CaMKII inhibition within the prelimbic cortex blunts incubated methamphetamine craving

Drug-associated cues are powerful drivers of drug craving that can lead to relapse in individuals with psychomotor stimulant use disorder. In both humans and laboratory rodent models, cue-elicited craving intensifies over the first 3-6 months into drug abstinence. This phenomenon is termed the incubation of craving and represents a relatively prolonged period of time during which drug-abstinent individuals are particularly vulnerable to craving-induced relapse. Currently, there exists no pharmacotherapy for reducing stimulant craving, let alone its incubation during protracted withdrawal. In humans, cue-elicited stimulant craving is associated with increased activity within the prefrontal cortex and previous studies by our group identified an increase in the activational state of calcium/calmodulin-dependent kinase II alpha (CaMKII) in the prelimbic subregion of the prefrontal cortex as necessary for the expression of incubated cocaine-craving in rats. To determine whether CaMKII within the prelimbic cortex is also necessary for the expression of incubated methamphetamine-craving, rats were surgically fitted with intravenous catheters and indwelling bilateral guide cannulae over the prelimbic cortex. Following 10 days methamphetamine self-administration (0.1 mg/ml; 6 h/day), rats were left undisturbed in their home cage for a period of 30 days. Rats were then infused with either vehicle or the CaMKII inhibitor myr-AIP (10 pg/side) and tested for cue-induced craving for 30 min. Relative to rats tested on withdrawal day 1 (WD1), vehicle-infused rats tested on WD30 exhibited higher cue-elicited drug-seeking, indicative of incubated craving. myr-AIP reduced the magnitude of this incubated methamphetamine-seeking, providing evidence that CaMKII activation within the prelimbic cortex is necessary for driving incubated methamphetamine-craving. Taken together with our prior cocaine study, these results argue that CaMKII hyperactivation within the prelimbic cortex may be a common driver of incubated stimulant-craving, the targeting of which may prove effective at mitigating cue super-reactivity during protracted withdrawal to promote recovery.