Cocaine and chronic stress exposure produce an additive increase in neuronal activity in the basolateral amygdala

Abstract

Cocaine addiction is a chronic, relapsing disorder. Stress and cues related to cocaine are two common relapse triggers. We have recently shown that exposure to repeated restraint stress during early withdrawal accelerates the time-dependent intensification or "incubation" of cue-induced cocaine craving that occurs during the first month of withdrawal, although craving ultimately plateaus at the same level observed in controls. These data indicate that chronic stress exposure during early withdrawal may result in increased vulnerability to cue-induced relapse during this period. Previous studies have shown that chronic stress exposure in drug-naïve rats increases neuronal activity in the basolateral amygdala (BLA), a region critical for behavioral responses to stress. Given that glutamatergic projections from the BLA to the nucleus accumbens are critical for the incubation of cue-induced cocaine craving, we hypothesized that cocaine withdrawal and chronic stress exposure produce separate increases that additively increase BLA neuronal activity. To assess this, we conducted in vivo extracellular single-unit recordings from the BLA of anesthetized adult male rats following cocaine or saline self-administration (6 h/day for 10 days) and repeated restraint stress or control conditions on withdrawal days (WD) 6-14. Recordings were conducted from WD15 to WD20. Interestingly, cocaine exposure alone increased the spontaneous firing rate in the BLA to levels observed following chronic stress exposure in drug-naïve rats. Chronic stress exposure during cocaine withdrawal further increased firing rate. These studies may identify a potential mechanism by which both cocaine and chronic stress exposure drive cue-induced relapse vulnerability during abstinence.

Role of prefrontal cortex projections to the nucleus accumbens core in mediating the effects of ceftriaxone on cue‐induced cocaine seeking

“…Ceftriaxone‐treated rats displayed reduced overall Fos expression in the PL which correlated with active lever presses during the test; neither effect was observed in the IL. This is in agreement with the literature demonstrating that subregions of the mPFC mediate different aspects of drug‐seeking, with the PL projections to the NA core promoting cue‐primed drug‐seeking, 29,32 and IL projections to the NA shell largely promoting extinction learning and inhibition of cocaine‐seeking after a period of drug abstinence 32–35 . We are the first to examine the relationship between attenuation of cocaine relapse after abstinence and activity of NA core‐projecting PL neurons.…”

“…To test this explicitly, future studies should employ pathway specific chemo/opto‐genetic techniques. The Fos data presented here in is agreement with observed increases in spontaneous firing of BLA projection neurons during incubation of cocaine‐seeking at 15 days of abstinence 30 . Although we were unable to assess Fos expression in BLA‐NA core projecting neurons due to technical difficulties, future studies will do so, especially in light of the role of this pathway in mediating cocaine seeking after 45 days of abstinence 16,31 …”

Protracted Abstinence From Extended Cocaine Self-Administration Is Associated With Hypodopaminergic Activity in the VTA but Not in the SNc

“…Therefore, cocaine-induced decreases in DA activity found in this study may originate from dysregulation in the BLA. In agreement with this hypothesis after long-term abstinence from cocaine, spontaneous firing rate and the number of spontaneously active neurons per track in the BLA have been shown to be increased in rats that had extended access to cocaine, indicating an overall increase in BLA population activity following cocaine treatment ( Munshi et al, 2019 ; Salin and Belujon, unpublished results). Since SNc DA neuron spontaneous activity is not altered during long-term abstinence, it is possible that potential cocaine-induced changes in afferent structures modulating SNc DA population activity are not sufficient to induce persistent modifications.…”

Effects of Sex and Estrous Cycle on the Time Course of Incubation of Cue-Induced Craving following Extended-Access Cocaine Self-Administration

“…Projections from the BLA to the NAc have been shown to play an important role in incubated cue-induced cocaine craving in male rats ( Lee et al, 2013 ; Ma et al, 2016 ) and other related studies have shown that inputs from the thalamus and cortex to the basal and/or lateral amygdala are critical in driving cue-induced reinstatement of drug seeking in male rats ( Arguello et al, 2017 ; Rich et al, 2019 , 2020 ). In addition, recent studies have shown an increase in BLA activity following early withdrawal (2–3 weeks) from extended-access cocaine self-administration in male rats, and that, when the magnitude of craving increases, so does BLA activity ( Munshi et al, 2021 ). As with the VTA, BLA activity changes across the estrous cycle ( Blume et al, 2017 , 2019 ), raising the possibility of an interaction among cocaine exposure, BLA activity, and estrous cycle stage that may influence incubated craving.…”