The Role of the Alpha7 and Alpha4 Beta2 Nicotinic Receptors in Nicotine Sensitization and Neural Plasticity in Rats Neonatally Treated with Quinpirole

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Aims: We have established that neonatal treatment with quinpirole, a dopamine D2/D3 agonist, results in increases of dopamine D2 receptor sensitivity throughout the animal’s lifetime and has a number of consistencies with schizophrenia. Aim 1: Analyze the roles of α7 and α4β2 nicotinic receptors in nicotine sensitization in adolescent male and female rats neonatally treated with quinpirole. Aim 2: The roles of the α7 and α4β2 nicotinic receptors were analyzed in their effects on Brain-Derived Neurotrophic Factor (BDNF) and mammalian target of rapamycin (mTOR) in rats neonatally treated with quinpirole and sensitized to nicotine. Methods: Animals were neonatally treated with quinpirole or saline from postnatal days (P)1-21. Beginning on P33, animals were ip injected with nicotine (0.5 mg/kg free base) or saline and tested every second day from P33-49. Approximately 15-30 min before the nicotine or saline injection, animals were ip injected with either the α7 nicotinic receptor (nAChR) antagonist methllycacontine (MLA; 2 or 4 mgkg) or the α4β2 nAChR antagonist dihyro-β (DhβE; 1 or 2.5 mg/kg) erythrodine. Brain tissue was taken 24 h after the last day of testing. Results: Neonatal quinpirole enhanced nicotine sensitization and DhβE blocked nicotine sensitization regardless of neonatal treatment and was more effective in blocking sensitization in males versus females. MLA failed to block nicotine sensitization. Howeer, MLA blocked the acute hypoactive response to nicotine in males, and the higher dose of MLA reduced sensitization in males. Neonatal quinpirole sensitized the accumbal BDNF response to nicotine, but neonatal quinpirole resulted in a decrease of mTOR in both brain areas. Conclusions: The α4β2 receptor plays a critical role in adolescent nicotine sensitization. Interstingly, the α7 nAChR appears to be important in the acute response to nicotine and is more important in nicotine sensitization in males. Both nAChRs appear to be important in accumbal BDNF and their roles will be analyzed in the mTOR response.


Phoenix, AZ

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