u-0126 and Cocaine-Related-Disorders

The reconsolidation of cocaine memories following retrieval is necessary for the sustained ability of a cocaine-paired environmental context to elicit cocaine seeking. Extracellular signal-regulated kinase (ERK) is an intracellular signaling molecule involved in nucleus accumbens core (NACc)-mediated reconsolidation of Pavlovian cocaine memories. Here, we used a rodent model of drug context-elicited relapse to test the hypothesis that ERK would be similarly required for the reconsolidation of context-response-cocaine memories that underlie drug context-induced reinstatement of instrumental cocaine-seeking behavior, with a focus on the NACc and on the basolateral amygdala (BLA), another important locus for the reconsolidation of cocaine memories. We show that the mitogen-activated protein kinase (MEK)/ERK1/2 inhibitor, U0126 (1.0 μg/0.5 μl/hemisphere), microinfused bilaterally into the BLA--but not the NACc--immediately after brief re-exposure to a previously cocaine-paired context (that is, cocaine-memory reactivation), significantly attenuated subsequent drug context-induced cocaine seeking relative to vehicle (VEH). This effect in the BLA was associated with a transient inhibition of ERK1/2 phosphorylation, and it depended on memory reactivation given that U0126 administered following exposure to a novel context did not alter subsequent cocaine seeking. Furthermore, similar to U0126, baclofen+muscimol-induced (B+M; 106.8/5.7 ng/0.5 μl/hemisphere) neural inactivation of the NACc, following cocaine-memory reactivation, failed to alter subsequent cocaine seeking. These findings demonstrate that ERK activation in the BLA, but not the NACc, is required for the reconsolidation of context-response-cocaine associative memories. Together with prior research, these results suggest that contextual drug-memory reconsolidation in Pavlovian and instrumental settings involves distinct neuroanatomical mechanisms.

Topics: Amygdala; Animals; Baclofen; Butadienes; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors; Extinction, Psychological; Extracellular Signal-Regulated MAP Kinases; GABA-B Receptor Agonists; Male; Memory; Muscimol; Nitriles; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Reinforcement Schedule; Self Administration; Signal Transduction

Cocaine-induced changes in glutamatergic synaptic transmission in the ventral tegmental area (VTA) and the nucleus accumbens (NAc) play a key role in cocaine behavioral effects. Activation of ionotropic glutamate receptor NMDA receptor (NMDAR) in the VTA is critical for the development of cocaine psychomotor sensitization. However, the role of NMDAR in the NAc, a brain area critical for the expression of cocaine psychomotor sensitization, remains to be explored. Here, we show that repeated noncontingent cocaine injections increased NAc NMDAR subunits, NR1, NR2A, and NR2B 21 d, but not 1 d, after withdrawal from cocaine. These changes were associated with an increase in the GluR1 subunit of the AMPA receptor. We also found a time-dependent increase in extracellular signal-regulated kinase (ERK) activity which correlated with the increased expression of NMDAR subunits. Furthermore, the increase in GluR1 and ERK activity was blocked after inhibition of NR2B-containing NMDAR during the development of cocaine psychomotor sensitization or when the MEK (mitogen-activated protein/ERK kinase) inhibitor was microinjected into the NAc 21 d after withdrawal from cocaine. Together, these results suggest that the development of cocaine psychomotor sensitization triggers a delayed increase in the expression of NMDAR subunits in the NAc, which in turn enhances the activity of ERK. Enhanced ERK activity drives the increased expression of the GluR1 subunits, which increases the excitability of NAc neurons after prolonged withdrawal from cocaine and results in enduring expression of psychomotor sensitization.

Topics: Analysis of Variance; Animals; Butadienes; Cocaine; Cocaine-Related Disorders; Disease Models, Animal; Dopamine Uptake Inhibitors; Drug Administration Schedule; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Locomotion; Male; Nitriles; Nucleus Accumbens; Piperidines; Psychomotor Performance; Rats; Receptors, N-Methyl-D-Aspartate; Subcellular Fractions; Time Factors

Using a rat model of craving and relapse, we have previously found time-dependent increases in cue-induced cocaine seeking over the first months of withdrawal from cocaine, suggesting that drug craving incubates over time. Here, we explored the role of the amygdala extracellular signal-regulated kinase (ERK) signaling pathway in this incubation. Cocaine seeking induced by exposure to cocaine cues was substantially higher after 30 withdrawal days than after 1 withdrawal day. Exposure to these cues increased ERK phosphorylation in the central, but not the basolateral, amygdala after 30 d, but not 1 d, of withdrawal. After 30 d of withdrawal from cocaine, inhibition of central, but not basolateral, amygdala ERK phosphorylation decreased cocaine seeking. After 1 d of withdrawal, stimulation of central amygdala ERK phosphorylation increased cocaine seeking. Results suggest that the incubation of cocaine craving is mediated by time-dependent increases in the responsiveness of the central amygdala ERK pathway to cocaine cues.

Topics: Amygdala; Anesthetics, Local; Animals; Behavior, Addictive; Behavior, Animal; Blotting, Western; Butadienes; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Cues; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Extinction, Psychological; Extracellular Signal-Regulated MAP Kinases; Food; Injections, Intravenous; Male; N-Methylaspartate; Nitriles; Phosphorylation; Rats; Rats, Long-Evans; Reinforcement, Psychology; Self Administration; Signal Transduction; Substance Withdrawal Syndrome; Time Factors