Establishment of Multi-stage Intravenous Self-administration Paradigms in Mice

Abstract

A major impediment to identifying the molecular substrates of addiction and developing effective therapeutics has been the lack of animal models that both recapitulate clinical disease presentation and are amenable to genetic manipulation. Intravenous self-administration is the “gold standard” for modeling cocaine and opioid addiction-associated behaviors in animals, but technical limitations have precluded its widespread use in mice, the mammalian species for which the most genetic tools are available. Here, we describe the establishment and demonstrate the utility of multi-stage cocaine and remifentanil paradigms that overcome classic challenges in murine intravenous self-administration. We evaluated self-administration acquisition, maintenance, extinction, and cue-induced reinstatement of drug seeking longitudinally in large cohorts of mice with indwelling catheters. In short daily sessions, mice without prior operant conditioning engaged in drug-associated lever responding that was fixed ratio- and dose-dependent, extinguished by the withholding of drugs, and reinstated by the reintroduction of paired cues. Multivariate statistics, to which this type of longitudinal data is well-suited, revealed that patterns of cocaine and remifentanil taking were similar while those of cocaine and remifentanil seeking were distinct. Individual performance in both drug paradigms was a function of two latent variables we termed incentive motivation and discriminative control. These latent variables identified drug class-specific self-administration phenotypes and were differentially predicted by a priori novelty- and drug-induced locomotor activity in the open field. Application of this behavioral and statistical analysis approach to genetically engineered mice will facilitate the identification of the cell types and neural circuits driving addictive behaviors and their underlying constructs.

Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via enhancement of dopamine release

“…Vehicle-treated mice exhibited a consistently high rate of cocaine infusions with a predominantly regularly spaced pattern over the entire 3-hour session; ESI-05 dose-dependently reduced the rate of cocaine infusions, which was characterized by unevenly spaced intervals and sporadic intake, particularly at the higher ESI-05 dose (10 mg/kg, Figure 1 -figure supplement 1). Consistent with a previous study (Slosky et al, 2021), no significant sex differences were observed for any measure, thus the data were pooled across sexes in subsequent studies.…”

“…We examined the effect of the selective Epac2 inhibitor ESI-05 on cocaine self-administration in roughly equal numbers of male and female mice using an Instech self-administration system that greatly extends the longevity of catheter patency (Slosky et al, 2020; Slosky et al, 2021). C57BL/6J mice underwent training for cocaine self-administration under a FR1 reinforcement schedule (0.5 mg/kg/infusion) in 3-hour sessions over 10 days, and 18 of 20 mice with patent catheters acquired stable cocaine self-administration (criteria are detailed in Materials and Methods).…”

“…The catheter was connected to a vascular access button (25-gauge; Instech, #VAM1B/25) and implanted subcutaneously on the back of the mice. This system decreases trauma to the inner lining of the vessel walls and allows the maintenance of positive pressure, which greatly prolongs the catheter patency and enables group housing (Slosky et al, 2020; Slosky et al, 2021). Catheters were flushed with 0.1 ml of heparinized saline (30 units/ml) after surgery to prevent coagulation.…”

“…We examined the effect of the selective Epac2 inhibitor ESI-05 on cocaine self-administration in roughly equal numbers of male and female mice using an Instech self-administration system that greatly extends the longevity of catheter patency (Slosky et al, 2020;Slosky et al, 2021).…”

Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via enhancement of dopamine release

“…We examined the effect of the selective Epac2 inhibitor ESI-05 on cocaine self-administration in roughly equal numbers of male and female mice using an Instech self-administration system that greatly extends the longevity of catheter patency ( Slosky et al, 2020 ; Slosky et al, 2021 ). C57BL/6J mice underwent training for cocaine self-administration under a FR1 reinforcement schedule (0.5 mg/kg/infusion) in 3 hr sessions over 10 days, and 18 of 20 mice with patent catheters acquired stable cocaine self-administration (criteria are detailed in Materials and methods).…”