Circuit and Synaptic Plasticity Mechanisms of Drug Relapse

Abstract

High rates of relapse to drug use during abstinence is a defining feature of human drug addiction. This clinical scenario has been studied at the preclinical level using different animal models in which relapse to drug seeking is assessed after cessation of operant drug self-administration in rodents and monkeys. In our Society for Neuroscience (SFN) session entitled "Circuit and Synaptic Plasticity Mechanisms of Drug Relapse," we will discuss new developments of our understanding of circuits and synaptic plasticity mechanisms of drug relapse from studies combining established and novel animal models with state-of-the-art cellular, electrophysiology, anatomical, chemogenetic, and optogenetic methods. We will also discuss the translational implications of these new developments. In the mini-review that introduces our SFN session, we summarize results from our laboratories on behavioral, cellular, and circuit mechanisms of drug relapse within the context of our session.

Keywords: CP-AMPARs; Daun02 inactivation; alcohol; circuit ablation; cocaine; diphtheria toxin receptors; drug cues; homeostatic plasticity; incubation of drug craving; reinstatement; relapse; silent synapse.

Figure 1.

Relapse rates in 1971 and 2011. A, B, Data redrawn from Figure 1 of Hunt et al. (1971) (A) and Figure 1 of Sinha et al. (2011) (B) on relapse to drug use in addiction clinics.

Figure 2.

A diagram showing a homeostatic cross talk between excitatory synaptic inputs and membrane properties in NAc MSNs. Specifically, in NAc MSNs, an increase or decrease in the excitatory synaptic strength induces a homeostatic decrease or increase in the intrinsic membrane excitability, and vice versa.

Figure 3.

Incubation of methamphetamine craving after choice-based voluntary abstinence: behavioral characterization and role of DMS neuronal ensembles. A, B, Voluntary abstinence and incubation of methamphetamine craving after forced or voluntary abstinence in food-sated in rats with a history of food self-administration (five 45 mg palatable food pellets per lever press) and either short-term extended daily access or long-term limited daily access to methamphetamine (0.1 mg/kg/infusion) self-administration. During voluntary abstinence, the rats were given 20 discrete trials every 10 min, during which they could earn either the food reward or the drug reward, but not both. During the drug relapse tests, only the drug lever was available, and lever presses on the previously methamphetamine-paired lever led to the delivery of a cue previously paired with drug infusions (extinction conditions). C, Role of DMS neuronal ensembles in the incubation of methamphetamine craving after voluntary abstinence. On abstinence day 18, the rats were exposed to the methamphetamine self-administration context and cues associated with methamphetamine injections in a 15 min extinction session to induce Fos in DMS. Next, 75 min after the induction session, a time of strong Fos and β-gal expression, the rats were injected with Daun02 (to inactivate the Fos-positive activated neurons) or vehicle. Three days later, the rats were tested for relapse to methamphetamine seeking as described above, and 90 min later the brains were taken for immunohistochemistry analysis of Fos and β-gal. Daun02 injections on abstinence day 18 decreased incubated methamphetamine seeking on abstinence day 21 and decreased relapse-associated neuronal activity in DMS, as assessed by β-gal. The data in A and B are from Caprioli et al. (2015), and the data in C are from Caprioli et al. (2017).

Figure 4.

Circuit ablation techniques and circuitry of extinction and reinstatement of alcohol seeking. A–F, Strategy for target-specific ablation of mPFC afferents. A, AAVrh10-DIO-DTR-FLAG was injected into the mPFC, and AAV6-Cre was injected into either the NAc (to target the mPFC → NAc pathway) or other pathways such as the mPFC → BLA pathway. B, Representative micrographs taken after targeting the mPFC → NAc pathway. Scale bar, 100 μm. C, Immunohistochemical staining with a FLAG-directed antibody (red) shows a reduction in the percentage of total fluorescent cells that are FLAG-positive after diphtheria toxin injection (*p < 0.05). D, Cre-directed antibody shows local expression of AAV-Cre in NAc shell and medial core. Scale bars, 300 μm. E, F, Cleaved caspase-3 staining 48 h after injection revealed an increased expression of this apoptosis marker in DT- vs saline-treated rats (*p < 0.05). G–I, Rats were injected with viruses to target the mPFC → NAC pathway as described in A and then were trained to self-administer oral alcohol (10%). G, The final 3 d of self-administration show equal levels of responding for both groups. H, I, Circuit ablation did not affect extinction training (H), but blocked cue-induced reinstatement (I; *p < 0.05). (Data are from Keistler et al., 2017). J, Hypothesized role of a circuitry-mediating extinction and reinstatement of alcohol seeking. Our data suggest that the mPFC → NAc projections, but not the mPFC → BLA projections, are necessary for cue-induced reinstatement of alcohol seeking. Additionally, BLA → NAc projections regulate both extinction and reinstatement (reprinted from Keistler et al., 2017, Yale University Ph.D. “Elucidating the neural circuitry underlying cue-motivated behavior for food and alcohol”).