AMPA Receptor Plasticity in Accumbens Core Contributes to Incubation of Methamphetamine Craving

Abstract

BACKGROUND The incubation of cue-induced drug craving in rodents provides a model of persistent vulnerability to craving and relapse in human addicts. After prolonged withdrawal, incubated cocaine craving depends on strengthening of nucleus accumbens (NAc) core synapses through incorporation of Ca2+-permeable AMPA receptors (CP-AMPARs). Through mGlu1-mediated synaptic depression, mGlu1 positive allosteric modulators (PAMs) remove CP-AMPARs from these synapses and thereby reduce cocaine craving. This study aimed to determine if similar plasticity accompanies incubation of methamphetamine craving. METHODS Rats self-administered saline or methamphetamine under extended-access conditions. Cue-induced seeking tests demonstrated incubation of methamphetamine craving. After withdrawal periods ranging from 1 to >40 days, rats underwent one of the following procedures: 1) whole-cell patch clamp recordings to characterize AMPAR transmission, 2) intra-NAc core injection of the CP-AMPAR antagonist 1-napthyl acetyl spermine (naspm) prior to a seeking test, or 3) systemic administration of an mGlu1 PAM prior to a seeking test. RESULTS Incubation of methamphetamine craving was associated with CP-AMPAR accumulation in NAc core, and both effects were maximal after ~1 week of withdrawal. Expression of incubated craving was decreased by intra-NAc naspm injection or systemic mGlu1 PAM administration. CONCLUSIONS These results are the first to demonstrate a role for the NAc in the incubation of methamphetamine craving and describe adaptations in synaptic transmission associated with this model. They establish that incubation of craving and associated CP-AMPAR plasticity occur much more rapidly during withdrawal from methamphetamine than cocaine. However, a common mGlu1-based therapeutic strategy may be helpful for recovering cocaine and methamphetamine addicts.

Role of Central Amygdala Neuronal Ensembles in Incubation of Nicotine Craving

“…Left, MeanϮ SEM ␤-gal-positiveneuronsintheOFCinthefourgroups.Right,Representativephotomicrographsof␤-galexpressionintheOFCofratsinthedifferenttreatmentgroups.WeinjectedtheratswithDaun02orvehicle 75 min after a short 15 min extinction session in the nicotine self-administration context or exposure to a novel context on withdrawal day 11. n ϭ 6 -8 per group. methamphetamine (Li et al, 2015b), and cocaine (Lu et al, 2009) craving are observed at this withdrawal time period, as well as after longer withdrawal periods (Lu et al, 2004a;Venniro et al, 2016;Wolf, 2016). These time course differences may reflect drug-specific differences in the duration of incubation of craving (Pickens et al, 2011), but may also reflect the use of a limitedaccess training procedure in our study.…”

“…We used an extinction-based experimental procedure (Pickens et al, 2011;Wolf, 2016) to study time-dependent increases in nicotine seeking after withdrawal (incubation of nicotine craving) after adolescent-and adult-onset drug self-administration in rats. We report four main findings.…”

“…We chose withdrawal day 14 because maximal "incubated" nicotine seeking in the extinction tests was observed on this day. We studied the role of medial prefrontal cortex (mPFC, ventral and dorsal regions), orbitofrontal cortex (OFC, lateral region), nucleus accumbens (NAc, core and shell), and central and basolateral amygdalar nuclei (CeA and BLA, respectively) based on previous studies on the role of these regions in incubation of drug craving for heroin, cocaine, and methamphetamine (Pickens et al, 2011;Marchant et al, 2013;Wolf, 2016).…”

“…There is also evidence for incubation of cocaine or heroin craving after adolescent-onset drug self-administration (Li and Frantz, 2009; Doherty and Frantz, 2012), but it is unknown whether incubation of nicotine craving would occur after adolescent-onset nicotine self-administration, the developmental phase in which most nicotine addicts initiate smoking (Eissenberg and Balster, 2000). In addition, the time course and mechanisms of incubation of nicotine craving are unknown (Pickens et al, 2011;Wolf, 2016).…”

Incubation of Methamphetamine but not Heroin Craving After Voluntary Abstinence in Male and Female Rats

“…Finally, the lack of sex differences in incubation of methamphetamine craving after forced abstinence were not predicted based on a comprehensive study of Kerstetter et al (2008) showing sex differences in incubation of cocaine craving. An important consideration regarding these discrepant results is that recent evidence indicates mechanistic differences in incubation of cocaine versus methamphetamine craving (Li et al, 2015;Scheyer et al, 2016). Thus, sex differences in brain function that impact mechanisms of …”