Brain regions and mechanisms involved in extinction and reinstatement of cocaine seeking behavior in rats

Abstract

Cocaine addiction can be defined as a psychological disease that is characterized by uncontrollable, compulsive drug-seeking and drug use despite negative health and social consequences. One obstacle for the treatment of cocaine addiction is the susceptibility to relapse which can persist several years despite prolonged periods of abstinence. Relapse can be triggered by drug predictive stimuli such as environmental context, drug associated cues, and addictive drug itself. The conditioned place preference (CPP) and self-administration behavioral paradigms are useful models for studying the ability of these drug predictive stimuli to reinstate drug-seeking behavior. Previously, we have reported that treatment with the D-serine, a NMDAR coagonist, is effective in facilitating the effects of extinction to reduce cocaine-primed reinstatement. Therefore, we sought to investigate the dose-dependent effects of D-serine on extinction training and drug-primed reinstatement in cocaine-conditioned rats. We showed that D-serine had no effect on the acquisition or development of cocaine-induced locomotor sensitization or CPP. Additionally, we demonstrated that the combination of extinction training along with D-serine treatment resulted in a significant reduction of drug-seeking behavior; this decrease was evident after up to 4 weeks abstinence. Furthermore, we assessed D-serine’s effectiveness in reducing drug-primed reinstatement under conditions in which extinction training is conducted in a novel environment. From this set of experiments we concluded that D-serine’s ability to reduce drug-prime reinstatement is not transferable to a novel context, rendering it ineffective as an adjunctive cognitive enhancement treatment as exposure therapy typically takes place in a novel environment. To conclude my dissertation work, the aim of my last report was to assess the effects of exposure to the cocaine self-administration environment on drug-seeking behavior and on Fos protein expression in the hippocampal formation. Exposure to the cocaine environment significantly increases Fos protein expression only in the ventral subiculum. However, there was a trend toward a significant effect in the ventral CA1 pyramidal cell layer. Although more work must be done to add to the clarity of the current results, these result suggest that the ventral subiculum and perhaps, the ventral CA1 pyramidal cell layer play a critical role in context-induced drug-seeking behavior.