Operant sensation seeking engages similar neural substrates to operant drug seeking in C57 mice

Abstract

Novelty and sensation seeking have been associated with elevated drug intake in human and animal studies, suggesting overlap in the circuitry mediating these behaviors. In this study, we found that C57Bl/6J mice readily acquired operant responding for dynamic visual stimuli, a phenomenon we term operant sensation seeking (OSS). Like operant studies using other reinforcers, mice responded on fixed and progressive ratio schedules, were resistant to extinction, and had sustained responding with extended access. We also found that OSS, like psychostimulant self-administration, is sensitive to disruption of dopamine signaling. Low doses of the dopamine antagonist cis-flupenthixol increased active lever responding, an effect reported for psychostimulant self-administration. Additionally, D1-deficient mice failed to acquire OSS, although they readily acquired lever pressing for food. Finally, we found that one common measure of novelty seeking, locomotor activity in a novel open field, did not predict OSS performance. OSS may have predictive validity for screening compounds for use in the treatment of drug addiction. In addition, we also discuss the potential relevance of this animal model to the field of behavioral addictions.

Figure 1

Mice acquire operant responding for varied visual stimuli. Untrained mice acquired a preference for the active lever delivering dynamic stimuli. (a) Active lever presses were significantly greater than inactive from days 5–14 (n=8, *p<0.05, **p<0.01). (b) A second cohort also increased active lever pressing relative to inactive lever pressing (*p<0.05, **p<0.01) and to nonreinforced lever pressing by controls (n=7–8, ^$p<0.05, ^$$p<0.01). (c) OSS mice also showed a significantly greater lever preference than C mice (**p<0.01). (d) Representative time course from an OSS and C mouse on session 10.

Figure 2

OSS maintains responding on progressive ratio and is resistant to extinction. (a) Number of reinforcers (left y-axis) obtained and associated final ratios (right y-axis) during five 2 h sessions. (b) Total active lever presses during sessions depicted in panel a, including control mice. OSS mice had significantly greater lever presses than C mice, which received yoked presentation of reinforcers (n=6–9 *p<0.05, **p<0.01). (c) Representative time course from OSS and Ctrl mice on PR day 4. Gray ticks indicate presentation of stimuli in both animals, as this C mouse was yoked to this OSS mouse. (d) Mice continued 1 h sessions until criteria were met or after eight sessions. Data are plotted as percent of the group to meet criteria for each hour.

Figure 3

Disruption of dopamine signaling alters OSS. (a) Low doses of cis-flupenthixol increased lever responding in OSS, but not C mice, whereas higher doses attenuated responding in both groups (n=6–8, **p<0.01). (b) Dopamine D1 null mice do not increase active lever pressing (c) nor do they develop an active lever preference (n=8–11, *p<0.05, **p<0.01). (d) D1 null mice increase active lever pressing (left) and develop an active lever preference (right) for food reinforcer (n=4–5).

Figure 4

Mice continue responding during extended access. Mice had 10 1-h FR-1 OSS sessions, and then were assigned to either short (1 h) or long (6 h) access for sessions 11–20. (a) Mice responded significantly more in 6-h compared to 1-h sessions (n=9–10, *p<0.05, **p<0.01). (b) First hour responding during sessions 11–20 did not differ between groups. (c) Individual means of first hour responding during sessions 19–20. (d) Extinction responding during hourly sessions differed between groups during the first hour only (**p<0.01).