Sensitization of Rapid Dopamine Signaling in the Nucleus Accumbens Core and Shell After Repeated Cocaine in Rats

Abstract

Addy NA, Daberkow DP, Ford JN, Garris PA, Wightman RM. Sensitization of rapid dopamine signaling in the nucleus accumbens core and shell after repeated cocaine in rats. J Neurophysiol 104: 922-931, 2010. First published June 16, 2010 doi:10.1152/jn.00413.2010. Repeated cocaine exposure and withdrawal leads to long-term changes, including behavioral and dopamine sensitization to an acute cocaine challenge, that are most pronounced after long withdrawal periods. However, the changes in dopamine neurotransmission after short withdrawal periods are less well defined. To study dopamine neurotransmission after 1-day withdrawal, we used fast-scan cyclic voltammetry (FSCV) to determine whether repeated cocaine alters rapid dopamine release and uptake in the nucleus accumbens (NAc) core and shell. FSCV was performed in urethane anesthetized male Sprague-Dawley rats that had previously received one or seven daily injections of saline or cocaine (15 mg/kg, ip). In response to acute cocaine, subjects showed increased dopamine overflow that resulted from both increased dopamine release and slowed dopamine uptake. One-day cocaine preexposure, however, did not alter dopaminergic responses to a subsequent cocaine challenge. In contrast, 7-day cocaine-treated subjects showed a potentiated rapid dopamine response in both the core and shell after an acute cocaine challenge. In addition, kinetic analysis during the cocaine challenge showed a greater increase in apparent K m of 7-day cocaine exposed subjects. Together, the data provide the first in vivo demonstration of rapid dopamine sensitization in the NAc core and shell after a short withdrawal period. In addition, the data clearly delineate cocaine's release and uptake effects and suggest that the observed sensitization results from greater uptake inhibition in cocaine pre-exposed subjects. I N T R O D U C T I O NCocaine acts in the brain to slow dopamine uptake through inhibition of the dopamine transporter (DAT) (Ritz et al. 1987) and thus increases the amount of time that dopamine is present in the extraneuronal space. Cocaine's ability to increase dopamine overflow, particularly in the nucleus accumbens (NAc), has been shown to play an important role in several models of addiction (Goeders and Smith 1983;Kalivas and Duffy 1993a;Ritz et al. 1988;Rodd-Henricks et al. 2002). Specifically, dopaminergic mechanisms in the NAc shell have been shown to alter motivation for rewards such as cocaine, whereas dopamine in the NA core is important for goal-directed behavior (Ikemoto 2007; Ito et al. 2000 Ito et al. , 2004. In addition, repeated cocaine administration also leads to a progressive, or sensitized, increase of dopamine overflow (Heidbreder et al. 1996; Kalivas and Duffy 1993a,b) because of changes in the brain (Vanderschuren and Kalivas 2000;Wolf 1998). Specifically, cocaine has been shown to alter synaptic plasticity (Argilli et al. 2008; Borgland et al. 2004;Saal et al. 2003) and to modulate second messenger signaling proteins implicated in neuronal plasticity (Bibb e...

Phasic Mesolimbic Dopamine Signaling Encodes the Facilitation of Incentive Motivation Produced by Repeated Cocaine Exposure

“…Such alterations in DA release may be the product of long-term adaptations in the mesolimbic DA system caused by repeated cocaine intake (Addy et al, 2010;Cass et al, 1993;Chen et al, 2008;Izenwasser and Cox, 1990;Kalivas and Duffy, 1990;Pettit et al, 1990). That said, drugassociated situational cues are known to alter DA system activity (Duvauchelle et al, 2000;Weitemier and Murphy, 2009) and expression of voluntary reward-seeking actions (Ostlund et al, 2010;Xie et al, 2012), and this raises the possibility that cocaine-induced learning contributed to the effects described here.…”

Temporal Pattern of Cocaine Intake Determines Tolerance vs Sensitization of Cocaine Effects at the Dopamine Transporter

“…An extensive literature, primarily using daily experimenteradministered intraperitoneal injections has documented neurochemical sensitization associated with the mesolimbic DA system Duffy, 1990, 1993;Parsons and Justice, 1993;Addy et al, 2010). Sensitization of cocaineinduced increases in extracellular DA has been linked not only to alterations in the regulation of DA release and reuptake (Jones et al, 1996;Addy et al, 2010), but also to influences such as glutamate (for a review, see Vanderschuren and Kalivas, 2000), GABA (for a review, see Steketee, 2005;Filip et al, 2006), and serotonin (Neumaier et al, 2002;Filip et al, 2010). By contrast, studies using self-administration procedures have generally shown tolerance to cocaine's DA-elevating and DAT-inhibiting effects.…”

Intermittent Cocaine Self-Administration Produces Sensitization of Stimulant Effects at the Dopamine Transporter

“…Conversely, intermittent-access (IntA) self-administration, where animals are given time-outs to force self-administration patterns that result in sharp increases in cocaine levels followed by rapid decreases, results in sensitized cocaine potency at the DAT. Sensitization and tolerance of cocaine potency following intermittent and continuous administration have been demonstrated using self-administration (Calipari et al, 2013c) and with noncontingent administration of intermittent (intraperitoneal injections) and continuous (mini-pumps) regimens of cocaine exposure (Addy et al, 2010). Although the effects of cocaine at the DAT are well established following a number of paradigms, how these cocaine self-administration protocols affect the potency of other psychostimulants, and what factors dictate the expression of tolerance/sensitization, remains to be determined.…”