Mechanisms underlying the effects of extinction and reinstatement behavior in the rat model of drug relapse
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Cocaine addiction is defined as a process that generally starts with recreational use of cocaine and deteriorates over time into a compulsive and chronically relapsing drug taking disorder. The occurrence of relapse is one of the major challenges in the treatment of drug addiction. The rodent self-administration and reinstatement model is accepted as having good predictive validity to study relapse preclinically. An extinction protocol is usually incorporated in this model before the animals are tested for reinstatement after the self-administration training. The lever presses are not reinforced during extinction and thus the animals extinguish their lever pressing behavior. Extinction involves a new learning process and the new learning process requires the recruitment of N-methyl D-aspartate receptor (NMDAR) mediated synaptic plasticity mechanisms. Alteration of the NMDAR activity during extinction is supposed to affect the extinction learning process and/or the effects of extinction on reinstatement. We altered the NMDAR activity during extinction pharmacologically by either blocking the NMDAR activity during extinction using a competitive antagonist of NMDAR, 3 (-2 carboxipiperazin-4-yl) propyl-1-phosphonic acid ((±) CPP) at a dose of 5 mg/kg i.p. or facilitating the NMDAR activity during extinction using a full agonist of NMDAR at the glycine site, D-serine at a dose of 100 mg/kg i.p. We found that activation of NMDAR mediated mechanisms during extinction is necessary for the effects of extinction on drug induced reinstatement. Facilitating the NMDAR activity during extinction is shown to enhance the effectiveness of extinction on reducing the drug induced reinstatement in animals trained to self-administer cocaine in a short and a long access protocol. The investigation on the requirement of NMDAR mediated mechanisms in the ventral hippocampus for extinction to be effective did not yield conclusive results. We also showed that abstinent animals incubate their drug seeking behavior only to the contextual drug stimuli and the extinguished animals show the effect of spontaneous recovery in response to the contextual drug stimuli and the drug prime when tested after 3 weeks of extinction. However extinction is always shown to be effective in reducing the reinstatement and thus preventing relapse even if there is a delay in the initiation of extinction training.