Cocaine-Induced Adaptations in Cellular Redox Balance Contributes to Enduring Behavioral Plasticity

Abstract

Impaired glutamate homeostasis in the nucleus accumbens has been linked to cocaine relapse in animal models, and results in part from cocaine-induced downregulation of the cystine-glutamate exchanger. In addition to regulating extracellular glutamate, the uptake of cystine by the exchanger is a rate-limiting step in the synthesis of glutathione (GSH). GSH is critical for balancing cellular redox in response to oxidative stress. Cocaine administration induces oxidative stress, and we first determined if downregulated cystineglutamate exchange alters redox homeostasis in rats withdrawn from daily cocaine injections and then challenged with acute cocaine. Among the daily cocaine-induced changes in redox homeostasis were an increase in protein S-glutathionylation and a decrease in expression of GSH-S-transferase pi (GSTpi). To mimic reduced GSTpi, a genetic mouse model of GSTpi deletion or pharmacological inhibition of GSTpi by administering ketoprofen during daily cocaine administration was used. The capacity of cocaine to induce conditioned place preference or locomotor sensitization was augmented, indicating that reducing GSTpi may contribute to cocaineinduced behavioral neuroplasticity. Conversely, an acute cocaine challenge after withdrawal from daily cocaine elicited a marked increase in accumbens GSTpi, and the expression of behavioral sensitization to a cocaine challenge injection was inhibited by ketoprofen pretreatment; supporting a protective effect by the acute cocaine-induced rise in GSTpi. Together, these data indicate that cocaineinduced oxidative stress induces changes in GSTpi that contribute to cocaine-induced behavioral plasticity.

Corticostriatal plasticity, neuronal ensembles, and regulation of drug-seeking behavior

“…In addition to GLT-1, cocaine, but not other addictive drugs, reduces the cystineglutamate exchanger (Baker et al, 2003). Cystine-glutamate exchange involves a one-to-one stoichiometric exchange of intracellular glutamate for extracellular cystine and is rate-limiting in the synthesis of glutathione (GSH) (Uys et al, 2011). Also, a variety of addictive drugs alter signaling through presynaptic metabotropic glutamate 2/3 autoreceptors (mGluR2/3) with a net result of increasing synaptic glutamate release probability in the NAc.…”

Role of Mitochondria on the Neurological Effects of Cocaine

“…Adaptation to oxidative stress may represent a compensatory mechanism against the increase in ROS induced by cocaine. Cocaine-induced adaptation to cellular redox seems to contribute to its enduring behavioral plasticity (Uys et al, 2011).…”

Oxidative Stress and Drugs of Abuse: An Update

“…In addition, adaptations in cellular redox balance induced by cocaine were found to contribute to enduring behavioral plasticity [78] and oxidative stress was found to be involved in cocaine-induced memory and learning impairments in rats, which could be involved in drug toxicity and addiction mechanisms [60]. Another example is the methamphetamine-induced impairment of adult hippocampal neural progenitor proliferation, which may affect learning and memory processes, and was suggested to be mediated by protein nitrotyrosination [182].…”

“…Induction of antioxidant defenses in models of repeated cocaine exposure could also explain the resistance to oxidative agents in these models. Moreover, cocaine-induced adaptations in cellular redox balance were suggested to contribute to enduring behavioral plasticity [78].…”