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 D2 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 D2 receptor priming was verified through a yawning behavioural test, a D2 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 D2 priming that was eliminated by olanzapine treatment. On the MWM place version, D2-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 D2 receptor priming and cognitive impairment and also alleviates decreases in neurotrophins and acetylcholinergic markers produced by D2 priming in the hippocampus.
Increases in dopamine D(2) receptor sensitivity are known to be common in drug abuse and neurological disorders. Past data from this laboratory have shown that long-term increases in D(2) sensitivity can be produced by quinpirole treatment (a D(2)/D(3) agonist) during early development. The present investigation was designed to test the hypothesis that nicotine administration in adulthood would reduce both cognitive and skilled reaching impairments produced by increases in D(2) sensitivity. Female Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal day 1 (PD 1) to PD 21. Beginning in adulthood (PD 61), rats were treated with nicotine (0.3 mg/kg free base) or saline twice daily for 14 consecutive days before behavioural testing commenced. Animals neonatally treated with quinpirole demonstrated performance deficits on the Morris water task and a skilled reaching task compared to controls. Deficits on both tasks were completely alleviated by adulthood nicotine treatment. Animals neonatally treated with quinpirole demonstrated a significant 36% decrease of ChAT in the hippocampus compared to saline controls that was partially eliminated by nicotine. Additionally, neonatal quinpirole produced a significant decrease in hippocampal NGF content compared to controls, however, nicotine failed to alleviate this decrease in NGF. The results of this investigation demonstrate that long-term increases in dopamine D(2) receptor sensitivity produce significant decreases in hippocampal cholinergic and NGF expression that may result in cognitive impairment. Nicotine alleviates both cognitive and skilled reaching impairments caused by increases in D(2) sensitivity, but the mechanism through which nicotine is acting is currently unknown.
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