Thinking Outside the Box: Orbitofrontal Cortex, Imagination, and How We Can Treat Addiction

Abstract

Addiction involves an inability to control drug-seeking behavior. While this may be thought of as secondary to an overwhelming desire for drugs, it could equally well reflect a failure of the brain mechanisms that allow addicts to learn about and mentally simulate non-drug consequences. Importantly, this process of mental simulation draws upon, but is not normally bound by, our past experiences. Rather we have the ability to think outside the box of our past, integrating knowledge gained from a variety of similar and not-so-similar life experiences to derive estimates or imagine what might happen next. These estimates influence our current behavior directly and also affect future behavior by serving as the background against which outcomes are evaluated to support learning. Here we will review evidence, from our own work using a Pavlovian over-expectation task as well as from other sources, that the orbitofrontal cortex is a critical node in the neural circuit that generates these estimates. Further we will offer the specific hypothesis that degradation of this function secondary to drug-induced changes is a critical and likely addressable part of addiction.

Figures

Figure 1

Cartoon illustration of the critical elements in the Pavlovian over-expectation task. The first phase consists of conditioning in which two distinct cues, such as a light, labeled V, and a tone, labeled A1, are paired with reward (represented in the image by a piece of cheese) (a). Subsequently, these cues are presented together in compound training, still followed by the standard reward (b). Finally, the tone is presented alone again in an unrewarded probe test (c).

Figure 2

Effect of orbitofrontal inactivation on Pavlovian over-expectation. The task used was similar to that in Figure 1, using V1 (visual stimulus, light) and A1 (auditory stimulus, tone). A1 and V1 both underwent conditioning in which they were independently paired with reward; data from V1 is not shown since it serves only as a tool to induce over-expectation. For direct comparison to A1, we included two additional auditory cues as controls: A2, which was paired with reward but never compounded (Control CS+), and A3, which was presented without reward (CS−). Upper panels show data from the control group, which received vehicle infusions into OFC prior to each compound session; bottom panels show data from the experimental group, which received infusions of GABA agonists into the OFC during compound sessions. (a, d) Conditioned responding to the three auditory cues across 10 days of conditioning in control (a) and experimental (d) groups. There were no differences between groups during conditioning. (b, e) Conditioning responding to cue presentation across 4 days of compound training in control (b) and experimental (e) groups. Bar graphs inset show responding to the compound cue (A1/V1) and A2 normalized to the last day of conditioning. Controls showed an ~30% increase in responding to A1 when it was compounded; inactivated rats showed no change. (c, f) Trial-by-trial (left) and average conditioned responding (right) to the three auditory cues in the unrewarded probe test in control (c) and experimental (f) groups. Controls show a significant reduction in responding to A1 on the first trial; inactivated rats show no change. Gray, black, and white colors indicate responding to A1 or A1/V1, A2, and A3 cues, respectively (*p<0.05, **p<0.01). Error bars=SEM. NS, nonsignificant; OFC, orbitofrontal cortex; OFCi, OFC inactivation group. Adapted from Takahashi et al (2009).

Figure 3

Orbitofrontal neurons signal integrated reward predictions when cues are compounded. Line plots show population responses to A1 (a) and A2 (b) across the transition between conditioning and compound training. There is a sudden increase in neural activity to the compound cue (A1/V) but no change for A2. Dark and light red indicate population response to A1 in the first half of the session and population response to A1/V in the second half, respectively. Dark and light blue indicate population responses to A2 in the first half and second half of the session, respectively. Gray shadings indicate SEM. Gray bars indicate a period of cue presentation. Reward was presented at the end of the cue period. Adapted from Takahashi et al (2013).

Figure 4

Inhibition of the OFC during presentation of the compound cues prevents learning as a result of Pavlovian over-expectation. (a–d) Conditioned responding to the three auditory cues (A1, A2, and A3) during the probe test at the end of the over-expectation in control (eYFP) (a, c) and experimental (NpHR) (b, d) groups. Top panels show responding after inhibition during the compound (CPD) cue. Bottom panels show responding after retraining and inhibition during the inter-trial intervals (ITI). The line plots show responding across eight trials, and bar graphs show average responding of eight trials. Red, blue, and green indicate A1, A2, and A3, respectively. Controls showed evidence of learning from over-expectation on the first trial in both cases (CS and ITI), whereas the experimental group showed evidence of learning only after ITI inhibition. Inhibition of OFC during the compound cue prevented the learning induced by over-expectation. ∗p<0.05. ∗∗p<0.01. Error bars=SEM.eYFP, enhanced yellow fluorescent protein; Np-HR, halorhodopsin; OFC, orbitofrontal cortex. Adapted from Takahashi et al (2013).

Figure 5

Effect of cocaine self-administration on Pavlovian over-expectation. The task used was identical to that used in Figure 2. Upper panels show data from the control group (Sucrose SA), which self-administered sucrose until approximately 3 weeks prior to the start of over-expectation training; bottom panels show data from the experimental group (Cocaine SA), which self-administered cocaine. (a, d) Conditioned responding to the three auditory cues across 10 days of conditioning. There were no differences between groups. (b, e) Conditioned responding to 4 days of compound training. Bar graphs inset show responding to A1/V1 and A2 normalized to the last day of conditioning. Controls showed an ~30% increase in responding to A1 when it was compounded; cocaine rats showed no change. (c, f) Trial-by-trial (left panel) and average conditioned responding (right panel) to the three auditory cues in the unrewarded probe test. Controls show a significant reduction in responding to A1 on the first trial; cocaine rats show no change. Gray, black, and white colors indicate responding to A1 or A1/V1, A2, and A3 cues, respectively (*p<0.05, **p<0.01). Error bars=SEM. NS, nonsignificant; OFC, orbitofrontal cortex; SA, self-administration. Adapted from Lucantonio et al (2014a).

Figure 6

Effect of sucrose and cocaine self-administration on reward predictions when cues are compounded in orbitofrontal cortex (OFC). Line plots show population responses to A1 and A2 across the transition between conditioning and compound training in sucrose (c, d) and cocaine (a, b) groups. There is a sudden increase in neural activity to the compound cue (A1/V) in sucrose but not cocaine-trained rats. Conventions as in Figure 3. Adapted from Lucantonio et al (2014b).

Figure 7

Excitation of OFC during presentation of the compound cues fixes cocaine-induced deficits in Pavlovian over-expectation. (a–d) Conditioned responding to the three auditory cues (A1, A2, and A3) during the probe test at the end of the over-expectation in control (eYFP) (a, c) and experimental (ChR2) (b, d) groups. Top panels show responding after excitation during the compound (CPD) cue. Bottom panels show responding after retraining and excitation during the inter-trial intervals (ITI). The line plots show responding across eight trials, and bar graphs show average responding of eight trials. Red, blue, and green indicate A1, A2, and A3, respectively. All rats had prior experience self-administering cocaine. Controls (eYFP) showed the same learning deficit observed in prior cocaine-experienced rats, whereas the experimental group (ChR2) showed evidence of restored learning after excitation during the cue or during the ITI. ∗p<0.05. ∗∗p<0.01. Error bars=SEM. ChR2, channelrhodopsin; eYFP, enhanced yellow fluorescent protein; NS, not significant; OFC, orbitofrontal cortex. Adapted from Lucantonio et al (2014b).