Polyreward models
Although polysubstance use has been consistently observed in the clinic (Mahoney et al., 2021), preclinical research has, until recently (Kuhn et al., 2019), focused solely on the neurobiological effects of single drugs. The lack of behavioral models exposing rodents to multiple rewards concurrently has prevented the exploration of a fundamental question in addiction research: do the same network-specific mechanisms underlie seeking of all rewards? To address this gap in knowledge, we propose to investigate how polysubstance exposure impacts coactive cellular networks in the brain.
So far, we have developed 2 self-administration and relapse models exposing genetically modified mice to different types of reward: the dual cocaine and sucrose model and the dual cocaine and heroin model.
Using the dual cocaine and sucrose self-administration model, we have shown that neural ensembles are specific to drug or natural rewards in the nucleus accumbens core, a key region of the brain reward circuitry (Bobadilla et al., 2020, Figure 1). These results suggest the finely tuned specificity of neural ensembles, and are consistent with other studies also exposing animals to similar rewards (Cameron and Carelli, 2012; Kane et al., 2020).
FIGURE 1
Dual cocaine and sucrose self-administration (SA) model and reward-specific ensemble tagging, modified from Bobadilla et al., 2020. A) Dual cocaine (coc) / sucrose (suc) self-administration (SA), *p< 0.05 comparing active to inactive Nose pokes (NP). B) Reward-specific seeking, as measured through reinstatement to either the cocaine-cue only (cocaine-cue RST) or the sucrose-cue only (sucrose cue RST), after dual cocaine and sucrose self-administration (SA) and extinction (Ext). In both cases, mice poked significantly more the port associated with the reward of the presented cue. C) Schematic of cocaine- and sucrose-seeking ensembles, overlapping ensembles (active during seeking for both rewards) and non-ensemble cells (non-active during seeking) in the NAcore. Results show the cocaine- and sucrose-seeking ensembles recruit ~0.7% of neurons in the NAcore. In the dual cocaine and sucrose self-administration model, reward-specific ensembles overlap by only ~30%.
Schematic by graduate student Carl Litif, MS.
Regarding the dual cocaine and heroin model, our aim is to better understand the combined use of multiple drugs, a public threat associated with the opioid epidemic (Khatri et al., 2018). From 2010 to 2016, for example, fentanyl, a powerful synthetic opioid, accounted for most of the increase in cocaine-related overdose deaths (Nolan et al., 2019). Understanding how the neuronal ensembles associated with cocaine and heroin seeking in the NAcore interact with each other during polysubstance use is a critical first step toward the development of ensemble-selective approaches to treat drug-specific symptoms such as withdrawal.
