Persistent Neuroadaptations in the Nucleus Accumbens Core Accompany Incubation of Methamphetamine Craving in Male and Female Rats

Abstract

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.SignificanceTo 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.

The estrous cycle has no effect on incubation of methamphetamine craving and associated Fos expression in dorsomedial striatum and anterior intralaminar nucleus of thalamus

“…Regarding incubation of methamphetamine craving, previous studies reported no sex differences in incubation of methamphetamine craving after either forced abstinence [ 10 , 12 , 14 , 26 ] or voluntary abstinence [ 31 , 32 ], similar to incubation studies using heroin [ 31 ] and oxycodone [ 33 ]. These findings are in contrast with previous preclinical studies demonstrating higher cue-induced cocaine seeking in female rats than male rats after forced abstinence [ 34 – 36 ].…”

“…For example, we demonstrated a critical role of dorsal striatum in this incubation in male rats [ 9 ]. A growing number of studies also began to examine neuroadaptations associated with incubation of methamphetamine craving in female rats [ 10 – 17 ], but only one published study has taken estrous cycle into consideration [ 10 ].…”

Neuropharmacological Evidence Implicating Drug-Induced Glutamate Receptor Dysfunction in Affective and Cognitive Sequelae of Subchronic Methamphetamine Self-Administration in Mice

“…The females in our initial dose-response study consumed more MA from each of the three concentrations tested during the 7-day course of self-administration, relative to the males (Figure 2B). While we have reported higher oral MA intakes during the acquisition of oral MA self-administration in females versus males [17], inconsistencies exist in the literature pertaining to sex differences in MA consumption under intravenous MA self-administration by rats [49][50][51][52][53], in low-concentration (0.02-0.08 g/L) MA drinking in the home cage by mice (e.g., [19][20][21]), and in MA intake under oral operant-conditioning procedures in both mice [17,18] and rats [24,25]. Indeed, we failed to detect any sex differences in the dose-response function for MA intake across an approximately 100-fold range of MA concentrations (0.025-3.2 g/kg) in our recent oral operant-conditioning study, despite females consuming 0.1 g/L MA more than males during the acquisition phase of the experiment [17], and we detected no sex differences in the intake of the 3.2 g/L MA solution in either of our two follow-up behavioral pharmacological studies.…”

The effect of CNQX on self-administration: present in nicotine, absent in methamphetamine model

“…Given the variations in the mechanisms of action among different stimulants, the effectiveness of AMPA/kainate antagonist treatment may differ depending on the specific drug. For example, when comparing the behavioral effects and subsequent neuroadaptations related to incubation of craving for cocaine and methamphetamine, numerous distinctions in glutamate synaptic plasticity in the nucleus accumbens core were reported (Scheyer et al, 2016;Murray et al, 2019;Funke et al, 2023). Hence, it is important to note that cocaine and amphetamine should not be grouped together when discussing the role of glutamate-related plasticity.…”