This study was designed to investigate the effects of acute eticlopride (0.02 mg/kg, D2 antagonist) treatment, given immediately before training, in rats neonatally treated with quinpirole, which has been shown to produce long-term D2 receptor supersensitization. Rats were given quinpirole (1mg/kg) or saline treatment from P1-21. Beginning on P22, rats were administered eticlopride or saline (i.p.) fifteen mins before each of seven days of training. Rats were tested on the Morris water task (MWT). For the first three consecutive days, rats were tested on the place version of the MWT with a stationary platform. Animals were given 24 training trials followed by a probe trial, and swim patterns were analyzed with platform removed. The next day, animals began testing on the match-to-place version for four consecutive days and two daily trials were given with the platform moved to a new location each day. On both the search time and target visit measures of the probe trial, animals neonatally treated with quinpirole demonstrated a deficit, and eticlopride eliminated this deficit. Interestingly, animals neonatally treated with saline but given eticlopride before training also demonstrated a deficit on both measures. On the match-to-place version, the difference in latency to locate the platform between the two daily trials served as the dependent measure. Similar to the MWT place version, eticlopride treatment eliminated deficits produced by neonatal quinpirole treatment on this task, and eticlopride produced a deficit in saline controls. This study demonstrates that in a model of dopamine D2 supersensitivity, it appears that the increased sensitivity of the D2 receptor is important for cognitive function.

Ontogenetic treatment of rats with the dopamine D(2)-like receptor agonist quinpirole produces a significant increase in dopamine D(2) receptor sensitivity that persists throughout the animal's lifetime, a phenomenon known as D(2) priming. The present study was designed to investigate the effects of priming of the D(2) receptor on the expression of three different members of the regulator of G-protein signaling (RGS) family: Rgs4, Rgs9 and Rgs17. Male offspring were ontogenetically treated with quinpirole or saline from postnatal days (P)1-21 and raised to adulthood. On approximately P65, animals were given an acute quinipirole injection (0.1 mg/kg) and the number of yawns was recorded for 1 h after the injection. Yawning has been shown to be a behavioural event mediated by the dopamine D(2)/D(3) receptor. Animals ontogenetically treated with quinpirole demonstrated a significant 2.5-fold increase in yawning as compared to controls. Rgs transcripts were analysed through in situ hybridization several weeks later. Rats ontogenetically treated with quinpirole demonstrated a significant decrease in Rgs9 expression in the frontal cortex, but a more robust decrease in the striatum and nucleus accumbens as compared to controls. Regarding Rgs17, ontogenetic quinpirole produced a modest but significant increase in expression in the same brain areas. There were no significant differences in Rgs4 expression produced by drug treatment in any of the brain regions analysed. This study demonstrates that ontogenetic quinpirole treatment, which results in priming of the D(2) receptor, results in significant decreases in Rgs9, which has been shown to regulate G-protein coupling to D(2) receptors.

Past studies have shown that ontogenetic treatment of quinpirole (QNP) produces a number of behavioral effects that can be alleviated by administration of antipsychotics such as haloperidol, providing a useful behavioral screen for disorders such as schizophrenia. In this study, 16 female Sprague-dawley rats were used, with 8 rats injected with QNP(1 mg/kg) and 8 rats injected with saline once daily from postnatal days (PD) 1-11. All rats were behaviorally tested as adults on several tasks: The reference and working memory versions of the Morris water task (MWT), the radial arm maze (RAM), the Whishaw reaching task, and locomotor activity. Results showed that on the MWT, QNP-treated rats demonstrated significant enhancement on acquisition latency of both versions, but a deficit on the probe trial of the reference memory version. The acquisition enhancement was due to hyperlocomotion observed in QNP-treated rats, because these animals demonstrated increased locomotion in an activity chamber compared to controls. On the RAM, QNP-treated rats demonstrated a deficit in reference memory but not working memory, congruent with MWT findings. Interestingly, QNP-treated rats demonstrated a significant enhancement in reaching accuracy on the Whishaw reaching task, which may due to an overactive dopaminergic system. Future studies will analyze underlying mechanisms.