DESCRIPTION (provided by applicant): Addiction can be devastating for addicts, their families, and society as a whole;the emotional and economic costs are astounding. Much of this damage occurs because addiction 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. When a gustatory stimulus serves as the cue, rats avoid intake of that taste cue following pairing with a drug of abuse such as morphine or cocaine. For decades, this phenomenon was interpreted as a conditioned taste aversion where a taste cue was paired with the aversive consequences of a drug. We have since hypothesized that rats avoid intake of the taste cue because the value of the taste cue pales in anticipation of the highly rewarding drug of abuse, much as it pales when predicting access to a highly palatable sucrose reward. In the last decade, we have amassed considerable support for this hypothesis. At the same time, however, we also have uncovered evidence for aversion. Published data reveal that rats avoid intake of a taste cue that has been paired with a drug of abuse, and this avoidance is associated with an elevation of the stress hormone, corticosterone, and blunting of the accumbens dopamine peak that normally accompanies ingestion of the sweet taste cue. Greater avoidance of the taste cue is correlated with greater cocaine self-administration and with greater drug-seeking following prolonged abstinence. Finally, intraoral delivery of the drug-associated taste cue elicits aversive taste reactivity (TR, i.e., gapes) and more gaping is associated with faster responding for drug, greater load up, and faster acquisition of drug taking behavior. Given these data, our working hypothesis is that, while rats initially avoid intake of the taste cue because it pales in comparison to the potent drug of abuse, with experience the taste cue is avoided as it comes to elicit the onset of a conditioned aversive state (i.e., withdrawal). Given that greater avoidance of the taste cue (and greater aversive TR) has been linked to greater drug-seeking and drug-taking, it is critical that we identify the underlying neurocircuitry. To this end, preliminary data have revealed a novel lesion site (thalamic orosensory area, TOA) that selectively disrupts avoidance of a taste cue when paired with a drug of abuse, such as morphine or cocaine, but not when paired with a highly rewarding 1.0 M sucrose solution or a putatively aversive agent, LiCl. Further, evidence suggests that the TOA may be essential for the development of cue-induced withdrawal following presentation of the drug-associated cue. Given these new findings, Specific Aim 1 will use a taste cue paired with experimenter delivered drug to verify lesion placement. Thereafter, Specific Aim 2 will use drug self-administration to test the hypothesis that the TOA lesion will disrupt not only drug-induced avoidance of the taste cue, but the resultant drug-seeking and drug-taking as well. Finally, Specific Aim 3 will measure aversive TR behavior, along with other indices, to test whether the lesion-induced disruption in behavior is accompanied by a disruption in the onset of the conditioned aversive state. PUBLIC HEALTH RELEVANCE: Drug addiction is a devastating chronic relapsing disorder and cues are potent initiators of relapse, in part because they elicit the onset of an aversive affective state. The present proposal tests the hypothesis that an intact thalamic trigeminal orosensory area (TOA) is essential for drug-induced devaluation of natural reward and cue-induced withdrawal. This study will further our understanding of the development of addiction and the underlying neurocircuitry.
|Effective start/end date||5/3/11 → 5/2/14|
- National Institutes of Health: $22,650.00
- National Institutes of Health: $27,726.00