anisomycin and Cocaine-Related-Disorders

Exposure to drug-associated cues can induce drug craving and relapse in abstinent addicts. Cue-induced craving that progressively intensifies ("incubates") during withdrawal from cocaine has been observed in both rats and humans. Building on recent evidence that aberrant protein translation underlies incubation-related adaptations in the NAc, we used male rats to test the hypothesis that translation is dysregulated during cocaine withdrawal and/or when rats express incubated cocaine craving. We found that intra-NAc infusion of anisomycin, a general protein translation inhibitor, or rapamycin, an inhibitor of mammalian target of rapamycin, reduced the expression of incubated cocaine craving, consistent with previous results showing that inhibition of translation in slices normalized the adaptations that maintain incubation. We then examined signaling pathways involved in protein translation using NAc synaptoneurosomes prepared after >47 d of withdrawal from cocaine or saline self-administration, or after withdrawal plus a cue-induced seeking test. The most robust changes were observed following seeking tests. Most notably, we found that eukaryotic elongation factor 2 (eEF2) and eukaryotic initiation factor 2α (eIF2α) are dephosphorylated when cocaine rats undergo a cue-induced seeking test; both effects are consistent with increased translation during the test. Blocking eIF2α dephosphorylation and thereby restoring its inhibitory influence on translation, via intra-NAc injection of Sal003 just before the test, substantially reduced cocaine seeking. These results are consistent with dysregulation of protein translation in the NAc during cocaine withdrawal, enabling cocaine cues to elicit an aberrant increase in translation that is required for the expression of incubated cocaine craving.

Topics: Animals; Anisomycin; Cocaine-Related Disorders; Craving; Cues; Elongation Factor 2 Kinase; Eukaryotic Initiation Factor-2; Male; MAP Kinase Signaling System; Nucleus Accumbens; Phosphorylation; Prefrontal Cortex; Protein Biosynthesis; Protein Synthesis Inhibitors; Rats; Rats, Sprague-Dawley; Signal Transduction; Substance Withdrawal Syndrome

Exposure to a cocaine-paired context increases the propensity for relapse in cocaine users and prompts cocaine-seeking behavior in rats. According to the reconsolidation hypothesis, upon context re-exposure, established cocaine-related associations are retrieved and can become labile. These associations must undergo reconsolidation into long-term memory to effect enduring stimulus control. The dorsal hippocampus (DH), dorsolateral caudate-putamen and dorsomedial prefrontal cortex are critical for the expression of context-induced cocaine seeking, and these brain regions may also play a role in the reconsolidation of cocaine-related memories that promote this behavior. To test this hypothesis, rats were trained to press a lever for unsignaled cocaine infusions (0.2 mg/infusion, i.v.) in a distinct environmental context (cocaine-paired context), followed by extinction training in a different context (extinction context). Rats were then re-exposed to the cocaine-paired context for 15 min in order to reactivate cocaine-related memories or received comparable exposure to a novel unpaired context. Immediately thereafter, rats received bilateral microinfusions of the protein synthesis inhibitor anisomycin, the sodium channel blocker tetrodotoxin or vehicle into one of the above brain regions. After additional extinction training in the extinction context, reinstatement of cocaine-seeking behavior (i.e., non-reinforced lever presses) was assessed in the cocaine-paired context. Tetrodotoxin, but not anisomycin, administered into the DH inhibited drug context-induced cocaine-seeking behavior in a memory reactivation-dependent manner. Other manipulations failed to alter this behavior. These findings suggest that the DH facilitates the reconsolidation of associative memories that maintain context-induced cocaine-seeking behavior, but it is not the site of anisomycin-sensitive memory restabilization per se.

Topics: Action Potentials; Analysis of Variance; Animals; Anisomycin; Basal Ganglia; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Extinction, Psychological; Hippocampus; Male; Memory; Motor Activity; Neural Conduction; Prefrontal Cortex; Protein Synthesis Inhibitors; Rats; Rats, Sprague-Dawley; Recurrence; Self Administration; Tetrodotoxin

Understanding the neurobiological underpinnings of putative memory stabilization processes that maintain context-response-cocaine associations in long-term memory and underlie contextual control over addictive behavior is of great interest from an addiction treatment perspective. Using an instrumental animal model of contextual drug relapse we show that the protein synthesis inhibitor anisomycin, administered into the basolateral amygdala (BLA) immediately after limited (15- or 60-min) re-exposure to a previously cocaine-paired context, subsequently disrupted the ability of the previously cocaine-paired context to reinstate extinguished cocaine-seeking behavior relative to vehicle. Consistent with a BLA-mediated memory reconsolidation deficit, a similar impairment in cocaine-seeking behavior was not observed in (i) 'no-reactivation' control groups that received anisomycin into the BLA after (re)exposure to either a novel unpaired or an extinction-paired context or in (ii) a neuroanatomical control group that received anisomycin into the posterior caudate-putamen, dorsally adjacent to the BLA, after re-exposure to the cocaine-paired context. Furthermore, anisomycin administered into the BLA after brief (5-min) or extensive (120-min) re-exposure to the cocaine-paired context (which was sufficient to extinguish cocaine-seeking behavior in a vehicle control group) also failed to alter responding. Together, these findings suggest that re-exposure to a cocaine-paired context in the absence of cocaine reinforcement is sufficient to trigger memory reconsolidation processes that support future drug-seeking behavior. The presence and duration of drug-related memory reactivation critically influences, and anisomycin-sensitive mechanisms in the BLA selectively control, this phenomenon. These findings support the feasibility of novel pharmacotherapeutic approaches that selectively inhibit the reconsolidation of cocaine-related memories in order to prevent drug relapse.

Topics: Amygdala; Analysis of Variance; Animals; Anisomycin; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Extinction, Psychological; Male; Memory; Motor Activity; Protein Synthesis Inhibitors; Rats; Rats, Sprague-Dawley; Recurrence; Self Administration