The influence of the trigeminal orosensory area in drug-induced devaluation of natural rewards and development of a conditioned state of withdrawal

Open Access
Nyland, Jennifer
Graduate Program:
Doctor of Philosophy
Document Type:
Date of Defense:
December 13, 2012
Committee Members:
  • Patricia Sue Grigson, Dissertation Advisor
  • Kevin Douglas Alloway, Committee Member
  • Ralph Norgren, Committee Member
  • Thomas C Pritchard Iii, Committee Member
  • Chester A Ray, Committee Member
  • reward
  • thalamus
  • addiction
  • lesion
  • withdrawal
Addiction is a disease of chronic relapse that costs society an estimated $484 billion per year as the addict repeatedly cycles from addiction to abstinence, withdrawal, drug seeking, and relapse. Additionally, the drug trade has far-reaching consequences that include human rights violations, increased criminal activity, community safety risks, adverse health effects, and environmental destruction. Along with society, the addict and his or her family also pay, as substance abuse, dependence, and addiction are associated with an apparent devaluation of, and inattention to, natural rewards. This consequence of addiction can be modeled using a reward comparison paradigm where rats avoid intake of a taste cue that comes to predict access to a drug of abuse. Evidence suggests rats avoid intake following such pairings, at least in part, because the taste cue pales in comparison to the highly rewarding drug expected in the near future. Along with the devaluation of natural rewards, addiction also is a disease of chronic relapse where drug seeking and drug taking are repeatedly initiated by exposure to stress, the drug itself, and drug-associated cues. Our paradigm also models this aspect of addiction. Thus, while rats may initially avoid intake of the taste cue because it pales in comparison to the drug's value, with experience, rats ultimately avoid intake because the taste cue comes to elicit the onset of a conditioned aversive state involving craving, withdrawal, and seeking. We have made progress in delineating the underlying circuitry involved in drug-induced avoidance of a taste cue. In accordance, lesions of the gustatory thalamus or cortex eliminate avoidance of a taste cue when paired with either a drug of abuse or a rewarding sucrose solution, but not when paired with the aversive agent, LiCl. The present dissertation investigated the role of a neighboring thalamic structure, the trigeminal orosensory area (TOA), using bilateral ibotenic acid lesions. In Chapter 2, we found that the TOA lesion eliminated avoidance of a taste cue when paired with experimenter-administered morphine or cocaine using our standard parameters. The TOA lesion, however, did not disrupt avoidance of a taste cue that predicted access to a preferred sucrose solution or the administration of the aversive agent, LiCl. This is the first lesion to selectively disrupt avoidance of an otherwise palatable taste cue when paired with a drug of abuse. In Chapter 3, we provided direct evidence that the drug-paired taste cue elicits withdrawal and that greater withdrawal elicits greater drug seeking and taking. Lesions of the TOA prevented the onset of cue-induced withdrawal. In Chapter 4, we showed that, unlike findings obtained in the home cage, the lesion failed to prevent avoidance of the drug-paired taste cue and accompanying signs of cue-induced withdrawal when tested in a runway apparatus. Factors that may have contributed to the successful performance by the lesioned rats in the runway study, such as the availability of contextual cues and a decreased inter-stimulus interval, were tested in Chapters 5 and 6. Specifically, in Chapter 5, using self-administration, we determined that contextual cues can, indeed, override the disruptive effect of the TOA lesion. In this context, TOA lesioned rats avoided the taste cue, showed signs of conditioned withdrawal, and exhibited increased instrumental responding for drug compared with intact rats. Furthermore, the TOA was essential not only for associating the explicit taste cue with the drug of abuse, but also for reactivating that memory in the absence of supporting contextual cues. Finally, in Chapter 6, we determined that the length of the interval between presentation of the taste cue and the unconditioned stimulus was pivotal for the development of drug-induced avoidance, but not sucrose-induced avoidance of a palatable cue in the lesioned rats. Therefore, in sum, we conclude that avoidance of a drug-paired taste cue develops, in part, as a result of devaluation of the taste cue, but with experience is intensified due to the onset of an aversive conditioned state of withdrawal. In the absence of other exteroceptive cues, the taste cue can support this conditioned state and lesions of the TOA block both avoidance of the taste cue and the onset of the accompanying aversive state. An intact TOA, however, is not required when the development of the phenomenon is augmented by the addition of contextual cues and/or by the use of a very short inter-stimulus interval. Thus, while a drug of abuse can be predicted by a myriad of cues, the TOA is essential for acquisition and retention of an explicit taste-drug association. Further, the TOA is implicated in the development of the opponent process that is integral to the development of addiction and, once the association is learned, to the precipitation of cue-induced relapse.