This proposal is based around a rodent model of schizophrenia that is accomplished through neonatal injection of the dopamine D2/D3 agonist quinpirole to rats from postnatal days (P) 1-21, which results in increased dopamine D2 receptor sensitivity that persists throughout the animal's lifetime. Increased dopamine D2 sensitivity is consistent with increased D2 activation in schizophrenia. Nicotine is the most frequently abused drug in schizophrenics. Preliminary data report four major findings: 1) Neonatal quinpirole treatment results in a significant increase in ?7 nicotinic receptors (nAChRs) in the striatum, a brain area important in drug reward;2) neonatal quinpirole treatment results in a sensitized dopamine response to nicotine in the nucleus accumbens core of adolescent rats as analyzed by microdialysis;3) we have reported enhanced behavioral sensitization and place conditioning to nicotine in rats neonatally treated with quinpirole;4) neonatal quinpirole enhanced the response of brain-derived neurotrophic factor (BDNF) to nicotine in several brain areas, and resulted in a substantial increase in accumbal phosphorylated cAMP response element binding protein (pCREB). Regarding this final finding, robust increases in accumbal pCREB have been hypothesized to be a physiological measure of anhedonia, a negative symptom of schizophrenia. Interestingly, nicotine reduced pCREB, which suggests nicotine may self-medicate anhedonia in schizophrenia, consistent with a sensitized dopamine response. We hypothesize that ?7nAChR upregulation produced by neonatal quinpirole treatment is critical to the enhanced behavioral and dopamine response to nicotine because of its pivotal role in nicotine's role in dopamine function in brain regions that mediate reward. The primary hypothesis of this proposal is that ?7nAChRs and changes in proteins related to neural plasticity are central to the sensitized behavioral and dopaminergic response to nicotine in rats neonatally treated with quinpirole.
Aim 1 will investigate the role of ?7 and ?4?2 nAChRs in nicotine behavioral sensitization and place conditioning. A sub-aim will analyze the roles of nAChRs on BDNF and pCREB in response to nicotine behavioral sensitization.
This aim will test the hypotheses that enhanced nicotine sensitization and place conditioning in neonatal quinpirole-treated rats is mediated by the ?7 nAChR, and the ?7 nAChR antagonist MLA will reduce nicotine-induced increased of BDNF and p-CREB protein in neonatal quinpirole rats.
Aim 2 will investigate the role of ?7 and ?4?2 nAChRs in the accumbal dopamine response to nicotine using the microdialysis technique.
This aim will test the hypothesis that dopamine overflow in response to nicotine pretreatment will depend on ?7nAChRs in neonatal quinpirole rats, but not controls.
Aim 3 will analyze nicotine self-administration in adult male rats neonatally treated wit quinpirole. The critical hypothesis tested is that adult rats neonatally treated with quinpirole wil self-administer more nicotine than animals neonatally treated with saline.
This project is designed to analyze behavioral and neurochemical mechanisms of nicotine sensitization, nicotine's behavioral associative effects, and nicotine self-administration in adolescent and adult rats using a rodent model of schizophrenia. The purpose of the project is to gain insight into mechanisms of the high level of nicotine addiction and schizophrenia, with the ultimate goal to better identify neurophysiological treatment targets for smoking in schizophrenia.