Economic demand predicts addiction-like behavior and therapeutic efficacy of oxytocin in the rat

Abstract

Development of new treatments for drug addiction will depend on high-throughput screening in animal models. However, an addiction biomarker fit for rapid testing, and useful in both humans and animals, is not currently available. Economic models are promising candidates. They offer a structured quantitative approach to modeling behavior that is mathematically identical across species, and accruing evidence indicates economic-based descriptors of human behavior may be particularly useful biomarkers of addiction severity. However, economic demand has not yet been established as a biomarker of addiction-like behavior in animals, an essential final step in linking animal and human studies of addiction through economic models. We recently developed a mathematical approach for rapidly modeling economic demand in rats trained to self-administer cocaine. We show here that economic demand, as both a spontaneous trait and induced state, predicts addiction-like behavior, including relapse propensity, drug seeking in abstinence, and compulsive (punished) drug taking. These findings confirm economic demand as a biomarker of addiction-like behavior in rats. They also support the view that excessive motivation plays an important role in addiction while extending the idea that drug dependence represents a shift from initially recreational to compulsive drug use. Finally, we found that economic demand for cocaine predicted the efficacy of a promising pharmacotherapy (oxytocin) in attenuating cocaine-seeking behaviors across individuals, demonstrating that economic measures may be used to rapidly identify the clinical utility of prospective addiction treatments.

Keywords: behavioral economics; extinction; long access; punished responding; reinstatement.

Fig. 1.

Example of a demand curve. Data points indicate cocaine consumption during the within-session threshold procedure from a single animal during a single session; the best-fit exponential demand curve has been added. Q₀ is the theoretical demand (Q) at null cost, and α is a measure of how quickly consumption falls with increasing price.

Fig. 2.

Economic demand predicts addiction-like behavior. (A) α, but not Q₀, predicted drug seeking during abstinence on extinction day 1 [(n = 28) (Q₀: β = −0.24, P > 0.05; α: β = −0.80, P < 1E-5)]. (B) After active responding was extinguished, α, but not Q₀, predicted cued reinstatement of drug seeking [(n = 26) (Q₀: β = 0.04, P > 0.05; α: β = −0.53, P < 0.01)], as well as (C) cocaine-primed reinstatement of drug seeking [(n = 24) (Q₀: β = 0.20, P > 0.05; α: β = −0.75, P < 1E-4)]. (D) α and Q₀ independently predicted compulsive drug taking, measured as the maximum electrical charge an animal would self-administer in a bin to defend initial, shock-free drug consumption [(n = 8) (Q₀: β = 0.35, P < 0.05; α: β = −0.83, P < 1E-3)].

Fig. 3.

LgA increases economic demand and compulsive drug taking. (A) Q₀ was significantly elevated the first day after LgA, and stabilized at a significantly greater value (*P < 0.05, Bonferroni). (B) α was significantly decreased the first day following LgA (*P < 0.05, Bonferroni); there also was a trend for the group to stabilize at a lower α (although not significant). (C) Low baseline demand animals had significantly greater baseline mean α (***P < 0.001, Bonferroni), and in contrast to high baseline demand animals, low-demand animals showed a significant decrease in α after LgA that persisted to stabilization (***P < 0.001, Bonferroni). (D) Animals exposed to LgA cocaine self-administration (n = 12) displayed significantly greater compulsive (punished) drug taking compared with a separate group of animals (n = 8) tested immediately after baseline demand was established (*P < 0.05, t test). (E) Regardless of LgA treatment, compulsivity remained associated with both Q₀ (β = 0.57, P < 0.01) and α (β = −0.55, P < 0.01). Error bars in A–D represent SEM.

Fig. 4.

Oxytocin pretreatment significantly decreases cocaine economic demand. (A) Animals (n = 14) pretreated with oxytocin (Oxy) displayed a significantly lower Q₀ than when pretreated with saline vehicle (Veh) (paired t test, **P < 0.01), (B) as well as increased demand elasticity (α) (paired t test, **P < 0.01). (C) Baseline demand (on the abscissa) predicted the treatment effect of oxytocin (percentage change in demand, on the ordinate; Pearson, r = −0.62, P < 0.05). (D) Oxytocin pretreatment (n = 14) significantly reduced active responding during cued reinstatement of cocaine seeking (paired t test, ***P < 0.001). Error bars in A, B, and D represent SEM.