Persistent neuroadaptations in the nucleus accumbens core accompany incubation of methamphetamine craving in male and female rats.

Relapse is a major problem in treating methamphetamine use disorder. 'Incubation of craving' during abstinence is a rat model for persistence of vulnerability to craving and relapse. While methamphetamine incubation has previously been demonstrated in male and female rats, it has not been demonstrated after withdrawal periods greater than 51 days and most mechanistic work used males. Here we address both gaps. First, although methamphetamine intake was higher in males during self-administration training (6 h/day x 10 days), incubation was similar in males and females, with 'incubated' craving persisting through withdrawal day (WD) 100. Second, using whole-cell patch-clamp recordings in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) core, we assessed synaptic levels of calcium-permeable AMPA receptors (CP-AMPARs), as their elevation is required for expression of incubation in males. In both sexes, compared to saline-self-administering controls, CP-AMPAR levels were significantly higher in methamphetamine rats across withdrawal, although this was less pronounced in WD100-135 rats than WD15-35 or WD40-75 methamphetamine rats. We also examined membrane properties and NMDA receptor transmission. In saline controls, MSNs from males exhibited lower excitability than females. This difference was eliminated after incubation due to increased excitability of MSNs from males. NMDAR transmission did not differ between sexes and was not altered after incubation. In conclusion, incubation persists for longer than previously described and equally persistent CP-AMPAR plasticity in NAc core occurs in both sexes. Thus, abstinence-related synaptic plasticity in NAc is similar in males and females even though other methamphetamine-related behaviors and neuroadaptations show differences. Significance To study the persistence of vulnerability to methamphetamine craving and relapse during abstinence, we use the 'incubation of craving' model. While incubation of methamphetamine craving has been demonstrated previously in male and female rats, most mechanistic work has used male rats and incubation has only been demonstrated through 51 days of abstinence. Here we show that incubation of methamphetamine craving persists in both sexes for at least 100 days and that an underlying mechanism previously described in males (elevation of synaptic CP-AMPARs in medium spiny neurons of the nucleus accumbens core) occurs in females as well and persists alongside incubation. Thus, a relatively limited period of methamphetamine experience produces extremely long-lasting vulnerability to craving and relapse.