Dramatically Decreased Cocaine Self-Administration in Dopamine But Not Serotonin Transporter Knock-Out Mice

Abstract

There has been much interest in the relative importance of dopamine and serotonin transporters in the abuse-related-effects of cocaine. We tested the hypotheses that mice lacking the dopamine transporter (DAT Ϫ/Ϫ ), the serotonin transporter (SERT Ϫ/Ϫ ), or both (DAT Ϫ/Ϫ SERT Ϫ/Ϫ ) exhibit decreased reinforcing effects of cocaine. We also assessed whether observed effects on selfadministration are specific to cocaine or if operant behavior maintained by food or a direct dopamine agonist are similarly affected. We used a broad range of experimental conditions that included acquisition without previous training, behavior established with food training and subsequent testing with food, cocaine or a direct dopamine agonist as reinforcers, fixed ratio and progressive ratio schedules of reinforcement, and a reversal procedure. Wild-type mice readily acquired cocaine self-administration and showed dose-response curves characteristic of the schedule of reinforcement that was used. While some DAT Ϫ/Ϫ mice appeared to acquire cocaine selfadministration transiently, almost all DAT Ϫ/Ϫ mice failed to self-administer cocaine reliably. Food-maintained behaviors were not decreased by the DAT mutation, and IV self-administration of a direct dopamine agonist was robust in the DAT Ϫ/Ϫ mice. In contrast to those mice, cocaine's reinforcing effects were not diminished in SERT Ϫ/Ϫ mice under any of the conditions tested, except for impaired initial acquisition of both food-and cocaine-maintained behavior. These findings support the notion that the DAT, but not the SERT, is critical in mediating the reinforcing effects of cocaine.

Lack of Cocaine Self-Administration in Mice Expressing a Cocaine-Insensitive Dopamine Transporter

“…Increased SERT blockade has been associated with decreased reinforcing value and/or a rate-decreasing effect on operant behavior in general (Peltier and Schenk, 1993;Roberts et al, 1999;Czoty et al, 2002;Wee et al, 2005). It was suggested that SERT blockade contributes to aversive effects of cocaine based on increased cocaine-conditioned place preferences in SERT knockout mice (Sora et al, 1998), although we found no difference in cocaine self-administration between SERT knockout and wild-type mice with use of a wide range of conditions (Thomsen et al, 2009). Conditioned taste aversion studies using relatively selective monoamine transporters in rats supported a critical involvement of NET blockade in cocaine's aversive effects (Freeman et al, 2005; Serafine and Riley, 2009).…”

“…However, the DATϪ/Ϫ mice have profound compensatory changes in dopamine homeostasis (e.g., delayed clearance of extracellular dopamine, reduced total dopamine, decreased dopamine receptor expression; Giros et al, 1996;Jones et al, 1998Jones et al, , 1999, whereas DATki mice show only moderate compensatory changes (Chen et al, 2006). In addition, we found that a separate line of DATϪ/Ϫ mice generally did not self-administer cocaine despite robust responding when reinforced with food or a direct dopamine agonist (Thomsen et al, 2009). The fact that cocaine was observed to increase extracellular dopamine levels in the nucleus accumbens of the line of DATϪ/Ϫ mice shown to self-administer cocaine, but not in the DATki mice (Carboni et al, 2001;Chen et al, 2006), also supports the crucial involvement of the nucleus accumbens in cocaine self-administration (Roberts et al, 1977(Roberts et al, , 1980Pettit et al, 1984;Caine and Koob, 1994).…”

“…However, constitutive knockout of the DAT leads to extensive compensatory changes in monoamine systems, which can complicate the interpretation of results obtained with use of constitutive DATϪ/Ϫ mice (Giros et al, 1996;Jones et al, 1998Jones et al, , 1999. We recently showed that a different line of DATϪ/Ϫ mice generally failed to self-administer cocaine (Thomsen et al, 2009). Those seemingly inconsistent findings illustrate the potential complications that can be associated with classic gene knockout strategies.…”

Impact of adolescent sucrose access on cognitive control, recognition memory, and parvalbumin immunoreactivity

“…However, separate neural mechanisms that underpin self-administration of food and drugs such as cocaine have been observed. Dopamine transporter knockout mice have low rates of cocaine self-administration, but no difference in responding for sucrose (Thomsen et al 2009) and contrasting roles of subsets of NAc neurons have been observed when rats respond for natural or drug rewards (Cameron and Carelli 2012). Furthermore, chronic exposure to drugs of abuse is associated with deficits in cognitive function and behavioral control (Nelson and Killcross 2006;Parsegian et al 2011;Porter et al 2011).…”

On the speed of cocaine

“…Dopamine uptake inhibitors that are injected locally in this dopamine terminal field are unlikely to influence dopamine impulse flow. He also neglects to mention the recent evidence that cocaine is not rewarding in mice that lack the dopamine transporter 11 . More importantly, Aragona offers no suggestion as to the mechanism that underlies the increased dopamine transients that he observes.…”