The Central Amygdala Nucleus is Critical for Incubation of Methamphetamine Craving

Abstract

Cue-induced methamphetamine seeking progressively increases after withdrawal but mechanisms underlying this 'incubation of methamphetamine craving' are unknown. Here we studied the role of central amygdala (CeA), ventral medial prefrontal cortex (vmPFC), and orbitofrontal cortex (OFC), brain regions implicated in incubation of cocaine and heroin craving, in incubation of methamphetamine craving. We also assessed the role of basolateral amygdala (BLA) and dorsal medial prefrontal cortex (dmPFC). We trained rats to self-administer methamphetamine (10 days; 9 h/day, 0.1 mg/kg/infusion) and tested them for cue-induced methamphetamine seeking under extinction conditions during early (2 days) or late (4-5 weeks) withdrawal. We first confirmed that 'incubation of methamphetamine craving' occurs under our experimental conditions. Next, we assessed the effect of reversible inactivation of CeA or BLA by GABAA+GABAB receptor agonists (muscimol+baclofen, 0.03+0.3 nmol) on cue-induced methamphetamine seeking during early and late withdrawal. We also assessed the effect of muscimol+baclofen reversible inactivation of vmPFC, dmPFC, and OFC on 'incubated' cue-induced methamphetamine seeking during late withdrawal. Lever presses in the cue-induced methamphetamine extinction tests were higher during late withdrawal than during early withdrawal (incubation of methamphetamine craving). Muscimol+baclofen injections into CeA but not BLA decreased cue-induced methamphetamine seeking during late but not early withdrawal. Muscimol+baclofen injections into dmPFC, vmPFC, or OFC during late withdrawal had no effect on incubated cue-induced methamphetamine seeking. Together with previous studies, results indicate that the CeA has a critical role in incubation of both drug and non-drug reward craving and demonstrate an unexpected dissociation in mechanisms of incubation of methamphetamine vs cocaine craving.

Incubation of Methamphetamine Craving Is Associated with Selective Increases in Expression ofBdnfandTrkb, Glutamate Receptors, and Epigenetic Enzymes in Cue-Activated Fos-Expressing Dorsal Striatal Neurons

“…These results extend those from previous studies on the role of accumbens BDNF in the incubation of cocaine craving and cue-induced cocaine seeking (Grimm et al, 2003;Lu et al, 2004b; and DS BDNF in the escalation of cocaine self-administration (Im et al, 2010). We also found increased expression of Grin2a mRNA in DS Fos-positive neurons, extending our findings using the context-induced reinstatement model (Rubio et al, 2015).…”

“…These results extend previous studies on the changes of these epigenetic enzymes in ventral striatum (accumbens) after cocaine exposure LaPlant et al, 2010;Maze et al, 2010;Robison and Nestler, 2011;Taniguchi et al, 2012;Rogge and Wood, 2013). The findings of a selective increase of Dnmt3a mRNA in Fos-positive DS neurons extend previous finding showing increased Dnmt3a mRNA in accumbens 28 d after chronic cocaine exposure (LaPlant et al, 2010).…”

“…We used an infusion volume (1 l) that is twice the volume we ) and others (Vanderschuren et al, 2005) used previously in studies on the role of DS in cue-and context-induced drug seeking because we wanted to inhibit activity in the whole DS. Based on the study by Vanderschuren et al (2005) on the role of DLS in cue-induced cocaine seeking and several subsequent studies showing that DLS and DMS play different roles in drug seeking and taking Jeanblanc et al, 2009;Wang et al, 2010a;Corbit et al, 2012;Murray et al, 2012;Rubio et al, 2015), we also examined the effect of SCH23390 in these subregions on cue-induced of methamphetamine seeking after prolonged withdrawal. We found that SCH23390 injection into either DS subregion decreased incubated cue-induced methamphetamine seeking.…”

“…The first class included BDNF and its receptor TrkB, previously implicated in incubation of cocaine craving and reinstatement of cocaine seeking (McGinty et al, 2010;Li and Wolf, 2015). The second class included glutamate receptors: AMPARs (Gria1, Gria2, Gria3), NMDARs (Grin1,Grin2a,Grin2b), mGluRs (Grm1, Grm5) implicated previously in incubation of cocaine craving (Ben-Shahar et al, 2013;Lee et al, 2013;Halbout et al, 2014;Loweth et al, 2014b) and reinstatement of cocaine seeking (Kalivas et al, 2009). The third class included genes encoding epigenetic enzymes involved in chromatin remodeling or DNA methylation (Kouzarides, 2007).…”

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

“…Based on their clinical observations, Gawin and Kleber (1986) proposed that cueinduced cocaine craving increases during early abstinence and remains elevated for extended time periods. An analogous phenomenon termed 'incubation of drug craving' has been observed in rats and mice trained to self-administer cocaine (Grimm et al, 2001;Mead et al, 2007;Neisewander et al, 2000) and rats trained to self-administer alcohol (Bienkowski et al, 2004), nicotine (Abdolahi et al, 2010;Funk et al, 2016), heroin (Fanous et al, 2012;Shalev et al, 2001), and methamphetamine (Li et al, 2015;Shepard et al, 2004). In animal models, incubation of drug craving refers to the time-dependent increase in drug seeking during forced abstinence (Pickens et al, 2011;Wolf, 2016).…”