc1h group), and extended 6-h access animals (Coc6h group) after 14 days of withdrawal.
Section snippets
Self-administration
As expected, self-administration rates of the saline control animals (n = 6) were very low (5 lever-presses/infusions per session on average). Coc1h (n = 6) animals exhibited stable self-administration patterns and showed no change in self-administration rates between the first and last day of the 8-day period (consuming on average 3.7 ± 0.2 mg on the first day and 4.1 ± 0.4 mg on the last day; see Fig. 1, panel A or B). Coc6h (n = 5) animals showed increased rates of self-administration (i.e.,
Discussion
Extended 6-h daily access to self-administered cocaine resulted in escalated drug use, whereas brief 1-h access yielded stable consumption, as shown before (Ahmed and Koob, 1998, Ben-Shahar et al., 2004, Ben-Shahar et al., 2005). After 14 days of withdrawal, DAT levels in the N.Acc core and dorsal striatum were higher in the brief access condition relative to both 6-h access and saline control animals, where DAT levels were similar. These data parallel our previous results, in that the 1-h
Subjects
The subjects (n = 24, 17 of which finished the experiment) were male albino Sprague–Dawley rats weighing 300–350 g at the beginning of the experiment obtained from Charles River Laboratories (Hollister, CA). The animals were housed individually in wire-hanging cages located within a temperature-controlled (22 °C), 12/12 h light/dark cycle (lights on at 0700) vivarium located in the Psychology Department at UCSB. Subjects had ad libitum access to food and water, except during operant training
Acknowledgments
This work was supported by National Institute of Drug Abuse grant DA017104 awarded to OBS and by grant DA05041 awarded to AE.
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2012, Pharmacology Biochemistry and BehaviorCitation Excerpt :For example, a significant increase in the proportion of high affinity DA D2 receptors in the dorsal striatum was seen at both 3 and 30 days of abstinence after cocaine self-administration (Briand et al., 2008). Further, increased DA transporter (DAT) binding in the dorsal striatum has been demonstrated following cocaine self-administration after 4 h (Wilson et al., 1994) or 14 days of abstinence (Ben-Shahar et al., 2006) as well as increased DAT surface expression in the dorsal striatum following three weeks of abstinence (Samuvel et al., 2008). Such changes in D2 receptor affinity states and DAT binding following cocaine self-administration and abstinence may impact dorsal striatum DA release in the presence of cocaine or cocaine associated cues.