Stimulus Complexity and Mouse Strain Drive Escalation of Operant Sensation Seeking Within and Across Sessions in C57BL/6J and DBA/2J Mice

Abstract

Sensation seeking is a heritable trait that is genetically correlated with substance use; the shared genetic mechanisms underlying these traits are largely unknown. The relationship of sensation seeking and substance use has practical importance because discovering genes that drive sensation seeking can reveal genes driving substance use, and quantification of sensation seeking in mice is higher throughput and less technically challenging than quantification of volitional drug use. In order to fully understand the genetic mechanisms driving sensation seeking, it is critical to first understand the nongenetic factors driving sensation seeking. In the present study, we used the operant sensation seeking paradigm to assess the effects of stimulus complexity on sensation seeking in C57BL/6J and DBA/2J mice. These strains are the founders of the BXD recombinant inbred mouse panel which enables the discovery of genes driving phenotypic variation. This study led to four principal conclusions. First, all sensory stimuli used in the study, regardless of complexity or number of stimulus modalities, served as reinforcers for C57BL/6J and DBA/2J mice. Second, for both C57BL/6J and DBA/2J mice, sensation seeking for a high complexity sensory stimulus was significantly greater than sensation seeking for a low complexity sensory stimulus. Third, for both C57BL/6J and DBA/2J mice, sensation seeking escalated significantly within-session when a multimodal sensory stimulus of medium or high complexity was used but not when a unimodal sensory stimulus of low complexity was used. Finally, both the magnitude of sensation seeking and the magnitude of within-session escalation of sensation seeking were significantly greater in mice from the DBA/2J strain relative to mice from the C57BL/6J strain. Collectively, these findings indicate that stimulus complexity and genetic background drive escalation of operant sensation seeking within and across sessions, and that the BXD recombinant inbred mouse panel can be used to discover the genetic mechanisms underlying these phenomena.

Keywords: BXD; addiction; habituation; novelty seeking; reward; sensitization; substance use; systems genetics.

Figure 1

Operant sensation seeking (OSS) is enhanced by stimulus complexity in C57BL/6J and DBA/2J mice. Following an active lever press in an operant conditioning chamber, male C57BL/6J and DBA/2J mice received one of the following stimulus presentations: no sensory stimuli, flashing lights, retracting levers, or the combination of flashing lights and retracting levers. The relationship between active lever pressing and inactive lever pressing varied significantly across sessions as a function of stimulus complexity as indicated by a statistically significant three-way interaction of these factors (three-way analysis of variance, ANOVA) in both C57BL/6J mice (F_(75,1025) = 1.89, p = 0.04) and DBA/2J mice (F_(75,1050) = 2.08, p = 0.04). Post hoc tests (Fisher’s least significant difference, LSD) were performed to characterize these relationships: (A,E) In the No stimuli condition, neither C57BL/6J nor DBA/2J mice distinguished the active lever from the inactive lever. (B,C,D,F,G,H) In all conditions in which sensory stimuli were used as a reinforcer, both C57BL/6J and DBA/2J mice pressed the active lever significantly more than the inactive lever on at least some sessions and exhibited an acquisition curve; the most robust response for both strains was observed in the Lights + Levers condition. *Sessions on which the number of active lever presses was significantly greater (p < 0.05) than the number of inactive lever presses within strain and stimulus condition. Data points represent means. Error bars represent standard errors.

Figure 2

The magnitude of operant sensation seeking varies with mouse strain and is enhanced by stimulus complexity. The effects of stimulus complexity and mouse strain on the magnitude of OSS were assessed in C57BL/6J and DBA/2J mice following 26 days of testing. The dependent measure was the mean of active lever presses on the final four sessions. A two-way ANOVA (stimulus complexity × mouse strain) revealed statistically significant main effects of stimulus complexity (F_(3,83) = 3.89, p = 0.01) and mouse strain (F_(1,83) = 4.34, p = 0.04). The two-way interaction of stimulus complexity and mouse strain was not statistically significant (F_(3,83) = 0.75, p = 0.52). Post hoc tests (Fisher’s LSD) for the two statistically significant main effects revealed that (A) mice in the Lights + Levers condition pressed the active lever significantly more than mice in the No stimuli condition (p = 0.004) and the Lights condition (p = 0.004), and (B) DBA/2J mice pressed the active lever significantly more (p = 0.04) than C57BL/6J mice. Bars represent means. Error bars represent standard errors.

Figure 3

Within-session escalation of OSS is enhanced by stimulus complexity in C57BL/6J and DBA/2J mice. The effect of stimulus complexity on the magnitude of within-session escalation of OSS was assessed in C57BL/6J and DBA/2J mice following 26 days of testing. The number of lever presses (mean of final four sessions) was used as the dependent variable. The relationship between active lever pressing and inactive lever pressing varied significantly across bins as a function of stimulus complexity as indicated by a statistically significant three-way interaction of these factors (three-way ANOVA) in both C57BL/6J mice (F_(9,123) = 3.23, p = 0.01) and DBA/2J mice (F_(9,126) = 2.92, p = 0.009). Post hoc tests (Fisher’s LSD) were performed to characterize these relationships: (A,B,E,F) Neither C57BL/6J nor DBA/2J mice in the No stimuli condition and Lights condition escalated active lever pressing across bins. (C,D,G,H) In contrast, both C57BL/6J and DBA/2J mice in the Levers condition and Lights + Levers condition escalated active but not inactive lever pressing across bins. ^†Bins (2, 3, or 4) on which the number of active lever presses was significantly greater (p < 0.05) than the number of active lever presses on Bin 1 within strain and stimulus complexity condition. *Bins on which the number of active lever presses was significantly greater (p < 0.05) than the number of inactive lever presses within strain and stimulus complexity condition. Data points represent means. Error bars represent standard errors.

Figure 4

The magnitude of within-session escalation of operant sensation seeking varies with mouse strain and is enhanced by stimulus complexity. The effects of stimulus complexity and mouse strain on the magnitude of within-session escalation of OSS were assessed in C57BL/6J and DBA/2J mice following 26 days of testing. The dependent variable was the mean of active lever presses on the final four sessions. A two-way ANOVA (stimulus complexity × mouse strain) revealed statistically significant main effects of stimulus complexity (F_(3,83) = 5.79, p = 0.001) and mouse strain (F_(1,83) = 3.92, p = 0.05). The two-way interaction of stimulus complexity and mouse strain was not statistically significant (F_(3,83) = 0.91, p = 0.43). Post hoc tests (Fisher’s LSD) for the two statistically significant main effects revealed that (A) mice in the Lights + Levers condition exhibited significantly greater escalation of active lever pressing across bins relative to mice in the No stimuli condition (p = 0.001) and the Lights condition (p = 0.0002), and (B) DBA/2J mice exhibited significantly greater escalation of active lever pressing across bins relative to C57BL/6J mice (p = 0.05). Bars represent means. Error bars represent standard errors.