Behavioral and Plasticity Mechanisms of the Associative Effects of Nicotine in the Neonatal Quinpirole Model of Schizophrenia

Schizophrenics are significantly more likely to smoke cigarettes than the general population. In Experiment 1, we analyzed the effects of a rewarding versus an aversive dose of nicotine using the neonatal quinpirole (QUIN; dopamine D2/D3 agonist) model of schizophrenia. In Experiment 2, we examined the effects of antipsychotic treatment upon the associative reward of nicotine within this same model. Neonatal QUIN treatment to rats results in increased dopamine D2 receptor sensitivity throughout the rat’s lifetime, consistent with schizophrenia. Rats were neonatally treated with QUIN (1 mg/kg dose) or saline from postnatal days (P)1-21. Animals were then raised to P41 without any further drug treatment. Subjects were administered two consecutive pre-conditioning drug free preference tests in a three chamber shuttle box on P41 and P42 to determine initial preference. In Experiment 1, beginning on P43, animals were conditioned with saline, a 0.6 mg/kg or a 1.8 mg/kg free base dose of nicotine for eight consecutive days. A drug free post-conditioning preference test was given on P51. Approximately 24 h following the post-conditioning test, brain tissue was harvested and analyzed for mammalian target of rapamycin (mTOR) and phosphorylated-CREB (pCREB) in the nucleus accumbens. In Experiment 2, animals were treated identically as in Experiment 1, but were conditioned with nicotine which was preceded by an injection of either a typical antipsychotic (haloperidol, 0.5 mg/kg dose) or an atypical antipsychotic (clozapine, 2.5 mg/kg dose) for a period of eight days which was followed by a drug free preference test. In both experiments, the difference between time spent in the paired context between pre-test and post-test was utilized as a measure of associative reward. Results revealed that neonatal QUIN enhanced the rewarding effects of nicotine, but neutralized the aversive effects compared to controls. Neonatal QUIN also significantly decreased accumbal mTOR and pCREB results will be presented. In Experiment 2, we found that treatment with clozapine reduced the enhancement of nicotine conditioned place preference, but haloperidol completely reduced nicotine place preference to control levels. These findings show that neonatal QUIN enhances the rewarding associative effects of nicotine, and that the typical antipsychotic haloperidol was more effective at eliminating the associative rewarding effects of nicotine likely due to its potent D2 antagonistic effects