Compulsion and substance use disorder: potential importance of boundary conditions

For the past several decades, preclinical modeling of substance use disorders (SUDs) has shifted away from tolerance and withdrawal, toward the creation of models thought to reflect translationally relevant aspects of the clinical condition. A telescoped focus has been placed on creating non-human models in attempt to recapitulate the behavioral aspects of human SUD, including escalation of drug use, taking drug despite negative consequences, drug seeking when the drug is unavailable or the response is associated with adverse consequences as a model of “compulsivity”, among others [1]. These models have resulted in a plethora of information regarding the neurobiology of various animal subgroups, defined by observed behavior within specific experimental contexts.

In this issue of Neuropsychopharmacology, Pascoli and colleagues used footshock during cocaine self-administration to identify two phenotypes of mice: shock-resistant or those that continue to self-administer cocaine in the presence of footshock (termed “perseverers”) and shock-sensitive or those that do not (termed “renouncers”) [2]. The authors used a fixed ratio schedule of cocaine reinforcement coupled intermittently with a single shock intensity (0.2 mA) to define the behavioral groups. The authors then used ex vivo electrophysiological methodologies to measure synaptic plasticity in orbitofrontal cortex (OFC) to dorsal striatum (DS) synapses (DS_OFC). The primary findings indicate that mice grouped as perseverers show higher ratios of AMPA-to-NMDA receptor currents in both dopamine D1 receptor (D1R)-expressing spiny projection neurons (SPNs) and D2R SPNs after a punishment session, whereas only synapses of D1R SPNs were strengthened following acquisition, when no punishment was given. In renouncers, D1R SPNs did not show strengthening following cocaine self-administration. The conclusions drawn from these findings is that potentiation of the D1R-expressing DS_OFC synapses gives insight into what neurobiological changes accompany compulsion-like behavior.

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