The effects of adulthood olanzapine treatment on cognitive performance and neurotrophic factor content in male and female rats neonatally treated with quinpirole Stephanie K. Thacker, 1 Marla K. Perna, 1 Jeffery J. Ward, 2 Tori L. Schaefer, 3 Michael T. Williams, 3 Richard M. Kostrzewa 2 and Russell W. Brown 1 1 Department of Psychology, East Tennessee State University, Johnson City, TN 37614, USA 2 Department of Pharmacology, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA 3 Division of Child Neurology, Cincinnati Children’s Medical Research Foundation and University of Cincinnati College of Medicine, Cincinnati, OH 45229–3039, USA Keywords: choline acetyltransferase, dopamine D2 receptor, Morris water maze, neurotrophic factors, olanzapine, quinpirole Abstract Male and female Sprague–Dawley rats were administered quinpirole (1 mg ⁄ kg, i.p.) or saline once daily from postnatal day (P)1 to P21. This drug treatment has been shown to produce long-term priming of the D 2 receptor. Beginning on P62, rats were administered the atypical antipsychotic olanzapine (2.5 mg ⁄ kg) or saline twice daily (i.p.) for 28 days. One day after olanzapine treatment ceased, rats were tested on the place and match-to-place versions of the Morris water maze (MWM) for seven consecutive days. Dopamine D 2 receptor priming was verified through a yawning behavioural test, a D 2 receptor-mediated event, before olanzapine was administered as well as after olanzapine treatment and behavioural testing were complete. Results showed that neonatal quinpirole treatment induced D 2 priming that was eliminated by olanzapine treatment. On the MWM place version, D 2 -primed rats demonstrated a significant impairment that was eliminated by olanzapine treatment, but olanzapine treatment to animals neonatally treated with saline produced a significant deficit on the place version of the MWM. There were no significant deficits on the match-to-place version. Brain tissue analyses revealed that neonatal quinpirole treatment produced a significant decrease in hippocampal NGF, BDNF and ChAT that was eliminated by olanzapine treatment. Neonatal quinpirole treatment produced a significant decrease in BDNF and ChAT in the frontal cortex that was unaffected by olanzapine treatment. These results show that olanzapine eliminates D 2 receptor priming and cognitive impairment and also alleviates decreases in neurotrophins and acetylcholinergic markers produced by D 2 priming in the hippocampus. Introduction The drug class of atypical antipsychotics has been shown to be therapeutically useful for the treatment of schizophrenia. Atypical antipsychotics have advantages over drugs in the typical class of antipsychotics because they avoid debilitating side-effects including extrapyramidal motor effects. One of the most promising and commonly prescribed atypical antipsychtoic drugs, olanzapine (trade name Zyprexa), gained FDA approval in the United States in 1996. Like many atypical antipsychotics, olanzapine acts through antagon- ism of both the dopamine D 2 receptor and the serotonin 5-HT 2A receptor (Owen et al., 1984; Krieckhaus et al., 1992; Itokawa et al., 1993). Interestingly, olanzapine has also been shown to alleviate cognitive impairment in schizophrenics tested on a number of cognitive tasks (Weiser et al., 2000; Smith et al., 2001). However, olanzapine has also been shown to produce weight gain, increase glycosylated haemoglobin and increase triglycerides, more so than other atypical and typical antipsychotic medications (Lieberman et al., 2005). Previous work from this laboratory has shown that neonatal quinpirole treatment to rats given during the first 3 weeks of life results in long-term increases in sensitivity of the dopamine D 2 receptor, a phenomenon called ‘priming’ (Kostrzewa, 1995; Nowak et al., 2001; Brown et al., 2004a,b, 2005). Increased activation of the dopamine D 2 receptor has been shown to play a major role in abnormal behaviours observed in schizophrenia (Crow, 1979; Kokkinidis & Anisman, 1980; Castaneda et al., 1988; Davis et al., 1991). Thus, it appears that neonatal D 2 receptor priming through neonatal quinpirole treatment may be a valid rodent model of schizophrenia, although it is recognized that other neurotrans- mitter systems also play an important role in this disorder. This increase in dopamine D 2 sensitivity is not accompanied by an increase in receptor proliferation (Kostrzewa & Brus, 1991, 1993, 1995, 2004). Priming of the D 2 receptor is verified through an acute quinpirole injection in adulthood and the number of yawns are counted for 1 h. Yawning has been shown to be a D 2 receptor- mediated behavioural event (Cooper et al., 1989; Eguibar et al., 2003). In a series of recent studies, we have shown that neonatal quinpirole treatment results in cognitive impairment on the Morris water maze (MWM; Brown et al., 2002, 2004a,b). Interestingly, neonatal Correspondence: Dr Russell W. Brown, as above. E-mail: brown1@mail.etsu.edu Received 22 March 2006, revised 13 June 2006, accepted 19 July 2006 European Journal of Neuroscience, Vol. 24, pp. 2075–2083, 2006 doi:10.1111/j.1460-9568.2006.05048.x ª The Authors (2006). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd