Evaluation of Glutamatergic Treatment in Reducing Nicotine Seeking Behavior in Rats

Moro, Federico (2017). Evaluation of Glutamatergic Treatment in Reducing Nicotine Seeking Behavior in Rats. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000c0ca


Although pharmacotherapy and psychosocial support can help smokers to quit, the high relapse rates indicate a high unmet need for more effective treatment. Recent studies have highlighted changes in glutamate (GLU) homeostasis in the circuitry from the prefrontal cortex (PFC) to the nucleus accumbens (Nacc) as vital in the reinstatement of drug-seeking behavior. Restoring basal concentrations of extracellular GLU, thereby increasing tonic activation of the presynaptic group II metabotropic GLU receptors (mGluR2/3) by a single injection of N- acetylcysteine (N-AC) prevented cues-induced cocaine- and heroin-seeking behavior in rats. Although nicotine-associated cues reinstate drug-seeking by acting on GLU transmission in the Nacc it is still not clear whether N-AC can inhibit cue-induced reinstatement in abstinent rats after nicotine self-administration. It is also not clear whether chronic N-AC treatment could elicit an enduring reduction in cue-induced reinstatement.

Rats were trained to associate discriminative stimuli (SDs) with intravenous nicotine vs. saline in two-lever operant cages. Reinforced response was followed by cue (CSs). Re-exposure to nicotine SD+/CS+, but not saline SD-/CS-, revived responding at the previously reinforced lever. A single dose of N-AC (100 mg/kg i.p.) increased extracellular GLU in the Nacc only in rats with an history of nicotine self-administration. Moreover, the same dose of N-AC induced a short-term reduction of cue-induced nicotine-seeking behavior that was completely prevented by pre-treatment with the selective mGluR2/3 antagonist LY341495 (1 mg/kg i.p.). Chronic treatment with N-AC (100 mg/kg) during 14 days of cues exposure therapy, induced long- lasting anti-relapse activity that was still present 50 days after the end of the treatment. To investigate the molecular mechanism in the Nacc underlying chronic N-AC effect, rats were killed at different time points. Western blot analysis revealed that 7 days after treatment, chronic N-AC restored the expression of proteins crucial for GLU homeostasis, while 51 days after treatment the expression of mGluR2 was increased only in chronic N-AC treated rats. Overall, the results of the Thesis suggest a potential therapeutic use of N-AC for cue-controlled nicotine-seeking behavior.

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